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1
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Lv J, Yu H, Du S, Xu P, Zhao Y, Qi W, Wang X. Targeting endoplasmic reticulum stress: an innovative therapeutic strategy for podocyte-related kidney diseases. J Transl Med 2025; 23:95. [PMID: 39838496 PMCID: PMC11752968 DOI: 10.1186/s12967-025-06076-3] [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: 09/29/2024] [Accepted: 01/03/2025] [Indexed: 01/23/2025] Open
Abstract
The endoplasmic reticulum (ER) is a vital organelle responsible for protein quality control, including the folding, modification, and transport of proteins. When misfolded or unfolded proteins accumulate in the ER, it triggers endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) to restore ER homeostasis. However, prolonged or excessive ERS can lead to apoptosis. The kidneys play a crucial role in maintaining physiological functions by excreting metabolic waste, regulating blood volume, balancing electrolytes and acid-base levels, and secreting various bioactive substances. Podocytes, epithelial cells situated outside the glomerular basement membrane, are essential for maintaining the structural integrity and permeability of the glomerular filtration barrier. Previous studies have shown that ERS in podocytes can contribute to the development of diseases such as glomerulonephritis, hereditary nephropathy, and diabetic kidney disease, potentially progressing to end-stage renal disease and causing patient mortality. As such, investigating ERS in podocytes has become a key area of focus in kidney disease research. This study examines recent advancements in understanding the effects of excessive ERS on podocytes across various kidney diseases, highlights the role of podocyte ERS in disease progression, and explores the potential therapeutic benefits of targeting the UPR to manage ERS in kidney diseases, thereby providing a scientific basis for clinical interventions.
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Affiliation(s)
- Jiao Lv
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Honghai Yu
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Sasa Du
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Pengyu Xu
- College of Acupuncture and Moxibustion, Changchun University of Traditional Chinese Medicine, Changchun, 130117, China
| | - Yunyun Zhao
- Endocrinology Department, First Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Wenxiu Qi
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Ministry of Education, Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Xiuge Wang
- Endocrinology Department, First Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130021, China.
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He W, Wang H, Yang G, Zhu L, Liu X. The Role of Chemokines in Obesity and Exercise-Induced Weight Loss. Biomolecules 2024; 14:1121. [PMID: 39334887 PMCID: PMC11430256 DOI: 10.3390/biom14091121] [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: 06/10/2024] [Revised: 08/21/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
Obesity is a global health crisis that is closely interrelated to many chronic diseases, such as cardiovascular disease and diabetes. This review provides an in-depth analysis of specific chemokines involved in the development of obesity, including C-C motif chemokine ligand 2 (CCL2), CCL3, CCL5, CCL7, C-X-C motif chemokine ligand 8 (CXCL8), CXCL9, CXCL10, CXCL14, and XCL1 (lymphotactin). These chemokines exacerbate the symptoms of obesity by either promoting the inflammatory response or by influencing metabolic pathways and recruiting immune cells. Additionally, the research highlights the positive effect of exercise on modulating chemokine expression in the obese state. Notably, it explores the potential effects of both aerobic exercises and combined aerobic and resistance training in lowering levels of inflammatory mediators, reducing insulin resistance, and improving metabolic health. These findings suggest new strategies for obesity intervention through the modulation of chemokine levels by exercise, providing fresh perspectives and directions for the treatment of obesity and future research.
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Affiliation(s)
- Wenbi He
- Graduate School, Guangzhou Sport University, Guangzhou 510500, China; (W.H.); (H.W.); (G.Y.)
| | - Huan Wang
- Graduate School, Guangzhou Sport University, Guangzhou 510500, China; (W.H.); (H.W.); (G.Y.)
| | - Gaoyuan Yang
- Graduate School, Guangzhou Sport University, Guangzhou 510500, China; (W.H.); (H.W.); (G.Y.)
| | - Lin Zhu
- School of Sport and Health, Guangzhou Sport University, Guangzhou 510500, China
- Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion, Guangzhou Sport University, Guangzhou 510500, China
| | - Xiaoguang Liu
- School of Sport and Health, Guangzhou Sport University, Guangzhou 510500, China
- Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion, Guangzhou Sport University, Guangzhou 510500, 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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Wang X, Xie L, Liu C. CCR2 antagonist attenuates calcium oxalate-induced kidney oxidative stress and inflammation by regulating macrophage activation. Exp Anim 2024; 73:211-222. [PMID: 38199255 PMCID: PMC11091353 DOI: 10.1538/expanim.23-0113] [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: 08/17/2023] [Accepted: 12/23/2023] [Indexed: 01/12/2024] Open
Abstract
C-C chemokine receptor type 2 (CCR2) is a monocyte chemokine associated with oxidative stress and inflammation. Kidney stones (KS) are composed of calcium oxalate (CaOx), which trigger renal oxidative stress and inflammatory. This study aims to evaluate the effects of CCR2 on KS in vivo and in vitro. Eight-week-old male C57BL/6J mice were intraperitoneally injected with glyoxylate (GOX) daily to establish a KS model, and along with CCR2 antagonist (INCB3344) treatment on days 2, 4, and 6. The results showed that CCR2 antagonist reduced renal injury markers (blood urea nitrogen and serum creatinine), alleviated renal tubular injury and CaOx crystal deposition. CCR2 antagonist also decreased CCR2 expression induced by GOX treatment and increased Nrf2 expression. GOX treatment promoted malondialdehyde (MDA) production, decreased glutathione (GSH) content, and inhibited catalase (CAT) and superoxide dismutase (SOD) activity, however, CCR2 antagonist attenuated the above effects of GOX. CCR2 antagonist had inhibitory effects on GOX-induced inflammatory cytokine expression (IL1B, IL6 and MCP1), and inhibited apoptosis by increasing Bcl-2 expression and decreasing Bax and cleaved-caspase 3 expression. In vitro experiments were performed by co-culture model of CaOx-induced damaged HK-2 cells and macrophage-like THP-1 cells. CCR2 antagonist inhibited CaOx-induced THP-1 cell M1 polarization by decreasing the TNF-α, IL6 and iNOS levels, and further alleviated CaOx-induced oxidative stress damage, inflammatory response and apoptosis of HK-2 cells. The study suggests that CCR2 antagonist may be resistant to CaOx crystals-induced oxidative stress and inflammation by inhibiting macrophage M1 polarization.
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Affiliation(s)
- Xinpeng Wang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin 300211, P.R. China
| | - Linguo Xie
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin 300211, P.R. China
| | - Chunyu Liu
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin 300211, P.R. China
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Kim HM, Kwon MH, Lee ES, Ha KB, Chung CH. DA-6034 ameliorates hepatic steatosis and inflammation in high fat diet-induced obese mice. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 41:103-112. [PMID: 38486464 DOI: 10.12701/jyms.2023.01389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 02/09/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride content and increased inflammatory macrophage infiltration through the C-C motif chemokine receptor (CCR) 5 pathway in the liver. DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone), is a synthetic derivative of eupatilin that exhibits anti-inflammatory activity in inflammatory bowel disease. However, the effect of DA-6034 on the inflammatory response in NAFLD is not well elucidated. Therefore, we aimed to determine the effect of DA-6034 on hepatic steatosis and inflammation. METHODS Forty male C57BL/6J mice were divided into the following four groups: (1) regular diet (RD), (2) RD with DA-6034, (3) high fat diet (HFD), and (4) HFD with DA-6034. All mice were sacrificed 12 weeks after the start of the experiment. The effects of DA-6034 on macrophages were assessed using RAW264.7 cells. RESULTS DA-6034 not only reduced hepatic triglyceride levels and lipid accumulation but also macrophage infiltration and proinflammatory cytokines in HFD-fed mice. According to fluorescence-activated cell sorter analysis, DA-6034 reduced the CD8+ T cell fraction in the liver of HFD-fed mice. DA-6034 also reduced CCR5 expression and the migration of liver macrophages in HFD-fed mice and inhibited CCR2 ligand and CCR4 ligand, which stimulated the migration of macrophages. CONCLUSION Overall, DA-6034 attenuates hepatic steatosis and inflammation in obesity by regulating CCR5 expression in macrophages.
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Affiliation(s)
| | - Mi-Hye Kwon
- The East Coast Research Institute of Life Science, Gangneung-Wonju National University, Gangneung, Korea
| | - Eun Soo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyung Bong Ha
- Department of Clinical Research, Vaccine Center for Assisting Safety & Technology, Hwasun, Korea
| | - Choon Hee Chung
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea
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Giriyappagoudar M, Vastrad B, Horakeri R, Vastrad C. Study on Potential Differentially Expressed Genes in Idiopathic Pulmonary Fibrosis by Bioinformatics and Next-Generation Sequencing Data Analysis. Biomedicines 2023; 11:3109. [PMID: 38137330 PMCID: PMC10740779 DOI: 10.3390/biomedicines11123109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/31/2023] [Accepted: 11/02/2023] [Indexed: 12/24/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with reduced quality of life and earlier mortality, but its pathogenesis and key genes are still unclear. In this investigation, bioinformatics was used to deeply analyze the pathogenesis of IPF and related key genes, so as to investigate the potential molecular pathogenesis of IPF and provide guidance for clinical treatment. Next-generation sequencing dataset GSE213001 was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified between IPF and normal control group. The DEGs between IPF and normal control group were screened with the DESeq2 package of R language. The Gene Ontology (GO) and REACTOME pathway enrichment analyses of the DEGs were performed. Using the g:Profiler, the function and pathway enrichment analyses of DEGs were performed. Then, a protein-protein interaction (PPI) network was constructed via the Integrated Interactions Database (IID) database. Cytoscape with Network Analyzer was used to identify the hub genes. miRNet and NetworkAnalyst databaseswereused to construct the targeted microRNAs (miRNAs), transcription factors (TFs), and small drug molecules. Finally, receiver operating characteristic (ROC) curve analysis was used to validate the hub genes. A total of 958 DEGs were screened out in this study, including 479 up regulated genes and 479 down regulated genes. Most of the DEGs were significantly enriched in response to stimulus, GPCR ligand binding, microtubule-based process, and defective GALNT3 causes HFTC. In combination with the results of the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, hub genes including LRRK2, BMI1, EBP, MNDA, KBTBD7, KRT15, OTX1, TEKT4, SPAG8, and EFHC2 were selected. Cyclothiazide and rotigotinethe are predicted small drug molecules for IPF treatment. Our findings will contribute to identification of potential biomarkers and novel strategies for the treatment of IPF, and provide a novel strategy for clinical therapy.
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Affiliation(s)
- Muttanagouda Giriyappagoudar
- Department of Radiation Oncology, Karnataka Institute of Medical Sciences (KIMS), Hubballi 580022, Karnataka, India;
| | - Basavaraj Vastrad
- Department of Pharmaceutical Chemistry, K.L.E. Socitey’s College of Pharmacy, Gadag 582101, Karnataka, India;
| | - Rajeshwari Horakeri
- Department of Computer Science, Govt First Grade College, Hubballi 580032, Karnataka, India;
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India
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An C, Pipia I, Ruiz AS, Argüelles I, An M, Wase S, Peng G. The molecular link between obesity and genomic instability in cancer development. Cancer Lett 2023; 555:216035. [PMID: 36502927 DOI: 10.1016/j.canlet.2022.216035] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/10/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Obesity has been known to be a major risk factor for various types of cancers for several decades. More recently, the relationship between dysregulated adipokines and cancer development has been the focus of much research. Adipose tissue is an important endocrine organ that secretes adipokines that affect both autocrine and paracrine signaling. These adipokines modulate inflammation, induce insulin resistance, and regulate their own behavior and production. Adipokine-production dysregulation is due to physiological changes in adipose tissue that prompt molecular modifications, including low-grade inflammation and the stimulatory production of reactive oxygen species. Additionally, studies have linked DNA damage response, genomic instability, and the innate immune response to tumorigenesis. Further investigation of adipokines and their role in the promotion of genomic instability may clarify the link between obesity and cancer, as well as elucidate potential pharmaceutical targets. In this review, we discuss the progress of recent literature, focusing on the impact of adipokines, genomic instability, and the innate immune response on increasing the risk of cancer.
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Affiliation(s)
- Clemens An
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Robert Larner, M.D. College of Medicine at The University of Vermont, Burlington, VT, USA.
| | - Ilissa Pipia
- Department of Biological Sciences, Cornell University, Ithaca, NY, USA
| | - Ana-Sofia Ruiz
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ivonne Argüelles
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Martino An
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Saima Wase
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Otolaryngology - Head & Neck Surgery, University of North Carolina Medical Center, Chapel Hill, NC, USA
| | - Guang Peng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Increased mRNA Levels of ADAM17, IFITM3, and IFNE in Peripheral Blood Cells Are Present in Patients with Obesity and May Predict Severe COVID-19 Evolution. Biomedicines 2022; 10:biomedicines10082007. [PMID: 36009555 PMCID: PMC9406212 DOI: 10.3390/biomedicines10082007] [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: 06/10/2022] [Revised: 08/12/2022] [Accepted: 08/15/2022] [Indexed: 11/21/2022] Open
Abstract
Gene expression patterns in blood cells from SARS-CoV-2 infected individuals with different clinical phenotypes and body mass index (BMI) could help to identify possible early prognosis factors for COVID-19. We recruited patients with COVID-19 admitted in Hospital Universitari Son Espases (HUSE) between March 2020 and November 2021, and control subjects. Peripheral blood cells (PBCs) and plasma samples were obtained on hospital admission. Gene expression of candidate transcriptomic biomarkers in PBCs were compared based on the patients’ clinical status (mild, severe and critical) and BMI range (normal weight, overweight, and obesity). mRNA levels of ADAM17, IFITM3, IL6, CXCL10, CXCL11, IFNG and TYK2 were increased in PBCs of COVID-19 patients (n = 73) compared with controls (n = 47), independently of sex. Increased expression of IFNE was observed in the male patients only. PBC mRNA levels of ADAM17, IFITM3, CXCL11, and CCR2 were higher in those patients that experienced a more serious evolution during hospitalization. ADAM17, IFITM3, IL6 and IFNE were more highly expressed in PBCs of patients with obesity. Interestingly, the expression pattern of ADAM17, IFITM3 and IFNE in PBCs was related to both the severity of COVID-19 evolution and obesity status, especially in the male patients. In conclusion, gene expression in PBCs can be useful for the prognosis of COVID-19 evolution.
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Chung H, Lee SW, Hyun M, Kim SY, Cho HG, Lee ES, Kang JS, Chung CH, Lee EY. Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway. Front Cell Dev Biol 2022; 10:800574. [PMID: 35706905 PMCID: PMC9189280 DOI: 10.3389/fcell.2022.800574] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 03/08/2022] [Indexed: 12/12/2022] Open
Abstract
Podocyte loss is well known to play a critical role in the early progression of diabetic nephropathy. A growing number of studies are paying attention to necroptosis, a programmed form of cell necrosis as a mechanism of podocyte loss. Although necroptosis is a recently established concept, the significance of receptor interacting serine/threonine kinase 3 (RIPK3), a gene that encodes for the homonymous enzyme RIPK3 responsible for the progression of necroptosis, is well studied. Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color of Curcuma longa, has drawn attention due to its antioxidant and anti-inflammatory effects on cells prone to necroptosis. Nonetheless, effects of curcumin on high glucose-induced podocyte necroptosis have not been reported yet. Therefore, this study investigated RIPK3 expression in high glucose-treated podocytes to identify the involvement of necroptosis via the RIPK3 pathway and the effects of curcumin treatment on RIPK3-dependent podocytopathy in a hyperglycemic environment. The study discovered that increased reactive oxygen species (ROS) in renal podocytes induced by high glucose was improved after curcumin treatment. Curcumin treatment also significantly restored the upregulated levels of VEGF, TGF-β, and CCL2 mRNAs and the downregulated level of nephrin mRNA in cultured podocytes exposed to a high glucose environment. High glucose-induced changes in protein expression of TGF-β, nephrin, and CCL2 were considerably reverted to their original levels after curcumin treatment. Increased expression of RIPK3 in high glucose-stimulated podocytes was alleviated by curcumin treatment as well as N-acetyl cysteine (NAC, an antioxidant) or GSK′872 (a RIPK3 inhibitor). Consistent with this, the increased necroptosis-associated molecules, such as RIPK3, pRIPK3, and pMLKL, were also restored by curcumin in high glucose-treated mesangial cells. DCF-DA assay confirmed that such a result was attributed to the reduction of RIPK3 through the antioxidant effect of curcumin. Further observations of DCF-DA-sensitive intracellular ROS in NAC-treated and GSK′872-treated podocyte groups showed a reciprocal regulatory relationship between ROS and RIPK3. The treatment of curcumin and GSK′872 in podocytes incubated with high glucose protected from excessive intracellular superoxide anion production. Taken together, these results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.
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Affiliation(s)
- Hyunsoo Chung
- College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Seong-Woo Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, South Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Miri Hyun
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, South Korea
| | - So Young Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, South Korea
| | - Hyeon Gyu Cho
- College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Eun Soo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
- Institution of Genetic Cohort, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Jeong Suk Kang
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, South Korea
- Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Choon Hee Chung
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
- Institution of Genetic Cohort, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Eun Young Lee
- College of Medicine, Soonchunhyang University, Cheonan, South Korea
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, South Korea
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, South Korea
- Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, South Korea
- *Correspondence: Eun Young Lee,
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Chen S, Chen J, Li S, Guo F, Li A, Wu H, Chen J, Pan Q, Liao S, Liu HF, Pan Q. High-Fat Diet-Induced Renal Proximal Tubular Inflammatory Injury: Emerging Risk Factor of Chronic Kidney Disease. Front Physiol 2021; 12:786599. [PMID: 34950058 PMCID: PMC8688947 DOI: 10.3389/fphys.2021.786599] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/16/2021] [Indexed: 01/01/2023] Open
Abstract
Nowadays, with the improvements in living standards and changes in living habits, high-fat diet (HFD) has become much more common in the populations worldwide. Recent studies have shown that HFD could induce lipid accumulation, and structural and functional abnormalities, accompanied by the release of large amounts of pro-inflammatory cytokines, in proximal tubular epithelial cells (PTECs). These findings indicate that, as an emerging risk factor, PTEC injury-induced by HFD may be closely related to inflammation; however, the potential mechanisms underlying this phenomenon is still not well-known, but may involve the several inflammatory pathways, including oxidative stress-related signaling pathways, mitochondrial dysfunction, the myeloid differentiation factor 2/Toll like receptor 4 (MD2/TLR4) signaling pathway, the ERK1/2-kidney injury molecule 1 (KIM-1)-related pathway, and nuclear factor-κB (NF-κB) activation, etc., and the detailed molecular mechanisms underlying these pathways still need further investigated in the future. Based on lipid abnormalities-induced inflammation is closely related to the development and progression of chronic kidney disease (CKD), to summarize the potential mechanisms underlying HFD-induced renal proximal tubular inflammatory injury, may provide novel approaches for CKD treatment.
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Affiliation(s)
- Shuxian Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jinxia Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shangmei Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengbiao Guo
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Aifen Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Han Wu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiaxuan Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Quanren Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuzhen Liao
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qingjun Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes. Int J Mol Sci 2021; 23:ijms23010221. [PMID: 35008648 PMCID: PMC8745741 DOI: 10.3390/ijms23010221] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 11/16/2022] Open
Abstract
Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.
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Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy. Sci Rep 2021; 11:23587. [PMID: 34880315 PMCID: PMC8654826 DOI: 10.1038/s41598-021-02864-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.
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Palau V, Villanueva S, Jarrín J, Benito D, Márquez E, Rodríguez E, Soler MJ, Oliveras A, Gimeno J, Sans L, Crespo M, Pascual J, Barrios C, Riera M. Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes. Int J Mol Sci 2021; 22:ijms222313093. [PMID: 34884897 PMCID: PMC8657896 DOI: 10.3390/ijms222313093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 12/14/2022] Open
Abstract
Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.
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Affiliation(s)
- Vanesa Palau
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Sofia Villanueva
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Josué Jarrín
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - David Benito
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Eva Márquez
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Eva Rodríguez
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - María José Soler
- Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain;
| | - Anna Oliveras
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Javier Gimeno
- Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain;
| | - Laia Sans
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
| | - Clara Barrios
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
- Correspondence: (C.B.); (M.R.); Tel.: +34-65-004-2149 (C.B.); +34-93-316-0626 (M.R.)
| | - Marta Riera
- Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; (V.P.); (S.V.); (J.J.); (D.B.); (E.M.); (E.R.); (A.O.); (L.S.); (M.C.); (J.P.)
- Correspondence: (C.B.); (M.R.); Tel.: +34-65-004-2149 (C.B.); +34-93-316-0626 (M.R.)
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Chen P, Chen X, Chu H, Xia W, Zou X, Wang D, Rong M. Periodontitis regulates renal impairment in obese mice via TGF-β/Smad pathway. Am J Transl Res 2021; 13:12523-12535. [PMID: 34956470 PMCID: PMC8661180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 10/09/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To determine the impact of periodontitis on renal impairment induced by obesity. METHODS Periodontitis and obesity models were induced using silk ligatures with bacteria and high-fat diet, respectively. Indicators of renal function were compared. Renal tubular epithelial cells (RTECs) were treated with lipopolysaccharides from periodontal pathogens in a high-fat environment to induce cell models of periodontitis and obesity. The transforming growth factor-β/mothers against decapentaplegic homolog (Smad) (TGF-β/Smad) pathway was evaluated both in vivo and in vitro. The indicators of renal function, renal pathological changes, and serum inflammatory cytokines were measured. The viability/apoptosis of RTECs and the expression of inflammatory cytokines were determined. RESULTS Periodontitis resulted in an increase in TGF-β/Smad activity in the kidney of obese mice. Moreover, the activity of RTECs was also increased in vitro. Downregulation of TGF-β led to reduced TGF-β, p-Smad2, p-Smad3, and Smad7 levels in kidney tissue and RTECs, ameliorated renal function indicators and renal pathological changes, increased viability and apoptosis of RTECs, and decreased levels of inflammatory cytokines. CONCLUSION Periodontitis regulates renal impairment via the TGF-β/Smad pathway in obese mice.
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Affiliation(s)
- Pei Chen
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China
| | - Xiao Chen
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China
| | - Hongxing Chu
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China
| | - Wei Xia
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China
| | - Xiaoyan Zou
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China
| | - Dan Wang
- Haizhu Square Branch of Stomatological Hospital, Southern Medical UniversityGuangzhou 510120, Guangdong, China
| | - Mingdeng Rong
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical UniversityGuangzhou 510280, Guangdong, China
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Guo J, Li J, Wei H, Liang Z. Maackiain Protects the Kidneys of Type 2 Diabetic Rats via Modulating the Nrf2/HO-1 and TLR4/NF-κB/Caspase-3 Pathways. Drug Des Devel Ther 2021; 15:4339-4358. [PMID: 34703210 PMCID: PMC8525417 DOI: 10.2147/dddt.s326975] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is aglobal health burden that accounts for about 90% of all cases of diabetes. Injury to the kidneys is aserious complication of type 2 diabetes. Maackiain, apterocarpan extracted from roots of Sophora flavescens, has been traditionally used for various disease conditions. However, nothing is known about its possible potential effect on HFD/STZ-T2D-induced nephrotoxicity. METHODS In this study, T2D rat model is created by high-fat diet (HFD) for 2 weeks with injection of asingle dose of streptozotocin (35mg/kg body weight). T2D rats were orally administered with maackiain (10 and 20mg/kg body weight) for 7 weeks. RESULTS Maackiain suppressed T2D-induced alterations in metabolic parameters, lipid profile and kidney functionality markers. By administering 10 and 20mg/kg maackiain to T2D rats, it was able to reduce lipid peroxidation while improving antioxidant levels (SOD, CAT, and GSH). Furthermore, the present study demonstrated the molecular mechanisms through which maackiain attenuated T2D-induced oxidative stress (mRNA: Nrf2, Nqo-1, Ho-1, Gclc and Gpx-1; protein: NRF2, NQO-1, HO-1 and NOX-4), inflammation (mRNA: Tlr, Myd88, IκBα, Mcp-1, Tgf-β, col4, Icam1, Vcam1 and E-selectin; Protein: TLR4, MYD88, NF-κB, IκBα, MCP-1; levels: TNF-α and MCP-1) and apoptosis (mRNA: Bcl-2, Bax, Bad, Apaf-1, Caspase-9 and Caspase-3; protein: Bcl-2, Bax, Caspase-3 and Caspase-9) mediated renal injury. Additionally, significant improvement in kidney architecture was observed after treatment of diabetic rats with 10 or 20mg/kg maackiain. CONCLUSION Maackiain protects the kidney by decreasing oxidative stress, inflammation, and apoptosis to preserve normal renal function in type 2 diabetes.
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Affiliation(s)
- Jiahong Guo
- Department of Nephrology, Xinxiang Central Hospital, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, 453000, People’s Republic of China
| | - Junying Li
- Department of Nephrology, The Affiliated Hospital of Qingdao University Pingdu district, Pingdu City, Qingdao, Shandong, 266000, People’s Republic of China
| | - Hua Wei
- Department of Nephrology, Xinxiang Central Hospital, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, 453000, People’s Republic of China
| | - Zhaozhi Liang
- Department of Nephrology, Xinxiang Central Hospital, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, 453000, People’s Republic of China
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CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease. Int J Mol Sci 2021; 22:ijms22147642. [PMID: 34299260 PMCID: PMC8304086 DOI: 10.3390/ijms22147642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/11/2021] [Accepted: 07/14/2021] [Indexed: 12/23/2022] Open
Abstract
The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.
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Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State? Int J Mol Sci 2021; 22:ijms22031500. [PMID: 33540898 PMCID: PMC7867366 DOI: 10.3390/ijms22031500] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 12/14/2022] Open
Abstract
The mechanisms of how obesity contributes to the development of cardio-metabolic diseases are not entirely understood. Obesity is frequently associated with adipose tissue dysfunction, characterized by, e.g., adipocyte hypertrophy, ectopic fat accumulation, immune cell infiltration, and the altered secretion of adipokines. Factors secreted from adipose tissue may induce and/or maintain a local and systemic low-grade activation of the innate immune system. Attraction of macrophages into adipose tissue and altered crosstalk between macrophages, adipocytes, and other cells of adipose tissue are symptoms of metabolic inflammation. Among several secreted factors attracting immune cells to adipose tissue, chemotactic C-C motif chemokine ligand 2 (CCL2) (also described as monocyte chemoattractant protein-1 (MCP-1)) has been shown to play a crucial role in adipose tissue macrophage infiltration. In this review, we aimed to summarize and discuss the current knowledge on CCL2 with a focus on its role in linking obesity to cardio-metabolic diseases.
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Kim SY, Park S, Lee SW, Lee JH, Lee ES, Kim M, Kim Y, Kang JS, Chung CH, Moon JS, Lee EY. RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death. Cells 2021; 10:245. [PMID: 33513913 PMCID: PMC7911493 DOI: 10.3390/cells10020245] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/15/2021] [Accepted: 01/25/2021] [Indexed: 01/02/2023] Open
Abstract
Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients' morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK'872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.
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Affiliation(s)
- So-Young Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea; (S.-Y.K.); (S.P.); (S.-W.L.); (J.S.K.)
| | - Samel Park
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea; (S.-Y.K.); (S.P.); (S.-W.L.); (J.S.K.)
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan 31151, Korea; (M.K.); (Y.K.)
| | - Seong-Woo Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea; (S.-Y.K.); (S.P.); (S.-W.L.); (J.S.K.)
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
| | - Ji-Hye Lee
- Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea;
| | - Eun Soo Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 03722, Korea; (E.S.L.); (C.H.C.)
| | - Miri Kim
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan 31151, Korea; (M.K.); (Y.K.)
| | - Youngjo Kim
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan 31151, Korea; (M.K.); (Y.K.)
| | - Jeong Suk Kang
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea; (S.-Y.K.); (S.P.); (S.-W.L.); (J.S.K.)
- Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
| | - Choon Hee Chung
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 03722, Korea; (E.S.L.); (C.H.C.)
| | - Jong-Seok Moon
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan 31151, Korea; (M.K.); (Y.K.)
| | - Eun Young Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Korea; (S.-Y.K.); (S.P.); (S.-W.L.); (J.S.K.)
- BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
- Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea
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Xu J, Liu L, Gan L, Hu Y, Xiang P, Xing Y, Zhu J, Ye S. Berberine Acts on C/EBPβ/lncRNA Gas5/miR-18a-5p Loop to Decrease the Mitochondrial ROS Generation in HK-2 Cells. Front Endocrinol (Lausanne) 2021; 12:675834. [PMID: 34526965 PMCID: PMC8435884 DOI: 10.3389/fendo.2021.675834] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/02/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Berberine (BBR) has therapeutic effect on diabetic nephropathy (DN), but its molecular mechanism is not completely clear. METHODS The DN model was established to observe the therapeutic effect of BBR. The expression levels of lncRNA Gas5 were detected by PCR. The transcriptional regulation of CCAAT enhancer binding protein beta (C/EBPβ) on Gas5 was analyzed by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) and luciferase reporter gene assay. The targeted regulation between Gas5 and miR-18a-5p and between miR-18a-5p and C/EBPβ 3'-untranslated region (3'-UTR) was also analyzed. RESULTS In HG environment, BBR decreased the mitochondrial reactive oxygen species (ROS) generation and activated the C/EBPβ expression in HK-2 cells; C/EBPβ could combine with the reaction element on the promoter of Gas5 to promote its expression. Gas5 also inhibited the miR-18a-5p expression as competing endogenous RNA (ceRNA) and reduce the negative regulatory effect of miR-18a-5p on C/EBPβ. BBR could activate C/EBPβ/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signal pathway, regulate mitochondrial energy metabolism, and inhibit ROS production and apoptosis by activating C/EBPβ/Gas5/miR-18a-5p positive feedback loop in HG environment. It also showed that BBR alleviated streptozotocin (STZ) induced renal injury in DN rats in vivo. CONCLUSIONS This study suggested that BBR could regulate the mitochondrial ROS generation by activating the positive feedback loop of C/EBPβ/Gas5/miR-18a-5p.
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Affiliation(s)
- Jiang Xu
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Linqing Liu
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lin Gan
- Department of Microbiology, Anhui Medical University, Hefei, China
| | - Yuanyuan Hu
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ping Xiang
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yan Xing
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jie Zhu
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- *Correspondence: Shandong Ye,
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Li Z, Li J, Miao X, Cui W, Miao L, Cai L. A minireview: Role of AMP-activated protein kinase (AMPK) signaling in obesity-related renal injury. Life Sci 2020; 265:118828. [PMID: 33253722 DOI: 10.1016/j.lfs.2020.118828] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/14/2022]
Abstract
Emerging evidence shows that the AMP-activated protein kinase (AMPK), a critical energy-sensing switch, plays an important role in the pathogenesis and development of obesity-related renal injury. In this review, we summarized the mechanisms underlying the protective effects of AMPK activation against obesity-related renal injury in preclinical studies, with the main purposes of increasing the understanding of AMPK and providing new insights into the future clinical therapeutic strategies. The renoprotective effects of AMPK mainly act by modulating lipid metabolism and autophagy and suppressing oxidative stress, inflammation, and fibrosis. More importantly, we discussed the recent advances in this field that require further investigation. Firstly, the inhibitory effect of AMPK on ferroptosis is a potential mechanism for its protection against renal injury. Secondly, the effect of AMPK on lipolysis is complex: AMPK induces basal lipolysis but also inhibits stimulated lipolysis. Thirdly, statins may play a renoprotective role by activating AMPK. Fourthly, some microRNAs targeting AMPK mRNA have been implicated in diabetic nephropathy in type 2 diabetes. Further, AMPK can regulate the expression of some microRNAs, suggesting that the stable renoprotective effects of AMPK may benefit from its epigenetic regulation. Lastly, several natural compounds and synthetic drugs have been recognized to protect against obesity-related renal injury by activating AMPK and its downstream pathways in animal models. It remains to be seen if combination of newly identified drugs with traditional renoprotective medicine will have any synergistic therapeutic benefits without adding to side effects.
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Affiliation(s)
- Zhuo Li
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, China
| | - Jia Li
- Department of Nephropathy, The First Hospital of Jilin University, Changchun 130021, China
| | - Xiao Miao
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun 130041, China
| | - Wenpeng Cui
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, China
| | - Lining Miao
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, China.
| | - Lu Cai
- Pediatric Research Institute, Departments of Pediatrics, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville 40202, USA
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21
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Yang J, Suo H, Song J. Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome. Crit Rev Food Sci Nutr 2020; 61:3857-3875. [PMID: 32815398 DOI: 10.1080/10408398.2020.1809344] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mitochondria control various processes in cellular metabolic homeostasis, such as adenosine triphosphate production, generation and clearance of reactive oxygen species, control of intracellular Ca2+ and apoptosis, and are thus a critical therapeutic target for metabolic syndrome (MetS). The mitochondrial targeted antioxidant mitoquinone (MitoQ) reduces mitochondrial oxidative stress, prevents impaired mitochondrial dynamics, and increases mitochondrial turnover by promoting autophagy (mitophagy) and mitochondrial biogenesis, which ultimately contribute to the attenuation of MetS conditions, including obesity, insulin resistance, hypertension and cardiovascular disease. The regulatory effect of MitoQ on mitochondrial homeostasis is mediated through AMPK and its downstream signaling pathways, including MTOR, SIRT1, Nrf2 and NF-κB. However, there are few reviews focusing on the critical role of MitoQ as a therapeutic agent in the treatment of MetS. The purpose of this review is to summarize the mitochondrial role in the pathogenesis of MetS, especially in obesity and type 2 diabetes, and discuss the effect and underlying mechanism of MitoQ on mitochondrial homeostasis in MetS.
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Affiliation(s)
- Jing Yang
- Chongqing Engineering Research Center for Processing & Storage of Distinct Agricultural Products, Chongqing Technology and Business University, Chongqing, China.,Graduate School, Chongqing Technology and Business University, Chongqing, China
| | - Huayi Suo
- College of Food Science, Southwest University, Chongqing, China
| | - Jiajia Song
- College of Food Science, Southwest University, Chongqing, China
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22
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Shi Y, Wang C, Zhou X, Li Y, Ma Y, Zhang R, Li R. Downregulation of PTEN promotes podocyte endocytosis of lipids aggravating obesity-related glomerulopathy. Am J Physiol Renal Physiol 2020; 318:F589-F599. [PMID: 31813249 DOI: 10.1152/ajprenal.00392.2019] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
With the increasing prevalence of obesity in adults worldwide, the incidence of obesity-related glomerulopathy (ORG) has increased yearly, becoming one of the leading causes of end-stage renal disease. Studies have demonstrated significant correlations between hyperlipidemia and impaired renal function in patients with ORG, indicating that hyperlipidemia causes damage in kidney cells. In podocytes, the endocytosis of lipids triggers an intracellular oxidative stress response that disrupts cellular integrity, resulting in proteinuria and glomerular sclerosis. However, the specific molecular mechanisms through which podocytes endocytose lipids remain unclear. Here, we demonstrated the enhanced endocytosis of lipids by podocytes from patients with ORG. This response was associated with decreased expression of phosphatase and tensin homolog (PTEN). In vitro silencing of PTEN promoted the endocytosis of low-density lipoprotein in mouse podocytes. Conversely, overexpression of PTEN inhibited the endocytosis of lipoproteins in podocytes. PTEN directly dephosphorylates and activates the actin-depolymerizing factor cofilin-1, leading to depolymerization of filamentous actin (F-actin), which is necessary for endocytosis. Notably, inhibition of PTEN resulted in the phosphorylation and inactivation of cofilin-1, leading to F-actin formation that enhanced the endocytosis of lipoproteins in podocytes. When hyperlipidemia was induced in mice with podocyte-specific deletion of PTEN, these mice recapitulated the major pathophysiological features of ORG. Thus, PTEN downregulation in podocytes may contribute to the pathogenesis of ORG.
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Affiliation(s)
- Yuanyuan Shi
- Nephrology Division, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
- Nephrology Division, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chen Wang
- Pathology Division, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoshuang Zhou
- Nephrology Division, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
| | - Yafeng Li
- Nephrology Division, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
| | - Yuehong Ma
- Nephrology Division, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
| | - Rui Zhang
- Nephrology Division, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
| | - Rongshan Li
- Nephrology Division, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
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23
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Tanshinone IIA Alleviates CCL2-Induced Leaning memory and Cognition Impairment in Rats: A Potential Therapeutic Approach for HIV-Associated Neurocognitive Disorder. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2702175. [PMID: 32185196 PMCID: PMC7060416 DOI: 10.1155/2020/2702175] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 12/16/2019] [Accepted: 01/10/2020] [Indexed: 12/19/2022]
Abstract
Chemokine CC motif ligand 2 (CCL2) is one of the most recognized proinflammatory chemokines, and the expression of CCL2 in the cerebrospinal fluid of patients infected with HIV-1 is significantly higher than that of healthy people. As such, it is seen as an important cause of HIV-associated neurocognitive disorder (HAND). Our previous investigation has confirmed the pathological role of CCL2 in mediating brain damage leading to cognitive dysfunction. Currently, however, research on therapeutic drugs for the central nervous system targeting CCL2 is very limited. Our present study used brain stereotactic technology to induce cognitive impairment in rats by injecting CCL2 (5 ng) into the bilateral hippocampus. To investigate the protective effect and mechanism of Tanshinone IIA (25, 50, 75 mg/kg/d) on CCL2-induced learning memory and cognitive impairment in rats, we performed the Morris water maze (MWM) and novel object recognition tests (NORT) on the rats. The results showed that Tanshinone IIA significantly alleviated CCL2-induced learning memory and cognitive dysfunction. Further studies on the hippocampal tissue of the rats revealed that Tanshinone IIA treatment significantly increased the activity of SOD and GSH-Px while the level of MDA decreased compared to the model group. Additionally, the relative expression of apoptosis-associated genes caspase-3, caspase-8, and caspase-9 and inflammation-associated genes IL-1β and IL-6 in Tanshinone IIA-treated rats was lower than that in model rats. Finally, we confirmed hippocampal neuron loss and apoptosis by Nissl staining and TdT-mediated dUTP Nick end labeling (TUNEL). Taken together, these data imply that Tanshinone IIA can ameliorate CCL2-induced learning memory and cognitive impairment by impacting oxidative stress, inflammation, and apoptosis. Tanshinone IIA may be a potential therapeutic agent for the treatment of HAND.
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24
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Almeida YE, Fessel MR, do Carmo LS, Jorgetti V, Farias-Silva E, Pescatore LA, Gamarra LF, Andrade MC, Simplicio-Filho A, Mangueira CLP, Rangel ÉB, Liberman M. Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice. Sci Rep 2020; 10:87. [PMID: 31919470 PMCID: PMC6952360 DOI: 10.1038/s41598-019-55501-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus accelerates vascular calcification (VC) and increases the risk of end-stage renal disease (ESRD). Nevertheless, the impact of VC in renal disease progression in type 2 diabetes mellitus (T2DM) is poorly understood. We addressed the effect of VC and mechanisms involved in renal dysfunction in a murine model of insulin resistance and obesity (ob/ob), comparing with their healthy littermates (C57BL/6). We analyzed VC and renal function in both mouse strains after challenging them with Vitamin D3 (VitD3). Although VitD3 similarly increased serum calcium and induced bone disease in both strains, 24-hour urine volume and creatinine pronouncedly decreased only in ob/ob mice. Moreover, ob/ob increased urinary albumin/creatinine ratio (ACR), indicating kidney dysfunction. In parallel, ob/ob developed extensive intrarenal VC after VitD3. Coincidently with increased intrarenal vascular mineralization, our results demonstrated that Bone Morphogenetic Protein-2 (BMP-2) was highly expressed in these arteries exclusively in ob/ob. These data depict a greater susceptibility of ob/ob mice to develop renal disease after VitD3 in comparison to paired C57BL/6. In conclusion, this study unfolds novel mechanisms of progressive renal dysfunction in diabetes mellitus (DM) after VitD3 in vivo associated with increased intrarenal VC and highlights possible harmful effects of long-term supplementation of VitD3 in this population.
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Affiliation(s)
- Youri E Almeida
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | - Melissa R Fessel
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | | | - Vanda Jorgetti
- Department of Nephrology, Medical School, Universidade de São Paulo, São Paulo/SP, 01246000, Brazil
| | | | - Luciana Alves Pescatore
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
- Laboratório de Biologia Vascular, LIM-64, InCor, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo/SP, Brazil
| | - Lionel F Gamarra
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | | | | | | | - Érika B Rangel
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | - Marcel Liberman
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil.
- Laboratório de Biologia Vascular, LIM-64, InCor, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo/SP, Brazil.
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