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Zhang Z, Wang Z, Kan M, Tian M, Zhang Z. Novel Dual-Emissive Up-conversion Fluorescent Probe for Imaging Ectopic Lipid Accumulation in Diabetes Mellitus. ACS Sens 2025; 10:1959-1969. [PMID: 40037932 DOI: 10.1021/acssensors.4c03149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Diabetic kidney disease (DKD) is a leading cause of death among diabetic patients, primarily due to ectopic lipid accumulation in nonadipose tissues. The lack of molecular tools for quantitatively visualizing this lipid accumulation has hindered in-depth studies. This study aims to develop a dual-emissive up-conversion fluorescent probe, DSDM, for precise in vivo and ex vivo analyses of lipid accumulation. DSDM exhibits up-conversion green emission and down-conversion near-infrared (NIR) fluorescence when excited at 561 nm. This allows for the simultaneous imaging of lipid droplets (LDs) and the endoplasmic reticulum (ER), the primary sites for lipid synthesis and storage. With intracellular lipid consumption and accumulation, the green emission in LDs decreased or increased, while the NIR fluorescence in the ER remained constant. Using the NIR emission as an internal control, the green-to-NIR emission intensity ratio can quantify the LD amount accurately, overcoming the possible interferences from inhomogeneous staining, variation in cell population, and other factors. With the probe, we quantitatively analyzed LD accumulation in human kidney cells with either overexpressed or silenced aquaporin 7 (AQP7), induced by palmitic acid. Herein, AQP7 is specifically expressed in kidney tubules and is the only channel that regulates adipose glycerol transport. In DKD mice with kidney-specific AQP7 knockout, the probe successfully detected up-regulated lipid accumulation and ER stress. Tissue imaging revealed that the inhibited close contact between LDs and ER might facilitate the assessment of lipid accumulation in DKD. This approach effectively addresses the limitations of precise tissue biopsy in DKD, thereby improving DKD management.
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Affiliation(s)
- Zheming Zhang
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, Shandong, China
| | - Zhiyuan Wang
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, Shandong, China
| | - Mengfan Kan
- Shandong Provincial Key Laboratory for Major Chronic Disease Prevention and Treatment, The Third Affiliated Hospital of Shandong First Medical University, Jinan 250031, China
- Clinical Immunological Translational Medicine Laboratory of Shandong Provincial University Laboratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250013, China
| | - Minggang Tian
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, Shandong, China
| | - Zhongwen Zhang
- Shandong Provincial Key Laboratory for Major Chronic Disease Prevention and Treatment, The Third Affiliated Hospital of Shandong First Medical University, Jinan 250031, China
- Shandong Provincial University Laboratory for Clinical Immuno-translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250013, China
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Folestad E, Mehlem A, Ning FC, Oosterveld T, Palombo I, Singh J, Olauson H, Witasp A, Thorell A, Stenvinkel P, Ebefors K, Nyström J, Eriksson U, Falkevall A. Vascular endothelial growth factor B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease. Kidney Int 2025; 107:492-507. [PMID: 39689809 DOI: 10.1016/j.kint.2024.11.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 11/11/2024] [Accepted: 11/18/2024] [Indexed: 12/19/2024]
Abstract
A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84%) and Type 1 diabetes (16%), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyses in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.
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Affiliation(s)
- Erika Folestad
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annika Mehlem
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Frank Chenfei Ning
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Timo Oosterveld
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Isolde Palombo
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jaskaran Singh
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Witasp
- Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Anders Thorell
- Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Surgery and Anaesthesiology, Ersta Hospital, Stockholm, Sweden
| | - Peter Stenvinkel
- Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Kerstin Ebefors
- Lundberg Laboratory for Kidney Research, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jenny Nyström
- Lundberg Laboratory for Kidney Research, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Eriksson
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annelie Falkevall
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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Jin R, Dai Y, Wang Z, Hu Q, Zhang C, Gao H, Yan Q. Unraveling Ferroptosis: A New Frontier in Combating Renal Fibrosis and CKD Progression. BIOLOGY 2024; 14:12. [PMID: 39857243 PMCID: PMC11763183 DOI: 10.3390/biology14010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/14/2024] [Accepted: 12/17/2024] [Indexed: 01/27/2025]
Abstract
Chronic kidney disease (CKD) is a global health concern caused by conditions such as hypertension, diabetes, hyperlipidemia, and chronic nephritis, leading to structural and functional kidney injury. Kidney fibrosis is a common outcome of CKD progression, with abnormal fatty acid oxidation (FAO) disrupting renal energy homeostasis and leading to functional impairments. This results in maladaptive repair mechanisms and the secretion of profibrotic factors, and exacerbates renal fibrosis. Understanding the molecular mechanisms of renal fibrosis is crucial for delaying CKD progression. Ferroptosis is a type of discovered an iron-dependent lipid peroxidation-regulated cell death. Notably, Ferroptosis contributes to tissue and organ fibrosis, which is correlated with the degree of renal fibrosis. This study aims to clarify the complex mechanisms of ferroptosis in renal parenchymal cells and explore how ferroptosis intervention may help alleviate renal fibrosis, particularly by addressing the gap in CKD mechanisms related to abnormal lipid metabolism under the ferroptosis context. The goal is to provide a new theoretical basis for clinically delaying CKD progression.
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Affiliation(s)
- Rui Jin
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yue Dai
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zheng Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qinyang Hu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongyu Gao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qi Yan
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (R.J.); (Y.D.); (Z.W.); (Q.H.); (C.Z.)
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Provincial Clinical Medical Research Center for Nephropathy, Enshi 445000, China
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Xu W, Zhu Y, Wang S, Liu J, Li H. From Adipose to Ailing Kidneys: The Role of Lipid Metabolism in Obesity-Related Chronic Kidney Disease. Antioxidants (Basel) 2024; 13:1540. [PMID: 39765868 PMCID: PMC11727289 DOI: 10.3390/antiox13121540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/01/2024] [Accepted: 12/13/2024] [Indexed: 01/03/2025] Open
Abstract
Obesity has emerged as a significant public health crisis, closely linked to the pathogenesis and progression of chronic kidney disease (CKD). This review explores the intricate relationship between obesity-induced lipid metabolism disorders and renal health. We discuss how excessive free fatty acids (FFAs) lead to lipid accumulation in renal tissues, resulting in cellular lipotoxicity, oxidative stress, and inflammation, ultimately contributing to renal injury. Key molecular mechanisms, including the roles of transcriptional regulators like PPARs and SREBP-1, are examined for their implications in lipid metabolism dysregulation. The review also highlights the impact of glomerular and tubular lipid overload on kidney pathology, emphasizing the roles of podocytes and tubular cells in maintaining kidney function. Various therapeutic strategies targeting lipid metabolism, including pharmacological agents such as statins and SGLT2 inhibitors, as well as lifestyle modifications, are discussed for their potential to mitigate CKD progression in obese individuals. Future research directions are suggested to better understand the mechanisms linking lipid metabolism to kidney disease and to develop personalized therapeutic approaches. Ultimately, addressing obesity-related lipid metabolism disorders may enhance kidney health and improve outcomes for individuals suffering from CKD.
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Affiliation(s)
- Wenchao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuting Zhu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Siyuan Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Jagdale AD, Angal MM, Patil RS, Tupe RS. Exploring the glycation association with dyslipidaemia: Novel approach for diabetic nephropathy. Biochem Pharmacol 2024; 229:116513. [PMID: 39218042 DOI: 10.1016/j.bcp.2024.116513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/14/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
The transcription factor known as sterol regulatory element-binding protein (SREBP) and the glycation pathways, specifically the formation of Advanced Glycation End Products (AGEs), have a significant and deleterious impact on the kidney. They alter renal lipid metabolism and promote glomerulosclerosis, mesangial cell expansion, tubulointerstitial fibrosis, and inflammation, leading to diabetic nephropathy (DN) progression. Although several pieces of scientific evidence are reported for potential causes of glycation and lipotoxicity in DN, the underlying mechanism of renal lipid accumulation still needs to be fully understood. We provide a rationalized view on how AGEs exert multiple effects that cause SREBP activation and inflammation, contributing to DN through Receptor for AGEs (RAGE) signaling, AGE-R1-dependent downregulation of Sirtuin 1 (SIRT-1), and increased SREBP Cleavage Activating Protein (SCAP) glycosylation. This review emphasizes the association between glycation and the SREBP pathway and how it affects the onset of DN associated with obesity. Finally, we discuss the correlation of glycation and the SREBP pathway with insulin resistance (IR), oxidative stress, endoplasmic reticulum stress, inflammation, and existing and emerging therapeutic approaches toward better controlling obesity-related DN.
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Affiliation(s)
- Ashwini D Jagdale
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, Maharashtra, India
| | - Mukul M Angal
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, Maharashtra, India
| | - Rahul S Patil
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Rashmi S Tupe
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, Maharashtra, India.
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Li X, Zhang L, Yan C, Zeng H, Chen G, Qiu J. Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study. Acta Diabetol 2024; 61:1251-1258. [PMID: 38762618 DOI: 10.1007/s00592-024-02293-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/14/2024] [Indexed: 05/20/2024]
Abstract
OBJECTIVE Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. METHODS We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. RESULTS A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. CONCLUSION Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.
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Affiliation(s)
- Xin Li
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, 518000, Guangdong, China
| | - Liangyou Zhang
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, 518000, Guangdong, China
- The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510405, China
| | - Chuang Yan
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, 518000, Guangdong, China
| | - Huo Zeng
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, 518000, Guangdong, China
| | - Gangyi Chen
- The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510405, China.
| | - Jianwen Qiu
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, 518000, Guangdong, China.
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Wang Y, Liu T, Liu W, Zhao H, Li P. Research hotspots and future trends in lipid metabolism in chronic kidney disease: a bibliometric and visualization analysis from 2004 to 2023. Front Pharmacol 2024; 15:1401939. [PMID: 39290864 PMCID: PMC11405329 DOI: 10.3389/fphar.2024.1401939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Background Disorders of lipid metabolism play a key role in the initiation and progression of chronic kidney disease (CKD). Recently, research on lipid metabolism in CKD has rapidly increased worldwide. However, comprehensive bibliometric analyses in this field are lacking. Therefore, this study aimed to evaluate publications in the field of lipid metabolism in CKD over the past 20 years based on bibliometric analysis methods to understand the important achievements, popular research topics, and emerging thematic trends. Methods Literature on lipid metabolism in CKD, published between 2004 and 2023, was retrieved from the Web of Science Core Collection. The VOSviewer (v.1.6.19), CiteSpace (v.6.3 R1), R language (v.4.3.2), and Bibliometrix (v.4.1.4) packages (https://www.bibliometrix.org) were used for the bibliometric analysis and visualization. Annual output, author, country, institution, journal, cited literature, co-cited literature, and keywords were also included. The citation frequency and H-index were used to evaluate quality and influence. Results In total, 1,285 publications in the field of lipid metabolism in CKD were identified in this study. A total of 7,615 authors from 1,885 institutions in 69 countries and regions published articles in 466 journals. Among them, China was the most productive (368 articles), and the United States had the most citations (17,880 times) and the highest H-index (75). Vaziri Nosratola D, Levi Moshe, Fornoni Alessia, Zhao Yingyong, and Merscher Sandra emerged as core authors. Levi Moshe (2,247 times) and Vaziri Nosratola D (1,969 times) were also authors of the top two most cited publications. The International Journal of Molecular Sciences and Kidney International are the most published and cited journals in this field, respectively. Cardiovascular disease (CVD) and diabetic kidney disease (DKD) have attracted significant attention in the field of lipid metabolism. Oxidative stress, inflammation, insulin resistance, autophagy, and cell death are the key research topics in this field. Conclusion Through bibliometric analysis, the current status and global trends in lipid metabolism in CKD were demonstrated. CVD and DKD are closely associated with the lipid metabolism of patients with CKD. Future studies should focus on effective CKD treatments using lipid-lowering targets.
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Affiliation(s)
- Ying Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Tongtong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Weijing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hailing Zhao
- China-Japan Friendship Hospital, Institute of Medical Science, Beijing, China
| | - Ping Li
- China-Japan Friendship Hospital, Institute of Medical Science, Beijing, China
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Dupont N, Terzi F. Lipophagy and Mitophagy in Renal Pathophysiology. Nephron Clin Pract 2024; 149:36-47. [PMID: 39182483 DOI: 10.1159/000540688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/31/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND The lysosomal autophagic pathway plays a fundamental role in cellular and tissue homeostasis, and its deregulation is linked to human pathologies including kidney diseases. Autophagy can randomly degrade cytoplasmic components in a nonselective manner commonly referred to as bulk autophagy. In contrast, selective forms of autophagy specifically target cytoplasmic structures such as organelles and protein aggregates, thereby being important for cellular quality control and organelle homeostasis. SUMMARY Research during the past decades has begun to elucidate the role of selective autophagy in kidney physiology and kidney diseases. KEY MESSAGES In this review, we will summarize the knowledge on lipophagy and mitophagy, two forms of selective autophagy important in renal epithelium homeostasis, and discuss how their deregulations contribute to renal disease progression.
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Affiliation(s)
- Nicolas Dupont
- NSERM U1151, CNRS UMR8253, Institut Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Fabiola Terzi
- NSERM U1151, CNRS UMR8253, Institut Necker Enfants Malades, Université Paris Cité, Paris, France
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Fan Y, He J, Shi L, Zhang M, Chen Y, Xu L, Han N, Jiang Y. Identification of potential key lipid metabolism-related genes involved in tubular injury in diabetic kidney disease by bioinformatics analysis. Acta Diabetol 2024; 61:1053-1068. [PMID: 38691241 DOI: 10.1007/s00592-024-02278-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 03/19/2024] [Indexed: 05/03/2024]
Abstract
AIMS Accumulating evidences indicate that abnormalities in tubular lipid metabolism play a crucial role in the development of diabetic kidney disease (DKD). We aim to identify novel lipid metabolism-related genes associated with tubular injury in DKD by utilizing bioinformatics approaches. METHODS Differentially expressed genes (DEGs) between control and DKD tubular tissue samples were screened from the Gene Expression Omnibus (GEO) database, and then were intersected with lipid metabolism-related genes. Hub genes were further determined by combined weighted gene correlation network analysis (WGCNA) and protein-protein interaction (PPI) network. We performed enrichment analysis, immune analysis, clustering analysis, and constructed networks between hub genes and miRNAs, transcription factors and small molecule drugs. Receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic efficacy of hub genes. We validated the relationships between hub genes and DKD with external datasets and our own clinical samples. RESULTS There were 5 of 37 lipid metabolism-related DEGs identified as hub genes. Enrichment analysis demonstrated that lipid metabolism-related DEGs were enriched in pathways such as peroxisome proliferator-activated receptors (PPAR) signaling and pyruvate metabolism. Hub genes had potential regulatory relationships with a variety of miRNAs, transcription factors and small molecule drugs, and had high diagnostic efficacy. Immune infiltration analysis revealed that 13 immune cells were altered in DKD, and hub genes exhibited significant correlations with a variety of immune cells. Through clustering analysis, DKD patients could be classified into 3 immune subtypes and 2 lipid metabolism subtypes, respectively. The tubular expression of hub genes in DKD was further verified by other external datasets, and immunohistochemistry (IHC) staining showed that except ACACB, the other 4 hub genes (LPL, AHR, ME1 and ALOX5) exhibited the same results as the bioinformatics analysis. CONCLUSION Our study identified several key lipid metabolism-related genes (LPL, AHR, ME1 and ALOX5) that might be involved in tubular injury in DKD, which provide new insights and perspectives for exploring the pathogenesis and potential therapeutic targets of DKD.
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Affiliation(s)
- Yuanshuo Fan
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Juan He
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
| | - Lixin Shi
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
| | - Miao Zhang
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Ye Chen
- Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Lifen Xu
- Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Na Han
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Yuecheng Jiang
- Guizhou Provincial People's Hospital, Guiyang, 550002, China
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Sulaiman MK. Molecular mechanisms and therapeutic potential of natural flavonoids in diabetic nephropathy: Modulation of intracellular developmental signaling pathways. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 7:100194. [PMID: 39071051 PMCID: PMC11276931 DOI: 10.1016/j.crphar.2024.100194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/30/2024] Open
Abstract
Recognized as a common microvascular complication of diabetes mellitus (DM), diabetic nephropathy (DN) is the principal cause of chronic end-stage renal disease (ESRD). Patients with diabetes have an approximately 25% risk of developing progressive renal disease. The underlying principles of DN control targets the dual outcomes of blood glucose regulation through sodium glucose cotransporter 2 (SGLT 2) blockade and hypertension management through renin-angiotensin-aldosterone inhibition. However, these treatments are ineffective in halting disease progression to kidney failure and cardiovascular comorbidities. Recently, the dysregulation of subcellular signaling pathways has been increasingly implicated in DN pathogenesis. Natural compounds are emerging as effective and side-effect-free therapeutic agents that target intracellular pathways. This narrative review synthesizes recent insights into the dysregulation of maintenance pathways in DN, drawing from animal and human studies. To compile this review, articles reporting DN signaling pathways and their treatment with natural flavonoids were collected from PubMed, Cochrane Library Web of Science, Google Scholar and EMBASE databases since 2000. As therapeutic interventions are frequently based on the results of clinical trials, a brief analysis of data from current phase II and III clinical trials on DN is discussed.
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Zhang H, Chang J, Dai Z, Wang Q, Qiao R, Huang Y, Ma B, Jiang J, Zhu C, Su W, Zhang X, Guan Y. Expression and localization of HSD17B13 along mouse urinary tract. Am J Physiol Renal Physiol 2024; 327:F146-F157. [PMID: 38779753 DOI: 10.1152/ajprenal.00069.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/25/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
17β-Hydroxysteroid dehydrogenase-13 (HSD17B13), a newly identified lipid droplet-associated protein, plays an important role in the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Emerging evidence demonstrates that NASH is an independent risk factor for chronic kidney disease, which is frequently accompanied by renal lipid accumulation. In addition, the HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven NAFLD. At present, the role of HSD17B13 in lipid accumulation in the kidney is unclear. This study utilized bioinformatic and immunostaining approaches to examine the expression and localization of HSD17B13 along the mouse urinary tract. We found that HSD17B13 is constitutively expressed in the kidney, ureter, and urinary bladder. Our findings reveal for the first time, to our knowledge, the precise localization of HSD17B13 in the mouse urinary system, providing a basis for further studying the pathogenesis of HSD17B13 in various renal and urological diseases.NEW & NOTEWORTHY HSD17B13, a lipid droplet-associated protein, is crucial in nonalcoholic fatty liver disease (NAFLD) development. NAFLD also independently raises chronic kidney disease (CKD) risk, often with renal lipid buildup. However, HSD17B13's role in CKD-related lipid accumulation is unclear. This study makes the first effort to examine HSD17B13 expression and localization along the urinary system, providing a basis for exploring its physiological and pathophysiological roles in the kidney and urinary tract.
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Affiliation(s)
- Haibo Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China
| | - Jiazhen Chang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China
| | - Zhihong Dai
- Department of Urology, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Qiuming Wang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China
| | - Rongfang Qiao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China
| | - Yingzhi Huang
- Health Science Center, East China Normal University, Shanghai, People's Republic of China
| | - Beibei Ma
- Health Science Center, East China Normal University, Shanghai, People's Republic of China
| | - Jiuchao Jiang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China
| | - Chunhua Zhu
- Health Science Center, East China Normal University, Shanghai, People's Republic of China
| | - Wen Su
- Department of Pathology, Health Science Center, Shenzhen University, Shenzhen, People's Republic of China
| | - Xiaoyan Zhang
- Health Science Center, East China Normal University, Shanghai, People's Republic of China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China
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Wang L, Su J, Liu Z, Ding S, Li Y, Hou B, Hu Y, Dong Z, Tang J, Liu H, Liu W. Identification of immune-associated biomarkers of diabetes nephropathy tubulointerstitial injury based on machine learning: a bioinformatics multi-chip integrated analysis. BioData Min 2024; 17:20. [PMID: 38951833 PMCID: PMC11218417 DOI: 10.1186/s13040-024-00369-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 06/10/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN. METHODS The gene chip data were retrieved from the GEO database using the search term ' diabetic nephropathy '. The ' limma ' software package was used to identify differentially expressed genes (DEGs) between DN and control samples. Gene set enrichment analysis (GSEA) was performed on genes obtained from the molecular characteristic database (MSigDB. The R package 'WGCNA' was used to identify gene modules associated with tubulointerstitial injury in DN, and it was crossed with immune-related DEGs to identify target genes. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on differentially expressed genes using the 'ClusterProfiler' software package in R. Three methods, least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest (RF), were used to select immune-related biomarkers for diagnosis. We retrieved the tubulointerstitial dataset from the Nephroseq database to construct an external validation dataset. Unsupervised clustering analysis of the expression levels of immune-related biomarkers was performed using the 'ConsensusClusterPlus 'R software package. The urine of patients who visited Dongzhimen Hospital of Beijing University of Chinese Medicine from September 2021 to March 2023 was collected, and Elisa was used to detect the mRNA expression level of immune-related biomarkers in urine. Pearson correlation analysis was used to detect the effect of immune-related biomarker expression on renal function in DN patients. RESULTS Four microarray datasets from the GEO database are included in the analysis : GSE30122, GSE47185, GSE99340 and GSE104954. These datasets included 63 DN patients and 55 healthy controls. A total of 9415 genes were detected in the data set. We found 153 differentially expressed immune-related genes, of which 112 genes were up-regulated, 41 genes were down-regulated, and 119 overlapping genes were identified. GO analysis showed that they were involved in various biological processes including leukocyte-mediated immunity. KEGG analysis showed that these target genes were mainly involved in the formation of phagosomes in Staphylococcus aureus infection. Among these 119 overlapping genes, machine learning results identified AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1 and FSTL1 as potential tubulointerstitial immune-related biomarkers. External validation suggested that the above markers showed diagnostic efficacy in distinguishing DN patients from healthy controls. Clinical studies have shown that the expression of AGR2, CX3CR1 and FSTL1 in urine samples of DN patients is negatively correlated with GFR, the expression of CX3CR1 and FSTL1 in urine samples of DN is positively correlated with serum creatinine, while the expression of DEFB1 in urine samples of DN is negatively correlated with serum creatinine. In addition, the expression of CX3CR1 in DN urine samples was positively correlated with proteinuria, while the expression of DEFB1 in DN urine samples was negatively correlated with proteinuria. Finally, according to the level of proteinuria, DN patients were divided into nephrotic proteinuria group (n = 24) and subrenal proteinuria group. There were significant differences in urinary AGR2, CCR2 and DEFB1 between the two groups by unpaired t test (P < 0.05). CONCLUSIONS Our study provides new insights into the role of immune-related biomarkers in DN tubulointerstitial injury and provides potential targets for early diagnosis and treatment of DN patients. Seven different genes ( AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1, FSTL1 ), as promising sensitive biomarkers, may affect the progression of DN by regulating immune inflammatory response. However, further comprehensive studies are needed to fully understand their exact molecular mechanisms and functional pathways in DN.
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Affiliation(s)
- Lin Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Jiaming Su
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhongjie Liu
- Beijing University of Chinese Medicine, Beijing, China
| | - Shaowei Ding
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yaotan Li
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Baoluo Hou
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yuxin Hu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhaoxi Dong
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Hongfang Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China.
| | - Weijing Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China.
- Beijing University of Chinese Medicine, Beijing, China.
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Fan X, Yang M, Lang Y, Lu S, Kong Z, Gao Y, Shen N, Zhang D, Lv Z. Mitochondrial metabolic reprogramming in diabetic kidney disease. Cell Death Dis 2024; 15:442. [PMID: 38910210 PMCID: PMC11194272 DOI: 10.1038/s41419-024-06833-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 06/25/2024]
Abstract
Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role in substance metabolism via oxidative phosphorylation to generate ATP. Cells undergo metabolic reprogramming as a compensatory mechanism to fulfill energy needs for survival and growth, attracting scholarly attention in recent years. Studies indicate that mitochondrial metabolic reprogramming significantly influences the pathophysiological progression of DKD. Alterations in kidney metabolism lead to abnormal expression of signaling molecules and activation of pathways, inducing oxidative stress-related cellular damage, inflammatory responses, apoptosis, and autophagy irregularities, culminating in renal fibrosis and insufficiency. This review delves into the impact of mitochondrial metabolic reprogramming on DKD pathogenesis, emphasizing the regulation of metabolic regulators and downstream signaling pathways. Therapeutic interventions targeting renal metabolic reprogramming can potentially delay DKD progression. The findings underscore the importance of focusing on metabolic reprogramming to develop safer and more effective therapeutic approaches.
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Affiliation(s)
- Xiaoting Fan
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Meilin Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Yating Lang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Shangwei Lu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Zhijuan Kong
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ying Gao
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ning Shen
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Dongdong Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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Mao TH, Huang HQ, Zhang CH. Clinical characteristics and treatment compounds of obesity-related kidney injury. World J Diabetes 2024; 15:1091-1110. [PMID: 38983811 PMCID: PMC11229974 DOI: 10.4239/wjd.v15.i6.1091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/22/2023] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.
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Affiliation(s)
- Tuo-Hua Mao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Han-Qi Huang
- Department of Endocrinology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei Province, China
| | - Chuan-Hai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, United States
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15
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Fang Z, Liu R, Xie J, He JC. Molecular mechanism of renal lipid accumulation in diabetic kidney disease. J Cell Mol Med 2024; 28:e18364. [PMID: 38837668 PMCID: PMC11151220 DOI: 10.1111/jcmm.18364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/10/2024] [Accepted: 04/16/2024] [Indexed: 06/07/2024] Open
Abstract
Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.
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Affiliation(s)
- Zhengying Fang
- Department of Nephrology, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Barbara T. Murphy Division of Nephrology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Ruijie Liu
- Barbara T. Murphy Division of Nephrology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Jingyuan Xie
- Department of Nephrology, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - John Cijiang He
- Barbara T. Murphy Division of Nephrology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Renal SectionJames J Peters Veterans Affair Medical CenterBronxNew YorkUSA
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16
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Nie H, Yang H, Cheng L, Yu J. Identification of Lipotoxicity-Related Biomarkers in Diabetic Nephropathy Based on Bioinformatic Analysis. J Diabetes Res 2024; 2024:5550812. [PMID: 38774257 PMCID: PMC11108700 DOI: 10.1155/2024/5550812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/10/2024] [Accepted: 04/20/2024] [Indexed: 05/24/2024] Open
Abstract
Objective: This study is aimed at investigating diagnostic biomarkers associated with lipotoxicity and the molecular mechanisms underlying diabetic nephropathy (DN). Methods: The GSE96804 dataset from the Gene Expression Omnibus (GEO) database was utilized to identify differentially expressed genes (DEGs) in DN patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the DEGs. A protein-protein interaction (PPI) network was established to identify key genes linked to lipotoxicity in DN. Immune infiltration analysis was employed to identify immune cells with differential expression in DN and to assess the correlation between these immune cells and lipotoxicity-related hub genes. The findings were validated using the external dataset GSE104954. ROC analysis was performed to assess the diagnostic performance of the hub genes. The Gene set enrichment analysis (GSEA) enrichment method was utilized to analyze the key genes associated with lipotoxicity as mentioned above. Result: In this study, a total of 544 DEGs were identified. Among them, extracellular matrix (ECM), fatty acid metabolism, AGE-RAGE, and PI3K-Akt signaling pathways were significantly enriched. Combining the PPI network and lipotoxicity-related genes (LRGS), LUM and ALB were identified as lipotoxicity-related diagnostic biomarkers for DN. ROC analysis showed that the AUC values for LUM and ALB were 0.882 and 0.885, respectively. The AUC values for LUM and ALB validated in external datasets were 0.98 and 0.82, respectively. Immune infiltration analysis revealed significant changes in various immune cells during disease progression. Macrophages M2, mast cells activated, and neutrophils were significantly associated with all lipotoxicity-related hub genes. These key genes were enriched in fatty acid metabolism and extracellular matrix-related pathways. Conclusion: The identified lipotoxicity-related hub genes provide a deeper understanding of the development mechanisms of DN, potentially offering new theoretical foundations for the development of diagnostic biomarkers and therapeutic targets related to lipotoxicity in DN.
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Affiliation(s)
- Han Nie
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
| | - Huan Yang
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
| | - Lidan Cheng
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
| | - Jianxin Yu
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
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Han YZ, Du BX, Zhu XY, Wang YZY, Zheng HJ, Liu WJ. Lipid metabolism disorder in diabetic kidney disease. Front Endocrinol (Lausanne) 2024; 15:1336402. [PMID: 38742197 PMCID: PMC11089115 DOI: 10.3389/fendo.2024.1336402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/09/2024] [Indexed: 05/16/2024] Open
Abstract
Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.
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Affiliation(s)
- Yi-Zhen Han
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Bo-Xuan Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xing-Yu Zhu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang-Zhi-Yuan Wang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Hui-Juan Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wei-Jing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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18
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Yang Q, Deng L, Feng C, Wen J. Comparing the effects of empagliflozin and liraglutide on lipid metabolism and intestinal microflora in diabetic mice. PeerJ 2024; 12:e17055. [PMID: 38500527 PMCID: PMC10946396 DOI: 10.7717/peerj.17055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 02/14/2024] [Indexed: 03/20/2024] Open
Abstract
Background and Objectives Recent studies have shown that the imbalance of intestinal flora is related to the occurrence and progression of diabetic nephropathy (DN) and can affect lipid metabolism. Sodium-dependent glucose transporters 2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist are commonly used hypoglycemic drugs and have excellent renal safety. The purpose of this study was to compare the protective effects of empagliflozin and liraglutide on kidneys, lipid metabolism, and intestinal microbiota in diabetic mice. Methods We established a mouse model of type two diabetes by feeding rats a high-fat diet (HFD) followed by an intraperitoneal injection of STZ. The mice were randomly divided into groups: normal control (NC), diabetic model (DM), liraglutide treatment (LirT), empagliflozin treatment (EmpT), and liraglutide combined with empagliflozin treatment (Emp&LirT) groups. Blood glucose, lipids, creatinine, and uric acid, as well as urinary nitrogen and albumin levels were measured. The renal tissues were subjected to HE, PAS and Masson's staining. These parameters were used to evaluate renal function and histopathological changes in mice. Mice feces were also collected for 16sRNA sequencing to analyze the composition of the intestinal flora. Results All the indexes related to renal function were significantly improved after treatment with drugs. With respect to lipid metabolism, both drugs significantly decreased the serum triglyceride levels in diabetic mice, but the effect of liraglutide on reducing serum cholesterol was better than that of empagliflozin. However, empagliflozin had a better effect on the reduction of low-density lipoproteins (LDL). The two drugs had different effects on intestinal flora. At the phylum level, empagliflozin significantly reduced the ratio of Firmicutes to Bacteroidota, but no effect was seen with liraglutide. At the genus level, both of them decreased the number of Helicobacter and increased the number of Lactobacillus. Empagliflozin also significantly increased the abundance of Muribaculaceae, Muribaculum, Olsenella, and Odoribacter, while liraglutide significantly increased that of Ruminococcus. Conclusion Liraglutide and empagliflozin were both able to improve diabetes-related renal injury. However, the ability of empagliflozin to reduce LDL was better compared to liraglutide. In addition, their effects on the intestine bacterial flora were significantly different.
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Affiliation(s)
- Qiong Yang
- Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Ling Deng
- Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Changmei Feng
- Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
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Huang J, Yang F, Liu Y, Wang Y. N6-methyladenosine RNA methylation in diabetic kidney disease. Biomed Pharmacother 2024; 171:116185. [PMID: 38237350 DOI: 10.1016/j.biopha.2024.116185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/13/2024] [Accepted: 01/16/2024] [Indexed: 02/08/2024] Open
Abstract
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, and hyperglycemic memory associated with diabetes carries the risk of disease occurrence, even after the termination of blood glucose injury. The existence of hyperglycemic memory supports the concept of an epigenetic mechanism involving n6-methyladenosine (m6A) modification. Several studies have shown that m6A plays a key role in the pathogenesis of DKD. This review addresses the role and mechanism of m6A RNA modification in the progression of DKD, including the regulatory role of m6A modification in pathological processes, such as inflammation, oxidative stress, fibrosis, and non-coding (nc) RNA. This reveals the importance of m6A in the occurrence and development of DKD, suggesting that m6A may play a role in hyperglycemic memory phenomenon. This review also discusses how some gray areas, such as m6A modified multiple enzymes, interact to affect the development of DKD and provides countermeasures. In conclusion, this review enhances our understanding of DKD from the perspective of m6A modifications and provides new targets for future therapeutic strategies. In addition, the insights discussed here support the existence of hyperglycemic memory effects in DKD, which may have far-reaching implications for the development of novel treatments. We hypothesize that m6A RNA modification, as a key factor regulating the development of DKD, provides a new perspective for the in-depth exploration of DKD and provides a novel option for the clinical management of patients with DKD.
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Affiliation(s)
- Jiaan Huang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, NO.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China
| | - Fan Yang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, NO.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China
| | - Yan Liu
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, NO.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China
| | - Yuehua Wang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, NO.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China.
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Liu W, Li F, Guo D, Du C, Zhao S, Li J, Yan Z, Hao J. Schisandrin B Alleviates Renal Tubular Cell Epithelial-Mesenchymal Transition and Mitochondrial Dysfunction by Kielin/Chordin-like Protein Upregulation via Akt Pathway Inactivation and Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase Pathway Activation in Diabetic Kidney Disease. Molecules 2023; 28:7851. [PMID: 38067580 PMCID: PMC10708382 DOI: 10.3390/molecules28237851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Diabetic kidney disease is a common complication of diabetes and remains the primary cause of end-stage kidney disease in the general population. Schisandrin B (Sch B) is an active ingredient in Schisandra chinensis. Our study illustrates that Sch B can mitigate renal tubular cell (RTC) epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction in db/db mice, accompanied by the downregulation of TGF-β1 and the upregulation of PGC-1α. Similarly, Sch B demonstrated a protective effect by reducing the expression of TGF-β1, α-SMA, fibronectin, and Col I, meanwhile enhancing the expression of E-cadherin in human RTCs (HK2 cells) stimulated with high glucose. Moreover, under high glucose conditions, Sch B effectively increased mitochondrial membrane potential, lowered ROS production, and increased the ATP content in HK2 cells, accompanied by the upregulation of PGC-1α, TFAM, MFN1, and MFN2. Mechanistically, the RNA-seq results showed a significant increase in KCP mRNA levels in HK2 cells treated with Sch B in a high glucose culture. The influence of Sch B on KCP mRNA levels was confirmed by real-time PCR in high glucose-treated HK2 cells. Depletion of the KCP gene reversed the impact of Sch B on TGF-β1 and PGC-1α in HK2 cells with high glucose level exposure, whereas overexpression of the KCP gene blocked EMT and mitochondrial dysfunction. Furthermore, the PI3K/Akt pathway was inhibited and the AMPK pathway was activated in HK2 cells exposed to a high concentration of glucose after the Sch B treatment. Treatment with the PI3K/Akt pathway agonist insulin and the AMPK pathway antagonist compound C attenuated the Sch B-induced KCP expression in HK2 cells exposed to a high level of glucose. Finally, molecular autodock experiments illustrated that Sch B could bind to Akt and AMPK. In summary, our findings suggested that Sch B could alleviate RTC EMT and mitochondrial dysfunction by upregulating KCP via inhibiting the Akt pathway and activating the AMPK pathway in DKD.
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Affiliation(s)
- Weilin Liu
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China (D.G.)
- Hebei Key Laboratory of Kidney Diseases, Shijiazhuang 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
- Department of Infectious Diseases, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Fan Li
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China (D.G.)
- Hebei Key Laboratory of Kidney Diseases, Shijiazhuang 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Dongwei Guo
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China (D.G.)
- Hebei Key Laboratory of Kidney Diseases, Shijiazhuang 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Congyuan Du
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China (D.G.)
- Hebei Key Laboratory of Kidney Diseases, Shijiazhuang 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Song Zhao
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China (D.G.)
- Hebei Key Laboratory of Kidney Diseases, Shijiazhuang 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Juan Li
- Department of Nephrology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Zhe Yan
- Department of Nephrology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Jun Hao
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China (D.G.)
- Hebei Key Laboratory of Kidney Diseases, Shijiazhuang 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
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Zhu Q, Li G, Ma L, Chen B, Zhang D, Gao J, Deng S, Chen Y. Virgin Camellia Seed Oil Improves Glycolipid Metabolism in the Kidney of High Fat-Fed Rats through AMPK-SREBP Pathway. Nutrients 2023; 15:4888. [PMID: 38068746 PMCID: PMC10708295 DOI: 10.3390/nu15234888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Camellia seed oil (CO) is used as edible oil in southern China because of its excellent fatty acid composition and abundant bioactive compounds. Chronic kidney disease (CKD) is one of the most common chronic degenerative diseases in China, and active compounds in vegetable oil, like virgin olive oil, have been demonstrated to be efficacious in the management of CKD. In this study, virgin CO was refined using a standard process. The refining had minimal impact on the fatty acid composition, but significantly reduced the presence of bioactive compounds like polyphenols in CO. Sprague-Dawley (SD) rats fed with high fat diet (Group G) were treated with either virgin (Group Z) or refined CO (Group R). The oral administration of CO alleviated lipid accumulation and decreased body and kidney weight gain. Furthermore, treatment with virgin CO increased the renal ATP content. The renal expression levels of AMPK and key enzymes involved in fatty acid oxidation (CPT-1 and ACOX1) and glycolysis (HK, PFK, PK and GAPDH) were up-regulated in Group Z, thereby enhancing the ATP production. Virgin CO treatment downregulated the expression level of SREBP2 and its downstream target genes, such as ACC, FAS, and HMGCR, which reduced lipid synthesis. These findings indicate that virgin CO improves glycolipid metabolism and restores energy homeostasis in the kidneys of rats fed with a high-fat diet by modulating the AMPK-SREBP-signaling pathway, suggesting the potential of active compounds in virgin CO for managing the renal failure associated with glycolipid dysmetabolism.
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Affiliation(s)
- Qinhe Zhu
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Guihui Li
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Li Ma
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
| | - Bolin Chen
- Co-Innovation Center for the Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Dawei Zhang
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Jing Gao
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
| | - Senwen Deng
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Yongzhong Chen
- National Engineering Research Center of Oiltea Camellia, State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Shao Shan South Road, No. 658, Changsha 410004, China; (Q.Z.); (G.L.); (L.M.); (D.Z.)
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22
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Chen Q, Xie C, Tang K, Luo M, Zhang Z, Jin Y, Liu Y, Zhou L, Kong Y. The E3 ligase Trim63 promotes podocyte injury and proteinuria by targeting PPARα to inhibit fatty acid oxidation. Free Radic Biol Med 2023; 209:40-54. [PMID: 37793501 DOI: 10.1016/j.freeradbiomed.2023.09.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/21/2023] [Accepted: 09/30/2023] [Indexed: 10/06/2023]
Abstract
Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.
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Affiliation(s)
- Qiyan Chen
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Division of Nephrology, The First People's Hospital of Foshan, Foshan, China
| | - Chao Xie
- Division of Nephrology, The First People's Hospital of Foshan, Foshan, China
| | - Kaiyue Tang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mujin Luo
- Division of Nephrology, The First People's Hospital of Foshan, Foshan, China
| | - Zhe Zhang
- Division of Nephrology, The First People's Hospital of Foshan, Foshan, China
| | - Yabin Jin
- Clinical Research Institute, The First People's Hospital of Foshan, Foshan, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Yaozhong Kong
- Division of Nephrology, The First People's Hospital of Foshan, Foshan, China.
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23
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Gouda W, Ahmed AE, Mageed L, Hassan AK, Afify M, Hamimy WI, Ragab HM, Maksoud NAE, Allayeh AK, Abdelmaksoud MDE. Significant role of some miRNAs as biomarkers for the degree of obesity. J Genet Eng Biotechnol 2023; 21:109. [PMID: 37930593 PMCID: PMC10628096 DOI: 10.1186/s43141-023-00559-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 10/08/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Obesity is one of the most serious problems over the world. MicroRNAs have developed as main mediators of metabolic processes, playing significant roles in physiological processes. Thus, the present study aimed to evaluate the expressions of (miR-15a, miR-Let7, miR-344, and miR-365) and its relationship with the different classes in obese patients. METHODS A total of 125 individuals were enrolled in the study and classified into four groups: healthy non-obese controls (n = 50), obese class I (n = 24), obese class II (n = 17), and obese class III (n = 34) concerning body mass index (BMI < 30 kg/m2, BMI 30-34.9 kg/m2, BMI 35-39.9 kg/m2 and BMI ≥ 40 kg/m2, respectively). BMI and the biochemical measurements (fasting glucose, total cholesterol, triglycerides, HDL and LDL, urea, creatinine, AST, and ALT) were determined. The expressions of (miR-15a, miR-Let7, miR-344, and miR-365) were detected through quantitative real-time PCR (RT-qPCR). RESULTS There was a significant difference between different obese classes and controls (P < 0.05) concerning (BMI, TC, TG, HDL, and LDL). In contrast, fasting glucose, kidney, and liver functions had no significant difference. Our data revealed that the expression of miR-15a and miR-365 were significantly associated with different obese classes. But the circulating miR-Let7 and miR-344 were not significantly related to obesity in different classes. CONCLUSION Our study indicated that miR-15a and miR-365 might consider as biomarkers for the obesity development into different obese classes. Thus, the relationship between regulatory microRNAs and disease has been the object of intense investigation.
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Affiliation(s)
- Weaam Gouda
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt.
| | - Amr E Ahmed
- Department of Biotechnology and Life Science, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef, Egypt
| | - Lamiaa Mageed
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
| | - Amgad K Hassan
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
| | - Mie Afify
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
| | - W I Hamimy
- Anesthesia Department, Obesity, Surgery Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Halla M Ragab
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
| | - Nabila Abd El Maksoud
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
| | - Abdou K Allayeh
- Environment and Climate Change Institute, National Research Centre, Giza, Egypt
| | - Mohamed D E Abdelmaksoud
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt
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24
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Mitrofanova A, Merscher S, Fornoni A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat Rev Nephrol 2023; 19:629-645. [PMID: 37500941 DOI: 10.1038/s41581-023-00741-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/29/2023]
Abstract
Chronic kidney disease (CKD) is a global health problem with rising incidence and prevalence. Among several pathogenetic mechanisms responsible for disease progression, lipid accumulation in the kidney parenchyma might drive inflammation and fibrosis, as has been described in fatty liver diseases. Lipids and their metabolites have several important structural and functional roles, as they are constituents of cell and organelle membranes, serve as signalling molecules and are used for energy production. However, although lipids can be stored in lipid droplets to maintain lipid homeostasis, lipid accumulation can become pathogenic. Understanding the mechanisms linking kidney parenchymal lipid accumulation to CKD of metabolic or non-metabolic origin is challenging, owing to the tremendous variety of lipid species and their functional diversity across different parenchymal cells. Nonetheless, multiple research reports have begun to emphasize the effect of dysregulated kidney lipid metabolism in CKD progression. For example, altered cholesterol and fatty acid metabolism contribute to glomerular and tubular cell injury. Newly developed lipid-targeting agents are being tested in clinical trials in CKD, raising expectations for further therapeutic development in this field.
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Affiliation(s)
- Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
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25
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Jiang Y, Peng Y, Yang X, Yu J, Yu F, Yuan J, Zha Y. PM 2.5 exposure aggravates kidney damage by facilitating the lipid metabolism disorder in diabetic mice. PeerJ 2023; 11:e15856. [PMID: 37671359 PMCID: PMC10476618 DOI: 10.7717/peerj.15856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/16/2023] [Indexed: 09/07/2023] Open
Abstract
Background Ambient fine particulate matter ≤ 2.5 µm (PM2.5) air pollution exposure has been identified as a global health threat, the epidemiological evidence suggests that PM2.5 increased the risk of chronic kidney disease (CKD) among the diabetes mellitus (DM) patients. Despite the growing body of research on PM2.5 exposure, there has been limited investigation into its impact on the kidneys and the underlying mechanisms. Past studies have demonstrated that PM2.5 exposure can lead to lipid metabolism disorder, which has been linked to the development and progression of diabetic kidney disease (DKD). Methods In this study, db/db mice were exposed to different dosage PM2.5 for 8 weeks. The effect of PM2.5 exposure was analysis by assessment of renal function, pathological staining, immunohistochemical (IHC), quantitative real-time PCR (qPCR) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) based metabolomic analyses. Results The increasing of Oil Red staining area and adipose differentiation related protein (ADRP) expression detected by IHC staining indicated more ectopic lipid accumulation in kidney after PM2.5 exposure, and the increasing of SREBP-1 and the declining of ATGL detected by IHC staining and qPCR indicated the disorder of lipid synthesisandlipolysis in DKD mice kidney after PM2.5 exposure. The expressions of high mobility group nucleosome binding protein 1 (HMGN1) and kidney injury molecule 1 (KIM-1) that are associated with kidney damage increased in kidney after PM2.5 exposure. Correlation analysis indicated that there was a relationship between HMGN1-KIM-1 and lipid metabolic markers. In addition, kidneys of mice were analyzed using LC-MS/MS based metabolomic analyses. PM2.5 exposure altered metabolic profiles in the mice kidney, including 50 metabolites. In conclusion the results of this study show that PM2.5 exposure lead to abnormal renal function and further promotes renal injury by disturbance of renal lipid metabolism and alter metabolic profiles.
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Affiliation(s)
- Yuecheng Jiang
- Zunyi Medical University, Guiyang, China
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Guiyang, China
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yanzhe Peng
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Xia Yang
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Guiyang, China
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
- School of Medicine, Guizhou University, Guiyang, China
| | - Jiali Yu
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Guiyang, China
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
- School of Medicine, Guizhou University, Guiyang, China
| | - Fuxun Yu
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Guiyang, China
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Jing Yuan
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yan Zha
- Zunyi Medical University, Guiyang, China
- NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Guiyang, China
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, China
- School of Medicine, Guizhou University, Guiyang, China
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Wang Y, Jin M, Cheng CK, Li Q. Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives. Front Endocrinol (Lausanne) 2023; 14:1238927. [PMID: 37600689 PMCID: PMC10433744 DOI: 10.3389/fendo.2023.1238927] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized the role of renal tubular injury in the pathogenesis of DKD. Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER stress, inflammation, EMT and programmed cell death, have been shown to induce renal tubular injury and contribute to the progression of DKD. Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence therapies, mineralocorticoid receptor antagonists, and stem cell therapies have demonstrated their potential to alleviate renal tubular injury in DKD. This review will provide insights into the latest research on the mechanisms and treatments of renal tubular injury in DKD.
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Affiliation(s)
- Yu Wang
- Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen, Guangdong, China
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Mingyue Jin
- Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen, Guangdong, China
| | - Chak Kwong Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Qiang Li
- Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen, Guangdong, China
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Zheng L, Qin R, Rao Z, Xiao W. High-intensity interval training induces renal injury and fibrosis in type 2 diabetic mice. Life Sci 2023; 324:121740. [PMID: 37120014 DOI: 10.1016/j.lfs.2023.121740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023]
Abstract
AIMS Previous studies showed that high-intensity interval training (HIIT) improved fasting blood glucose and insulin resistance in type 2 diabetes mellitus (T2DM) mice. However, the effect of HIIT on the kidneys of mice with T2DM has not been examined. This study aimed to investigate the impact of HIIT on the kidneys of T2DM mice. MATERIALS AND METHODS T2DM mice were induced with a high-fat diet (HFD) and one-time 100 mg/kg streptozotocin intraperitoneal injection, and then T2DM mice were treated with 8 weeks of HIIT. Renal function and glycogen deposition were observed by serum creatinine levels and PAS staining, respectively. Sirius red staining, hematoxylin-eosin staining, and Oil red O staining were used to detect fibrosis and lipid deposition. Western blotting was performed to detect the protein levels. KEY FINDINGS HIIT significantly ameliorated the body composition, fasting blood glucose, and serum insulin of the T2DM mice. HIIT also improved glucose tolerance, insulin tolerance, and renal lipid deposition of T2DM mice. However, we found that HIIT increased serum creatinine and glycogen accumulation in the kidneys of T2DM mice. Western blot analysis showed that the PI3K/AKT/mTOR signaling pathway was activated after HIIT. The expression of fibrosis-related proteins (TGF-β1, CTGF, collagen-III, α-SMA) increased, while the expression of klotho (sklotho) and MMP13 decreased in the kidneys of HIIT mice. SIGNIFICANCE This study concluded that HIIT induced renal injury and fibrosis, although it also improved glucose homeostasis in T2DM mice. The current study reminds us that patients with T2DM should be cautious when participating in HIIT.
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Affiliation(s)
- Lifang Zheng
- College of Physical Education, Shanghai University, Shanghai 200444, China; Shanghai Key Lab of Human Performance, Shanghai University of sport, Shanghai 200438, China
| | - Ruiting Qin
- College of Physical Education, Shanghai University, Shanghai 200444, China
| | - Zhijian Rao
- College of Physical Education, Shanghai Normal University, Shanghai 200234, China; Exercise Biological Center, China Institute of Sport Science, Beijing, China.
| | - Weihua Xiao
- Shanghai Key Lab of Human Performance, Shanghai University of sport, Shanghai 200438, China.
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28
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Li Y, Liu Y, Liu S, Gao M, Wang W, Chen K, Huang L, Liu Y. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther 2023; 8:152. [PMID: 37037849 PMCID: PMC10086073 DOI: 10.1038/s41392-023-01400-z] [Citation(s) in RCA: 168] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 02/19/2023] [Accepted: 02/28/2023] [Indexed: 04/12/2023] Open
Abstract
Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease (DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment, basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts, mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline.
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Affiliation(s)
- Yiwen Li
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Yanfei Liu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China
- The Second Department of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Shiwei Liu
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Mengqi Gao
- Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Wenting Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Keji Chen
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China.
| | - Luqi Huang
- China Center for Evidence-based Medicine of TCM, China Academy of Chinese Medical Sciences, Beijing, 100010, China.
| | - Yue Liu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100091, China.
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Liu CJ, Ho KT, Tsai YS, Huang HS. Increased renal uptake and urine excretion of oxidized LDL is possibly associated with formation of large calcium oxalate nephrolithiasis: a preliminary study. World J Urol 2023; 41:1423-1430. [PMID: 36977786 DOI: 10.1007/s00345-023-04360-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/09/2023] [Indexed: 03/30/2023] Open
Abstract
PURPOSE Growing evidence have suggested an association between nephrolithiasis and cardiovascular disease (CVD) with unclear mechanism. Oxidized low-density lipoproteins (oxLDL) induces atherosclerosis and was found to be the possible link between these two diseases. Our study aimed to examine the serum, urine and kidney expression of oxLDL in relation to large calcium oxalate (CaOx) renal stone disease. METHODS A total of 67 large CaOx dominant renal stone patients and 31 stone-free controls were enrolled in the prospective case-control study. All participants were without known CVD history. Serum, urine, and kidney biopsy were collected before and during percutaneous nephrolithotomy, respectively. Enzyme-linked immunosorbent assays were used to assess serum and urine oxLDL, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and high-sensitivity C-reactive protein (hsCRP). RESULTS There was no significantly difference in circulating oxLDL, but serum hsCRP was significantly near two-fold higher in nephrolithiasis patients. Serum hsCRP was also correlated with stone maximal length. Urine oxLDL was significantly higher in the nephrolithiasis group and correlated with serum hsCRP and stone maximal length. Increased oxLDL uptake in kidney was found in nephrolithiasis patients, whereas no significantly renal expression of oxLDL was observed in controls. CONCLUSIONS The renal uptake of oxLDL with increased oxLDL excretion from large CaOx renal stone formers, independent of increased circulating oxLDL, is a novel pathological finding in kidney stone disease and brings attention to the possible involvement of renal steatosis in the process of urolithiasis formation.
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Affiliation(s)
- Chan-Jung Liu
- Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan
- Department of Urology, College of Medicine, National Cheng Kung University, Tainan, 704302, Taiwan
| | - Kuan-Ta Ho
- Department of Urology, College of Medicine, National Cheng Kung University, Tainan, 704302, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 704302, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704302, Taiwan
| | - Yau-Sheng Tsai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704302, Taiwan.
- Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, 704302, Taiwan.
| | - Ho-Shiang Huang
- Department of Urology, National Cheng Kung University Hospital, Tainan, Taiwan.
- Department of Urology, College of Medicine, National Cheng Kung University, Tainan, 704302, Taiwan.
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Chen HH, Zhang YX, Lv JL, Liu YY, Guo JY, Zhao L, Nan YX, Wu QJ, Zhao YH. Role of sirtuins in metabolic disease-related renal injury. Biomed Pharmacother 2023; 161:114417. [PMID: 36812714 DOI: 10.1016/j.biopha.2023.114417] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/08/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Poor control of metabolic diseases induces kidney injury, resulting in microalbuminuria, renal insufficiency and, ultimately, chronic kidney disease. The potential pathogenetic mechanisms of renal injury caused by metabolic diseases remain unclear. Tubular cells and podocytes of the kidney show high expression of histone deacetylases known as sirtuins (SIRT1-7). Available evidence has shown that SIRTs participate in pathogenic processes of renal disorders caused by metabolic diseases. The present review addresses the regulatory roles of SIRTs and their implications for the initiation and development of kidney damage due to metabolic diseases. SIRTs are commonly dysregulated in renal disorders induced by metabolic diseases such as hypertensive nephropathy and diabetic nephropathy. This dysregulation is associated with disease progression. Previous literature has also suggested that abnormal expression of SIRTs affects cellular biology, such as oxidative stress, metabolism, inflammation, and apoptosis of renal cells, resulting in the promotion of invasive diseases. This literature reviews the research progress made in understanding the roles of dysregulated SIRTs in the pathogenesis of metabolic disease-related kidney disorders and describes the potential of SIRTs serve as biomarkers for early screening and diagnosis of these diseases and as therapeutic targets for their treatment.
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Affiliation(s)
- Huan-Huan Chen
- Department of Oncology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yi-Xiao Zhang
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Urology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Jia-Le Lv
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yu-Yang Liu
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Jing-Yi Guo
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Lu Zhao
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yu-Xin Nan
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Qi-Jun Wu
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Yu-Hong Zhao
- Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China; Clinical Research Center, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
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Li FZ, Fang S. Adipophilin: roles in physiology and pathology. J Clin Pathol 2023; 76:98-102. [PMID: 36600632 DOI: 10.1136/jcp-2022-208677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022]
Abstract
Adipophilin (ADRP/ADPH/PLIN2), an adipocyte differentiation-related protein, is highly expressed at a very early time during the differentiation of adipocytes. It assists in the formation and maintenance of intracellular lipid droplets and plays a role in regulating the physiological functions of the body. More and more studies indicate that it is involved in the occurrence and development of a variety of glycolipid metabolic diseases and tumours. In this review, we comprehensively stated the expression and functions of adipophilin and introduced its roles in physiology and pathology.
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Affiliation(s)
- Feng-Zeng Li
- Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Sheng Fang
- Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Ma X, Zhang X, Leng T, Ma J, Yuan Z, Gu Y, Hu T, Liu Q, Shen T. Identification of Oxidative Stress-Related Biomarkers in Diabetic Kidney Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:1067504. [PMID: 36624863 PMCID: PMC9825216 DOI: 10.1155/2022/1067504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 12/04/2022] [Accepted: 12/06/2022] [Indexed: 01/02/2023]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease throughout the world. In kidney disease, oxidative stress has been linked to both antioxidant depletions and increased reactive oxygen species (ROS) production. Thus, the objective of this study was to identify biomarkers related to oxidative stress in DKD. METHODS The gene expression profile of the DKD was extracted from the Gene Expression Omnibus (GEO) database. The identification of the differentially expressed genes (DEGs) was performed using the "limma" R package, and weighted gene coexpression network analysis (WGCNA) was used to find the gene modules that were most related to DKD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed using "Org.Hs.eg.db" R package. The protein-protein interaction (PPI) network was constructed using the STRING database. The hub genes were identified by the Molecular Complex Detection (MCODE) plug-in of Cytoscape software. The diagnostic capacity of hub genes was verified using the receiver operating characteristic (ROC) curve. Correlations between diagnostic genes were analyzed using the "corrplot" package. In addition, the miRNA gene transcription factor (TF) network was used to explain the regulatory mechanism of hub genes in DKD. RESULTS DEGs analysis and WGCNA-identified 160 key genes were identified in DKD patients. Among them, nine oxidative stress-related genes were identified as candidate hub genes for DKD. Using the PPI network, five hub genes, NR4A2, DUSP1, FOS, JUN, and PTGS2, were subsequently identified. All the hub genes were downregulated in DKD and had a high diagnostic value of DKD. The regulatory mechanism of hub genes was analyzed from the miRNA gene-TF network. CONCLUSION Our study identified NR4A2, DUSP1, FOS, JUN, and PTGS2 as hub genes of DKD. These genes may serve as potential therapeutic targets for DKD patients.
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Affiliation(s)
- Xiaoju Ma
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaobo Zhang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tian Leng
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jingru Ma
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Zhongzhu Yuan
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yalin Gu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tingting Hu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiuyan Liu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tao Shen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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den Braanker DJW, Maas RJH, van Mierlo G, Parr NMJ, Bakker-van Bebber M, Deegens JKJ, Jansen PWTC, Gloerich J, Willemsen B, Dijkman HB, van Gool AJ, Wetzels JFM, Rinschen MM, Vermeulen M, Nijenhuis T, van der Vlag J. Primary Focal Segmental Glomerulosclerosis Plasmas Increase Lipid Droplet Formation and Perilipin-2 Expression in Human Podocytes. Int J Mol Sci 2022; 24:ijms24010194. [PMID: 36613637 PMCID: PMC9820489 DOI: 10.3390/ijms24010194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Many patients with primary focal segmental glomerulosclerosis (FSGS) develop recurrence of proteinuria after kidney transplantation. Several circulating permeability factors (CPFs) responsible for recurrence have been suggested, but were never validated. We aimed to find proteins involved in the mechanism of action of CPF(s) and/or potential biomarkers for the presence of CPF(s). Cultured human podocytes were exposed to plasma from patients with FSGS with presumed CPF(s) or healthy and disease controls. Podocyte proteomes were analyzed by LC-MS. Results were validated using flow cytometry, RT-PCR, and immunofluorescence. Podocyte granularity was examined using flow cytometry, electron microscopy imaging, and BODIPY staining. Perilipin-2 protein expression was increased in podocytes exposed to presumed CPF-containing plasmas, and correlated with the capacity of plasma to induce podocyte granularity, identified as lipid droplet accumulation. Elevated podocyte perilipin-2 was confirmed at protein and mRNA level and was also detected in glomeruli of FSGS patients whose active disease plasmas induced podocyte perilipin-2 and lipid droplets. Our study demonstrates that presumably, CPF-containing plasmas from FSGS patients induce podocyte lipid droplet accumulation and perilipin-2 expression, identifying perilipin-2 as a potential biomarker. Future research should address the mechanism underlying CPF-induced alterations in podocyte lipid metabolism, which ultimately may result in novel leads for treatment.
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Affiliation(s)
- Dirk J. W. den Braanker
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Rutger J. H. Maas
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Guido van Mierlo
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Naomi M. J. Parr
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Marinka Bakker-van Bebber
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Jeroen K. J. Deegens
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Pascal W. T. C. Jansen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Jolein Gloerich
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Brigith Willemsen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Henry B. Dijkman
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Alain J. van Gool
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Jack F. M. Wetzels
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Markus M. Rinschen
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Tom Nijenhuis
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Correspondence:
| | - Johan van der Vlag
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
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Zhou Y, Tao H, Xu N, Zhou S, Peng Y, Zhu J, Liu S, Chang Y. Chrysin improves diabetic nephropathy by regulating the AMPK-mediated lipid metabolism in HFD/STZ-induced DN mice. J Food Biochem 2022; 46:e14379. [PMID: 35976957 DOI: 10.1111/jfbc.14379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 07/17/2022] [Accepted: 08/01/2022] [Indexed: 01/13/2023]
Abstract
Diabetic nephropathy (DN) is a highly prevalent and severe diabetic complication. It is urgent to explore high efficiency and minor side effects therapy for DN. Chrysin is a natural flavonoid with various biological activities found in honey and propolis, and has considerable potential to improve DN. The study was designed to explore the effects and the specific underlying mechanism of chrysin for DN in high-fat-diet (HFD) and streptozotocin (STZ) induced DN mice. Firstly, the study revealed that chrysin effectively improved obesity, insulin resistance (IR), renal function, and pathological injury in DN mice. Secondly, the study found that chrysin improved the key indices and markers of lipid accumulation, oxidative stress, and inflammation which are closely related to the development or progression of DN. Moreover, chrysin markedly modulated lipid metabolism by regulating Adenosine 5' monophosphate-activated protein kinase (AMPK) and essential downstream proteins. Furthermore, AMPK inhibitor (Dorsomorphin) intervention partially suppressed the positive effects of chrysin on all testing indicators, indicating that activated AMPK is crucial for chrysin action on DN. The present study demonstrated that chrysin may improve DN by regulating lipid metabolism, and activated AMPK plays a critical role in the regulation of chrysin. PRACTICAL APPLICATIONS: The study verified the positive effects of chrysin on obesity, insulin resistance, kidney injury, renal function, lipid accumulation, inflammation, and oxidative stress, which are closely related to the development or progression of diabetic nephropathy (DN). Moreover, we explored that chrysin improves DN by regulating AMPK-mediated lipid metabolism. Furthermore, the AMPK inhibitor was used to confirm that activated AMPK plays a critical role in the effects of chrysin. These results could offer a full explanation and a potential option for adjuvant therapy of DN diabetes with chrysin.
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Affiliation(s)
- Yingjun Zhou
- The State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Heng Tao
- The State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Nuo Xu
- The State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Shichun Zhou
- Agricultural and Rural Bureau, Haiyang, Shandong, People's Republic of China
| | - Yuke Peng
- The State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Jianxiang Zhu
- Shanghai Cao Yang No. 2 High School, Shanghai, People's Republic of China
| | - Shaowei Liu
- The State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yaning Chang
- The State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai, People's Republic of China
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Pan S, Li Z, Wang Y, Liang L, Liu F, Qiao Y, Liu D, Liu Z. A Comprehensive Weighted Gene Co-expression Network Analysis Uncovers Potential Targets in Diabetic Kidney Disease. J Transl Int Med 2022; 10:359-368. [PMID: 36860636 PMCID: PMC9969566 DOI: 10.2478/jtim-2022-0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Background and Objectives Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes. It has always been difficult to explore novel biomarkers and therapeutic targets of DKD. We aimed to identify new biomarkers and further explore their functions in DKD. Methods The weighted gene co-expression network analysis (WGCNA) method was used to analyze the expression profile data of DKD, obtain key modules related to the clinical traits of DKD, and perform gene enrichment analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression of the hub genes in DKD. Spearman's correlation coefficients were used to determine the relationship between gene expression and clinical indicators. Results Fifteen gene modules were obtained via WGCNA analysis, among which the green module had the most significant correlation with DKD. Gene enrichment analysis revealed that the genes in this module were mainly involved in sugar and lipid metabolism, regulation of small guanosine triphosphatase (GTPase) mediated signal transduction, G protein-coupled receptor signaling pathway, peroxisome proliferator-activated receptor (PPAR) molecular signaling pathway, Rho protein signal transduction, and oxidoreductase activity. The qRT-PCR results showed that the relative expression of nuclear pore complex-interacting protein family member A2 (NPIPA2) and ankyrin repeat domain 36 (ANKRD36) was notably increased in DKD compared to the control. NPIPA2 was positively correlated with the urine albumin/creatinine ratio (ACR) and serum creatinine (Scr) but negatively correlated with albumin (ALB) and hemoglobin (Hb) levels. ANKRD36 was positively correlated with the triglyceride (TG) level and white blood cell (WBC) count. Conclusion NPIPA2 expression is closely related to the disease condition of DKD, whereas ANKRD36 may be involved in the progression of DKD through lipid metabolism and inflammation, providing an experimental basis to further explore the pathogenesis of DKD.
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Affiliation(s)
- Shaokang Pan
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Zhengyong Li
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Yixue Wang
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Lulu Liang
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Fengxun Liu
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Yingjin Qiao
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Dongwei Liu
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
| | - Zhangsuo Liu
- Department of TCM-Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University; Research Institute of Nephrology, Zhengzhou University; Research Center for Kidney Disease, Henan Province; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province; Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Henan Province, China
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Expression profiles of tRNA‑derived fragments in high glucose‑treated tubular epithelial cells. Exp Ther Med 2022; 25:26. [PMID: 36561608 PMCID: PMC9748664 DOI: 10.3892/etm.2022.11725] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/28/2022] [Indexed: 11/24/2022] Open
Abstract
Transfer RNA-derived fragments (tRFs), a novel class of small non-coding RNA produced by the cleavage of pre- and mature tRNAs, are involved in various diseases. Renal tubulointerstitial fibrosis is a common final pathway in diabetic nephropathy (DN) in which hyperglycemia-induced tubular extracellular matrix (ECM) accumulation serves a vital role. The present study aimed to detect and investigate the role of tRFs in the accumulation of tubular ECM. Differentially expressed tRFs were analysed with high-throughput sequencing in primary mouse tubular epithelial cells treated with high glucose (HG). The Gene Ontology (GO) was used to analyze the potential molecular functions of these differentially expressed tRFs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the associated signaling pathways involved in these differentially expressed tRFs. tRF-1:30-Gln-CTG-4 was overexpressed using tRF-1:30-Gln-CTG-4 mimic, followed by HG treatment. A total of 554 distinct tRFs were detected and 64 differentially expressed tRFs (fold change >2; P<0.05) were identified in tubular epithelial cells following high glucose (HG) treatment, among which 27 were upregulated and 37 were downregulated. Ten selected tRFs with the greatest difference (fold change >2; P<0.05) were verified to be consistent with small RNA-sequencing data, of which tRF-1:30-Gln-CTG-4 showed the most pronounced difference in expression and was significantly decreased in response to HG. GO analysis indicated that the differentially expressed tRFs were associated with 'cellular process', 'biological regulation' and 'metabolic process'. An analysis of the KEGG database suggested that these differentially expressed tRFs were involved in 'autophagy' and signaling pathways for 'forkhead box O', 'the mammalian target of rapamycin' and 'mitogen-activated protein kinase'. Finally, the overexpression of tRF-1:30-Gln-CTG-4 ameliorated HG-induced ECM accumulation in tubular epithelial cells. Therefore, the present study demonstrated that there may be a significant association between tRFs and HG-induced ECM accumulation in tubular epithelial cells; these differentially expressed tRFs warrant further study to explore the pathogenesis of DN.
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A comprehensive weighted gene co-expression network analysis uncovers potential targets in diabetic kidney disease. J Transl Int Med 2022. [DOI: 10.2478/jtim-2022-0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Abstract
Background and Objectives
Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes. It has always been difficult to explore novel biomarkers and therapeutic targets of DKD. We aimed to identify new biomarkers and further explore their functions in DKD.
Methods
The weighted gene co-expression network analysis (WGCNA) method was used to analyze the expression profile data of DKD, obtain key modules related to the clinical traits of DKD, and perform gene enrichment analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression of the hub genes in DKD. Spearman’s correlation coefficients were used to determine the relationship between gene expression and clinical indicators.
Results
Fifteen gene modules were obtained via WGCNA analysis, among which the green module had the most significant correlation with DKD. Gene enrichment analysis revealed that the genes in this module were mainly involved in sugar and lipid metabolism, regulation of small guanosine triphosphatase (GTPase) mediated signal transduction, G protein-coupled receptor signaling pathway, peroxisome proliferator-activated receptor (PPAR) molecular signaling pathway, Rho protein signal transduction, and oxidoreductase activity. The qRT-PCR results showed that the relative expression of nuclear pore complex-interacting protein family member A2 (NPIPA2) and ankyrin repeat domain 36 (ANKRD36) was notably increased in DKD compared to the control. NPIPA2 was positively correlated with the urine albumin/creatinine ratio (ACR) and serum creatinine (Scr) but negatively correlated with albumin (ALB) and hemoglobin (Hb) levels. ANKRD36 was positively correlated with the triglyceride (TG) level and white blood cell (WBC) count.
Conclusion
NPIPA2 expression is closely related to the disease condition of DKD, whereas ANKRD36 may be involved in the progression of DKD through lipid metabolism and inflammation, providing an experimental basis to further explore the pathogenesis of DKD.
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Zhao C, Li L, Li C, Tang C, Cai J, Liu Y, Yang J, Xi Y, Yang M, Jiang N, Han Y, Liu Y, Luo S, Xiao L, Sun L. PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease. Mol Med 2022; 28:117. [PMID: 36138342 PMCID: PMC9502582 DOI: 10.1186/s10020-022-00545-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/09/2022] [Indexed: 11/18/2022] Open
Abstract
Background Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. Methods Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2−/− mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2−/− mice. Results Diabetic PT-Pacs-2−/− mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2−/− mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. Conclusions PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00545-x.
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Affiliation(s)
- Chanyue Zhao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Li Li
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Chenrui Li
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Chengyuan Tang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Juan Cai
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yu Liu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Jinfei Yang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yiyun Xi
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ming Yang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Na Jiang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yachun Han
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Yan Liu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Shilu Luo
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Li Xiao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Lin Sun
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China.
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Ranches G, Zeidler M, Kessler R, Hoelzl M, Hess MW, Vosper J, Perco P, Schramek H, Kummer KK, Kress M, Krogsdam A, Rudnicki M, Mayer G, Huettenhofer A. Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 28:794-813. [PMID: 35664695 PMCID: PMC9136061 DOI: 10.1016/j.omtn.2022.04.035] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/28/2022] [Indexed: 12/02/2022]
Abstract
Exosomes have emerged as a valuable repository of novel biomarkers for human diseases such as chronic kidney disease (CKD). From a healthy control group, we performed microRNA (miRNA) profiling of urinary exosomes and compared it with a cell culture model of renal proximal tubular epithelial cells (RPTECs). Thereby, a large fraction of abundant urinary exosomal miRNAs could also be detected in exosomes derived from RPTECs, indicating them as a suitable model system for investigation of CKD. We subsequently analyzed exosomes from RPTECs in pro-inflammatory and pro-fibrotic states, mimicking some aspects of CKD. Following cytokine treatment, we observed a significant increase in exosome release and identified 30 dysregulated exosomal miRNAs, predominantly associated with the regulation of pro-inflammatory and pro-fibrotic-related pathways. In addition to miRNAs, we also identified 16 dysregulated exosomal mitochondrial RNAs, highlighting a pivotal role of mitochondria in sensing renal inflammation. Inhibitors of exosome biogenesis and release significantly altered the abundance of selected candidate miRNAs and mitochondrial RNAs, thus suggesting distinct sorting mechanisms of different non-coding RNA (ncRNA) species into exosomes. Hence, these two exosomal ncRNA species might be employed as potential indicators for predicting the pathogenesis of CKD and also might enable effective monitoring of the efficacy of CKD treatment.
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Affiliation(s)
- Glory Ranches
- Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Maximilian Zeidler
- Institute of Physiology, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Roman Kessler
- Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Martina Hoelzl
- Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Michael W. Hess
- Institute of Histology and Embryology, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Jonathan Vosper
- Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Paul Perco
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Herbert Schramek
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Kai K. Kummer
- Institute of Physiology, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Michaela Kress
- Institute of Physiology, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Anne Krogsdam
- Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Michael Rudnicki
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Gert Mayer
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Alexander Huettenhofer
- Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
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Hinden L, Ahmad M, Hamad S, Nemirovski A, Szanda G, Glasmacher S, Kogot-Levin A, Abramovitch R, Thorens B, Gertsch J, Leibowitz G, Tam J. Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function. Nat Commun 2022; 13:1783. [PMID: 35379807 PMCID: PMC8980033 DOI: 10.1038/s41467-022-29124-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/25/2022] [Indexed: 12/13/2022] Open
Abstract
Activation of the cannabinoid-1 receptor (CB1R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB1R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB1R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB1R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB1R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions. Renal proximal tubules modulate whole-body homeostasis by sensing various nutrients. Here the authors describe the existence and importance of a unique CB1/mTORC1/GLUT2 signaling axis in regulating nutrient homeostasis in healthy and diseased kidney.
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41
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Pereira PR, Carrageta DF, Oliveira PF, Rodrigues A, Alves MG, Monteiro MP. Metabolomics as a tool for the early diagnosis and prognosis of diabetic kidney disease. Med Res Rev 2022; 42:1518-1544. [PMID: 35274315 DOI: 10.1002/med.21883] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/26/2022] [Accepted: 02/22/2022] [Indexed: 01/21/2023]
Abstract
Diabetic kidney disease (DKD) is one of the most prevalent comorbidities of diabetes mellitus and the leading cause of the end-stage renal disease (ESRD). DKD results from chronic exposure to hyperglycemia, leading to progressive alterations in kidney structure and function. The early development of DKD is clinically silent and when albuminuria is detected the lesions are often at advanced stages, leading to rapid kidney function decline towards ESRD. DKD progression can be arrested or substantially delayed if detected and addressed at early stages. A major limitation of current methods is the absence of albuminuria in non-albuminuric phenotypes of diabetic nephropathy, which becomes increasingly prevalent and lacks focused therapy. Metabolomics is an ever-evolving omics technology that enables the study of metabolites, downstream products of every biochemical event that occurs in an organism. Metabolomics disclosures complex metabolic networks and provide knowledge of the very foundation of several physiological or pathophysiological processes, ultimately leading to the identification of diseases' unique metabolic signatures. In this sense, metabolomics is a promising tool not only for the diagnosis but also for the identification of pre-disease states which would confer a rapid and personalized clinical practice. Herein, the use of metabolomics as a tool to identify the DKD metabolic signature of tubule interstitial lesions to diagnose or predict the time-course of DKD will be discussed. In addition, the proficiency and limitations of the currently available high-throughput metabolomic techniques will be discussed.
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Affiliation(s)
- Pedro R Pereira
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.,Department of Nephrology, Centro Hospitalar de Trás-os-Montes e Alto Douro (CHTMAD, EPE), Vila Real, Portugal
| | - David F Carrageta
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - Pedro F Oliveira
- Department of Chemistry, QOPNA & LAQV, University of Aveiro, Aveiro, Portugal
| | - Anabela Rodrigues
- Department of Nephrology and Department of Clinical Pathology, Santo António General Hospital (Hospital Center of Porto, EPE), Porto, Portugal.,Nephrology, Dialysis and Transplantation, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
| | - Marco G Alves
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.,Biotechnology of Animal and Human Reproduction (TechnoSperm), Institute of Food and Agricultural Technology, University of Girona, Girona, Spain.,Department of Biology, Unit of Cell Biology, Faculty of Sciences, University of Girona, Girona, Spain
| | - Mariana P Monteiro
- Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
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Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy. Acta Pharmacol Sin 2022; 43:659-671. [PMID: 34103688 PMCID: PMC8888565 DOI: 10.1038/s41401-021-00689-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/26/2021] [Indexed: 02/05/2023]
Abstract
Tubulointerstitial inflammation plays an important role in the progression of diabetic nephropathy (DN), and tubular epithelial cells (TECs) are crucial promoters of the inflammatory cascade. Exchange protein activated by cAMP (Epac) has been shown to suppress the angiotensin II (Ang-II)-induced release of inflammatory cytokines in tubular cells. However, the role of Epac in TEC-mediated tubulointerstitial inflammation in DN remains unknown. We found that administering the Epac agonist 8-pCPT-2'-O-Me-cAMP (8-O-cAMP) to db/db mice inhibited tubulointerstitial inflammation characterized by macrophage infiltration and increased inflammatory cytokine release and consequently alleviated tubulointerstitial fibrosis in the kidney. Furthermore, 8-O-cAMP administration restored CCAAT/enhancer binding protein β (C/EBP-β) expression and further upregulated the expression of Suppressor of cytokine signaling 3 (SOCS3), while inhibiting p-STAT3, MCP-1, IL-6, and TNF-α expression in the kidney cortex in db/db mice. And in vitro study showed that macrophage migration and MCP-1 expression induced by high glucose (HG, 30 mM) were notably reduced by 8-O-cAMP in human renal proximal tubule epithelial (HK-2) cells. In addition, 8-O-cAMP treatment restored C/EBP-β expression in HK-2 cells and promoted C/EBP-β translocation to the nucleus, where it transcriptionally upregulated SOCS3 expression, subsequently inhibiting STAT3 phosphorylation. Under HG conditions, siRNA-mediated knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on the release of MCP-1. In contrast, SOCS3 overexpression inhibited HG-induced activation of STAT3 and MCP-1 expression in HK-2 cells. These findings indicate that Epac activation via 8-O-cAMP ameliorates tubulointerstitial inflammation in DN through the C/EBP-β/SOCS3/STAT3 pathway.
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Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention. J Physiol Biochem 2022; 78:389-399. [PMID: 35192189 DOI: 10.1007/s13105-022-00874-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/14/2022] [Indexed: 10/19/2022]
Abstract
Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established in Sprague-Dawley (SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells.
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Zou M, Chen Y, Zheng Z, Sheng S, Jia Y, Wang X, Ren S, Yang Y, Li X, Dong W, Guan M, Zhang Q, Xue Y. High-Salt Attenuates the Efficacy of Dapagliflozin in Tubular Protection by Impairing Fatty Acid Metabolism in Diabetic Kidney Disease. Front Pharmacol 2022; 12:741087. [PMID: 34987387 PMCID: PMC8720966 DOI: 10.3389/fphar.2021.741087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 11/23/2021] [Indexed: 11/19/2022] Open
Abstract
High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.
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Affiliation(s)
- Meina Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanrong Chen
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zongji Zheng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuyue Sheng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yijie Jia
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiangyu Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shijing Ren
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanling Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaomin Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenhui Dong
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meiping Guan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yaoming Xue
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Resveratrol ameliorates diabetic kidney injury by reducing lipotoxicity and modulates expression of components of the junctional adhesion molecule-like/sirtuin 1 lipid metabolism pathway. Eur J Pharmacol 2022; 918:174776. [DOI: 10.1016/j.ejphar.2022.174776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/15/2022] [Accepted: 01/21/2022] [Indexed: 12/25/2022]
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Song Y, Guo F, Zhao Y, Zhao L, Fan X, Zhang Y, Liu Y, Qin G. Verapamil ameliorates proximal tubular epithelial cells apoptosis and fibrosis in diabetic kidney. Eur J Pharmacol 2021; 911:174552. [PMID: 34627808 DOI: 10.1016/j.ejphar.2021.174552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 11/22/2022]
Abstract
Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus for which there is still no effective treatment. We previously showed that upregulation of thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (TRX), accelerates the progression of DKD. In this study, we hypothesized whether verapamil, a calcium channel blocker and an established TXNIP inhibitor, might exert a renal-protective effect on DKD by regulating TXNIP expression. Herein, a systemic pharmacological network study was performed and multiple molecules and pathways targeted by verapamil on DKD were characterized. Furthermore, diabetic mice were induced by streptozotocin (STZ), and verapamil (100 mg/kg/day) or saline was intraperitoneally injected into the mice. After 16 weeks, mice were analyzed for blood glucose, blood pressure, and functional parameters followed by sacrifice and evaluation of renal tubular injury, alterations in TXNIP, apoptosis and fibrosis markers. Additionally, the effects of treatment with verapamil (50 μM, 100 μM, 150 μM) under high glucose conditions on the expression of TXNIP and signaling pathway components in proximal tubular epithelial cells (PTEC, HK-2 cells) were explored. According to these findings, we conclude that verapamil might serve as a potential agent for the prevention and treatment of DKD.
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Affiliation(s)
- Yi Song
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Feng Guo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yanyan Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lin Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xunjie Fan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuanyuan Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yanling Liu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Guijun Qin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Wang H, Zhang S, Guo J. Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:751529. [PMID: 34760900 PMCID: PMC8573085 DOI: 10.3389/fmed.2021.751529] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/27/2021] [Indexed: 01/23/2023] Open
Abstract
The pathogenesis of diabetic nephropathy is a complex process that has a great relationship with lipotoxicity. Since the concept of “nephrotoxicity” was proposed, many studies have confirmed that lipotoxicity plays a significant role in the progression of diabetic nephropathy and causes various renal dysfunction. This review will make a brief summary of renal injury caused by lipotoxicity that occurs primarily and predominantly in renal tubules during diabetic progression, further leading to glomerular dysfunction. The latest research suggests that lipotoxicity-mediated tubular injury may be a major event in diabetic nephropathy.
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Affiliation(s)
- Hua Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Guo
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Nephrology, Nephropathy Research Institutes of Zhengzhou University, Zhengzhou, China
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Han Y, Xiong S, Zhao H, Yang S, Yang M, Zhu X, Jiang N, Xiong X, Gao P, Wei L, Xiao Y, Sun L. Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy. Cell Death Dis 2021; 12:1031. [PMID: 34718329 PMCID: PMC8557213 DOI: 10.1038/s41419-021-04326-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 12/21/2022]
Abstract
Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.
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Affiliation(s)
- Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Shan Xiong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Hao Zhao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Xuejing Zhu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Na Jiang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Xiaofen Xiong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Peng Gao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Ling Wei
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
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Caus M, Eritja À, Bozic M. Role of microRNAs in Obesity-Related Kidney Disease. Int J Mol Sci 2021; 22:ijms222111416. [PMID: 34768854 PMCID: PMC8583993 DOI: 10.3390/ijms222111416] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Obesity is a major global health problem and is associated with a significant risk of renal function decline. Obesity-related nephropathy, as one of the complications of obesity, is characterized by a structural and functional damage of the kidney and represents one of the important contributors to the morbidity and mortality worldwide. Despite increasing data linking hyperlipidemia and lipotoxicity to kidney injury, the apprehension of molecular mechanisms leading to a development of kidney damage is scarce. MicroRNAs (miRNAs) are endogenously produced small noncoding RNA molecules with an important function in post-transcriptional regulation of gene expression. miRNAs have been demonstrated to be important regulators of a vast array of physiological and pathological processes in many organs, kidney being one of them. In this review, we present an overview of miRNAs, focusing on their functional role in the pathogenesis of obesity-associated renal pathologies. We explain novel findings regarding miRNA-mediated signaling in obesity-related nephropathies and highlight advantages and future perspectives of the therapeutic application of miRNAs in renal diseases.
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Phenolic Compounds from Mori Cortex Ameliorate Sodium Oleate-Induced Epithelial-Mesenchymal Transition and Fibrosis in NRK-52e Cells through CD36. Molecules 2021; 26:molecules26206133. [PMID: 34684716 PMCID: PMC8540367 DOI: 10.3390/molecules26206133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 11/25/2022] Open
Abstract
Lipid deposition in the kidney can cause serious damage to the kidney, and there is an obvious epithelial–mesenchymal transition (EMT) and fibrosis in the late stage. To investigate the interventional effects and mechanisms of phenolic compounds from Mori Cortex on the EMT and fibrosis induced by sodium oleate-induced lipid deposition in renal tubular epithelial cells (NRK-52e cells), and the role played by CD36 in the adjustment process, NRK-52e cells induced by 200 μmol/L sodium oleate were given 10 μmoL/L moracin-P-2″-O-β-d-glucopyranoside (Y-1), moracin-P-3′-O-β-d-glucopyranoside (Y-2), moracin-P-3′-O-α-l-arabinopyranoside (Y-3), and moracin-P-3′-O-[β-glucopyranoside-(1→2)arabinopyranoside] (Y-4), and Oil Red O staining was used to detect lipid deposition. A Western blot was used to detect lipid deposition-related protein CD36, inflammation-related protein (p-NF-κB-P65, NF-κB-P65, IL-1β), oxidative stress-related protein (NOX1, Nrf2, Keap1), EMT-related proteins (CD31, α-SMA), and fibrosis-related proteins (TGF-β, ZEB1, Snail1). A qRT-PCR test detected inflammation, EMT, and fibrosis-related gene mRNA levels. The TNF-α levels were detected by ELISA, and the colorimetric method was used to detects SOD and MDA levels. The ROS was measured by flow cytometry. A high-content imaging analysis system was applied to observe EMT and fibrosis-related proteins. At the same time, the experiment silenced CD36 and compared the difference between before and after drug treatment, then used molecular docking technology to predict the potential binding site of the active compounds with CD36. The research results show that sodium oleate can induce lipid deposition, inflammation, oxidative stress, and fibrosis in NRK-52e cells. Y-1 and Y-2 could significantly ameliorate the damage caused by sodium oleate, and Y-2 had a better ameliorating effect, while there was no significant change in Y-3 or Y-4. The amelioration effect of Y-1 and Y-2 disappeared after silencing CD36. Molecular docking technology showed that the Y-1 and Y-2 had hydrogen bonds to CD36 and that, compared with Y-1, Y-2 requires less binding energy. In summary, moracin-P-2″-O-β-d-glucopyranoside and moracin-P-3′-O-β-d-glucopyranoside from Mori Cortex ameliorated lipid deposition, EMT, and fibrosis induced by sodium oleate in NRK-52e cells through CD36.
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