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1
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Zhou H, Mao Y, Ye M, Zuo Z. Exploring the nonlinear association between cardiometabolic index and hypertension in U.S. Adults: an NHANES-based study. BMC Public Health 2025; 25:1092. [PMID: 40119367 PMCID: PMC11929247 DOI: 10.1186/s12889-025-22231-3] [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: 09/22/2024] [Accepted: 03/07/2025] [Indexed: 03/24/2025] Open
Abstract
BACKGROUND Hypertension is a prevalent chronic disease affecting over 1.2 billion people worldwide, representing a major modifiable risk factor for cardiovascular diseases. The Waist-to-Height Ratio (WHtR) and Triglyceride to High-Density Lipoprotein Cholesterol (TG/HDL-C) ratio are established metabolic indicators linked to the risk of cardiovascular and metabolic diseases. Recently, a Cardiometabolic Index (CMI), combining WHtR and TG/HDL-C ratios, has been proposed to provide a comprehensive assessment of metabolic health. This study investigates the association between CMI and hypertension using data from the National Health and Nutrition Examination Survey (NHANES). METHODS The study utilized NHANES data from nine cycles spanning 2001 to 2018, encompassing 20,049 participants aged over 20. Exclusions were made for individuals with incomplete CMI or hypertension data, and pregnant women. CMI was calculated by multiplying the WHtR by the TG/HDL-C ratio. Hypertension was defined according to American Heart Association guidelines. The relationship between CMI and hypertension was evaluated using multivariate logistic regression analyses, with additional subgroup analyses conducted based on demographic factors. Nonlinear relationships were analyzed using smoothing curve fitting techniques. RESULTS The study identified a significant positive correlation between CMI and hypertension risk, with an increase of one unit in CMI associated with a 9% heightened risk of hypertension (OR: 1.09, 95% CI: 1.05, 1.13). The association remained significant across various demographic subgroups. A nonlinear relationship was observed, with a critical CMI threshold of 2.64. Below this threshold, higher CMI values were associated with a progressively higher prevalence of hypertension, whereas beyond this threshold, further increases in CMI did not significantly correlate with an elevated risk of hypertension. CONCLUSION The study demonstrates that CMI is significantly associated with hypertension risk and may serve as a valuable tool for early screening and risk assessment, particularly in identifying individuals at higher risk before reaching the critical CMI threshold. These results underscore the importance of addressing metabolic health in the prevention and management of hypertension. Future research should focus on longitudinal studies to establish causality, explore the clinical utility of CMI in hypertension screening, and examine its applicability in diverse populations.
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Affiliation(s)
- Huatao Zhou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yu Mao
- Department of Thyroid Surgery, The Second Xiangya Hospital, Central South University, Hunan Province, No. 139Renmin East Road, Changsha, 410011, People's Republic of China
| | - Muyao Ye
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Zhongkun Zuo
- Department of Thyroid Surgery, The Second Xiangya Hospital, Central South University, Hunan Province, No. 139Renmin East Road, Changsha, 410011, People's Republic of China.
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Xing L, Wu S, Shi Y, Wei L, Yue F, Lam SM, Shui G, Russell R, Zhang D. Metformin alleviates sphingolipids dysregulation and improves obesity-related kidney disease in high-fat diet rats. J Pharmacol Exp Ther 2025; 392:103388. [PMID: 39921942 DOI: 10.1016/j.jpet.2025.103388] [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: 09/21/2024] [Revised: 12/17/2024] [Accepted: 01/09/2025] [Indexed: 02/10/2025] Open
Abstract
Obesity-related kidney disease (ORKD) has recently become a global health issue. Metformin is widely used in patients with type 2 diabetes with concomitant obesity, but its effects on ORKD are insufficiently understood. Accumulation of lipid species including sphingolipids has been reported to disrupt glomerular functions and drive progression of chronic kidney disease. The present study aimed to test the hypothesis that metformin could exert beneficial effects on ORKD, which may be associated with changes in renal lipidomics. Male Sprague-Dawley rats were divided into normal chow diet (ND) group or high-fat diet (HFD)-fed group. After 8 weeks, HFD-fed group was subdivided into metformin treatment (HFD-Met) group and control (HFD-C) group for an additional 8 weeks. Sphingolipids and phospholipids in renal cortex were measured by targeted lipidomics. Compared with ND group, HFD-C group developed histopathological features of ORKD. Metformin alleviated dyslipidemia, renal dysfunction, proteinuria, glomerular hypertrophy, podocyte damage, and renal fibrosis in HFD-fed rats. Renal sphingolipid analysis showed elevations of total ceramide, sphingosine, glucosylceramide, and galactosylceramide levels in HFD-C versus ND group. Specific species, such as ceramide d18:1/22:0, glucosylceramide d18:1/20:0, and galactosylceramide d18:1/16:0, which were positively associated with oxidative stress and insulin resistance, were reduced in HFD-Met versus HFD-C group. Renal phospholipid analysis showed increased levels of total phosphatidylcholine and lysophosphatidylcholine (LPC) in HFD-C rats versus ND rats. The ratio of saturated and monounsaturated LPCs to polyunsaturated LPCs was significantly reduced in HFD-Met rats. These results suggest that metformin alleviates sphingolipids dysregulation and improves ORKD in HFD-fed rats. SIGNIFICANCE STATEMENT: To date, this is the first report to explore effects of metformin on renal lipidomics. These findings reveal specific changes of renal lipid species, which are crucial for deeper understanding the underlying mechanisms of obesity-related kidney disease and effects of metformin on it. The associated signature sphingolipids and phospholipids in the study may have significant implications for developing targeted therapeutic strategies for obesity-related kidney disease.
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Affiliation(s)
- Lin Xing
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shanyu Wu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Shi
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Wei
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangzhi Yue
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Ryan Russell
- Department of Health and Human Performance, College of Health Professions, University of Texas Rio Grande Valley, Brownsville, Texas
| | - Dongmei Zhang
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Li N, Li G. Sphingolipid signaling in kidney diseases. Am J Physiol Renal Physiol 2025; 328:F431-F443. [PMID: 39933715 DOI: 10.1152/ajprenal.00193.2024] [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: 07/02/2024] [Revised: 07/22/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025] Open
Abstract
Sphingolipids are a family of bioactive lipids. The key components include ceramides, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. Sphingolipids were originally considered to be primarily structural elements of cell membranes but were later recognized as bioactive signaling molecules that play diverse roles in cellular behaviors such as cell differentiation, migration, proliferation, and death. Studies have demonstrated changes in key components of sphingolipids in the kidneys under different conditions and their important roles in the renal function and the pathogenesis of various kidney diseases. This review summarizes the most recent advances in the role of sphingolipid signaling in kidney diseases.
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Affiliation(s)
- Ningjun Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Guangbi Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
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Hill C, McKnight AJ, Smyth LJ. Integrated multiomic analyses: An approach to improve understanding of diabetic kidney disease. Diabet Med 2025; 42:e15447. [PMID: 39460977 PMCID: PMC11733670 DOI: 10.1111/dme.15447] [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: 06/06/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024]
Abstract
AIM Diabetes is increasing in prevalence worldwide, with a 20% rise in prevalence predicted between 2021 and 2030, bringing an increased burden of complications, such as diabetic kidney disease (DKD). DKD is a leading cause of end-stage kidney disease, with significant impacts on patients, families and healthcare providers. DKD often goes undetected until later stages, due to asymptomatic disease, non-standard presentation or progression, and sub-optimal screening tools and/or provision. Deeper insights are needed to improve DKD diagnosis, facilitating the identification of higher-risk patients. Improved tools to stratify patients based on disease prognosis would facilitate the optimisation of resources and the individualisation of care. This review aimed to identify how multiomic approaches provide an opportunity to understand the complex underlying biology of DKD. METHODS This review explores how multiomic analyses of DKD are improving our understanding of DKD pathology, and aiding in the identification of novel biomarkers to detect disease earlier or predict trajectories. RESULTS Effective multiomic data integration allows novel interactions to be uncovered and empathises the need for harmonised studies and the incorporation of additional data types, such as co-morbidity, environmental and demographic data to understand DKD complexity. This will facilitate a better understanding of kidney health inequalities, such as social-, ethnicity- and sex-related differences in DKD risk, onset and progression. CONCLUSION Multiomics provides opportunities to uncover how lifetime exposures become molecularly embodied to impact kidney health. Such insights would advance DKD diagnosis and treatment, inform preventative strategies and reduce the global impact of this disease.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Amy Jayne McKnight
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Laura J. Smyth
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
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Warmuzińska N, Łuczykowski K, Stryjak I, Wojtal E, Woderska-Jasińska A, Masztalerz M, Włodarczyk Z, Bojko B. Metabolomic and Lipidomic Profiling for Pre-Transplant Assessment of Delayed Graft Function Risk Using Chemical Biopsy with Microextraction Probes. Int J Mol Sci 2024; 25:13502. [PMID: 39769265 PMCID: PMC11728147 DOI: 10.3390/ijms252413502] [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: 11/27/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
Organ shortage remains a significant challenge in transplantology, prompting efforts to maximize the use of available organs and expand the donor pool, including through extended criteria donors (ECDs). However, ECD kidney recipients often face poorer outcomes, including a higher incidence of delayed graft function (DGF), which is linked to worse graft performance, reduced long-term survival, and an increased need for interventions like dialysis. This underscores the urgent need for strategies to improve early DGF risk assessment and optimize post-transplant management for high-risk patients. This study conducted multi-time point metabolomic and lipidomic analyses of donor kidney tissue and recipient plasma to identify compounds predicting DGF risk and assess the translational potential of solid-phase microextraction (SPME) for graft evaluation and early complication detection. The SPME-based chemical biopsy enabled a direct kidney analysis, while thin-film microextraction facilitated high-throughput plasma preparation. Following high-performance liquid chromatography coupled with a mass spectrometry analysis, the random forest algorithm was applied to identify compounds with predictive potential for assessing DGF risk before transplantation. Additionally, a comparison of metabolomic and lipidomic profiles of recipient plasma during the early post-operative days identified metabolites that distinguish between DGF and non-DGF patients. The selected compounds primarily included amino acids and their derivatives, nucleotides, organic acids, peptides, and lipids, particularly phospholipids and triacylglycerols. In conclusion, this study highlights the significant translational potential of chemical biopsies and plasma metabolite analyses for risk assessments and the non-invasive monitoring of DGF. The identified metabolites provide a foundation for developing a comprehensive DGF assessment and monitoring method, with potential integration into routine clinical practice.
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Affiliation(s)
- Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
| | - Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
| | - Iga Stryjak
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
| | - Emilia Wojtal
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Aleksandra Woderska-Jasińska
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Marek Masztalerz
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Zbigniew Włodarczyk
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
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Yang F, Zhang X, Huang J, Ma Y, Guo S, Liu Y, Wang P, Wang Y. Lumbrokinase (LK) ameliorates diabetic kidney disease renal fibrosis through regulating snail via m6A RNA methyltransferase 3. Sci Rep 2024; 14:28671. [PMID: 39562622 PMCID: PMC11576886 DOI: 10.1038/s41598-024-80168-w] [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: 04/24/2024] [Accepted: 11/15/2024] [Indexed: 11/21/2024] Open
Abstract
The present study was undertaken to investigate the therapeutic effect and underlying mechanisms of lumbrokinase (LK) on diabetic kidney disease (DKD). Kidney tissue samples from DKD patients and normal controls were collected from hospitals. The type 2 diabetic nephropathy model was induced in db/db mice. The mice were then randomly divided into a model group (DM group) and an LK group. db/m mice were used as the control group (Con group). After 12 weeks of treatment with LK (234 KU/kg/day), biochemical parameters were tested, and pathological changes in the kidney were observed under a light microscope. The epithelial-to-mesenchymal transition (EMT), mRNA m6A methylation proteins, and activated TGF-β1/Smad pathway components were assessed by western blot or immunofluorescence in DKD patients, model mice, and high glucose-stimulated HK-2 cells. We found that the m6A eraser METTL3 was expressed at low levels in DKD patients, model mice, and high glucose-stimulated HK-2 cells. METTL3 overexpression reversed the high glucose-induced activation of the TGF-β1/Smad pathway and EMT through snail in vitro. However, LK can restore the expression of the m6A-modifying enzyme METTL3 in vivo and in vitro, suppressed EMT, and alleviated renal interstitial fibrosis by downregulating snail. Overall, LK ameliorated renal fibrosis through the regulation of Snail via m6A RNA METTL3.
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Affiliation(s)
- Fan Yang
- Hebei University of Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei, China
| | - Xiaoyun Zhang
- Hebei University of Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei, China
| | - Jiaan Huang
- Hebei University of Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei, China
| | - Yun Ma
- Hebei University of Chinese Medicine, Hebei, China
- The First Hospital of Hebei University of Chinese Medicine, Hebei, China
| | - Shuai Guo
- The Third Hospital of Hebei Medical University, Hebei, China
| | - Yan Liu
- Hebei University of Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei, China
| | - Peng Wang
- Hebei University of Chinese Medicine, Hebei, China.
- The Second Hospital of Hebei University of Chinese Medicine, Hebei, China.
| | - Yuehua Wang
- Hebei University of Chinese Medicine, Hebei, China.
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei, China.
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7
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Cheval L, Poindessous V, Sampaio JL, Crambert G, Pallet N. Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications. FUNCTION 2024; 5:zqae016. [PMID: 38985001 PMCID: PMC11237892 DOI: 10.1093/function/zqae016] [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: 12/01/2023] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 07/11/2024] Open
Abstract
A detailed knowledge of the lipid composition of components of nephrons is crucial for understanding physiological processes and the development of kidney diseases. However, the lipidomic composition of kidney tubular segments is unknown. We manually isolated the proximal convoluted tubule (PCT), the cortical thick ascending limb of Henle's loop, and the cortical collecting duct from 5 lean and obese mice and subjected the samples to shotgun lipidomics analysis by high-resolution mass spectrometry acquisition. Across all samples, more than 500 lipid species were identified, quantified, and compared. We observed significant compositional differences among the 3 tubular segments, which serve as true signatures. These intrinsic lipidomic features are associated with a distinct proteomic program that regulates highly specific physiological functions. The distinctive lipidomic features of each of the 3 segments are mostly based on the relative composition of neutral lipids, long-chain polyunsaturated fatty acids, sphingolipids, and ether phospholipids. These features support the hypothesis of a lipotype assigned to specific tubular segments. Obesity profoundly impacts the lipotype of PCT. In conclusion, we present a comprehensive lipidomic analysis of 3 cortical segments of mouse kidney tubules. This valuable resource provides unparalleled detail that enhances our understanding of tubular physiology and the potential impact of pathological conditions.
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Affiliation(s)
- Lydie Cheval
- Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, 75006 Paris, France
- CNRS EMR 8228-Unité Métabolisme et Physiologie Rénale, 75006 Paris, France
| | - Virginie Poindessous
- Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, 75015, Paris, France
| | - Julio L Sampaio
- CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, 75005, Paris, France
| | - Gilles Crambert
- Laboratoire de Physiologie Rénale et Tubulopathies, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, 75006 Paris, France
- CNRS EMR 8228-Unité Métabolisme et Physiologie Rénale, 75006 Paris, France
| | - Nicolas Pallet
- Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, 75015, Paris, France
- Department of Clinical Chemistry, Assistance Publique Hôpitaux de Paris, Georges Pompidou European Hospital, 75015, Paris, France
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Lee LE, Doke T, Mukhi D, Susztak K. The key role of altered tubule cell lipid metabolism in kidney disease development. Kidney Int 2024; 106:24-34. [PMID: 38614389 PMCID: PMC11193624 DOI: 10.1016/j.kint.2024.02.025] [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: 02/26/2023] [Revised: 02/16/2024] [Accepted: 02/27/2024] [Indexed: 04/15/2024]
Abstract
Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism are observed in patients with kidney disease. Defects in fatty acid oxidation and increased lipid uptake, especially in the context of hyperlipidemia and proteinuria, contribute to this excess lipid build-up and exacerbate kidney disease development. Recent studies have also highlighted the role of increased de novo lipogenesis in kidney fibrosis. The defect in fatty acid oxidation causes energy starvation. Increased lipid uptake, synthesis, and lower fatty acid oxidation can cause toxic lipid build-up, reactive oxygen species generation, and mitochondrial damage. A better understanding of these metabolic processes may open new treatment avenues for kidney diseases by targeting lipid metabolism.
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Affiliation(s)
- Lauren E Lee
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn-Children's Hospital of Philadelphia Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Tomohito Doke
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn-Children's Hospital of Philadelphia Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn-Children's Hospital of Philadelphia Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn-Children's Hospital of Philadelphia Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
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9
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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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10
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Liang H, Kong X, Ren Y, Wang H, Liu E, Sun F, Zhu G, Zhang Q, Zhou Y. Application of serum Raman spectroscopy in rapid and early discrimination of aplastic anemia and myelodysplastic syndrome. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 302:123008. [PMID: 37328404 DOI: 10.1016/j.saa.2023.123008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/24/2023] [Accepted: 06/10/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Raman spectroscopy of hematological diseases has gained attention from various researchers. However, serum analysis of bone marrow failure (BMF), represented by aplastic anemia (AA) and myelodysplastic syndromes (MDS) has not been fully investigated. In this study, we aimed at establishing a simple, non-invasive serum detection method for AA and MDS. METHOD Serum samples from 35 AA patients (N = 35), MDS patients (N = 25), and control volunteers (N = 23) were systematically analyzed via laser Raman spectroscopy, and orthogonal partial least squares discrimination analysis (OPLS-DA). Then, discrimination models between the BMFs and control were constructed and evaluated using the prediction set. RESULTS Compared to control volunteers, serum spectral data for BMF patients were specific. The intensities of Raman peaks representing nucleic acids (726, 781, 786, 1078, 1190, 1415 cm-1), proteins (1221 cm-1), phospholipid/cholesterol (1285 cm-1), and β-carotene (1162 cm-1) significantly decreased, while the intensity of lipids (1437 and 1446 cm-1) significantly increased. Intensities of Raman peaks representing nucleic acids (726 cm-1) and collagen (1344 cm-1) in the AA group were significantly lower than in the control group. Intensities of Raman peaks representing nucleic acids (726 and 786 cm-1), proteins (1003 cm-1), and collagen (1344 cm-1) in the MDS group were significantly lower than those of the control group. The intensity of Raman peaks representing lipids (1437 and 1443 cm-1) in the MDS group was significantly higher than in the control group. Patients with AA and MDS exhibited increased serum triglyceride levels and decreased high-density lipoprotein levels. CONCLUSIONS The relationship between serological test data for patients and typing of AA and MDS provides essential information for rapid and early identification of BMF. This study shows the potential of Raman spectroscopy for non-invasive detection of different BMF types.
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Affiliation(s)
- Haoyue Liang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China
| | - Xiaodong Kong
- Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yansong Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China
| | - Haoyu Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China
| | - Ertao Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China
| | - Fanfan Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China
| | - Guoqing Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China.
| | - Qiang Zhang
- Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Yuan Zhou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China.
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11
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Chao Y, Li N, Xiong S, Zhang G, Gao S, Dong X. Lipidomics based on liquid chromatography-high resolution mass spectrometry reveals the protective role of peroxisome proliferator-activated receptor alpha on kidney stone formation in mice treated with glyoxylate. J Sep Sci 2023; 46:e2300452. [PMID: 37880903 DOI: 10.1002/jssc.202300452] [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: 06/25/2023] [Revised: 09/25/2023] [Accepted: 10/01/2023] [Indexed: 10/27/2023]
Abstract
Few studies have examined the relationship between lipid metabolism and kidney stone formation, particularly the role of key lipid regulatory factors in kidney stone formation. We evaluated the effect of the lipid regulatory factor-peroxisome proliferator-activated receptor alpha on the formation of renal stones in mice by injecting them with glyoxylate followed by treatment with either a peroxisome proliferator-activated receptor alpha agonist fenofibrate or an antagonist GW6471 (GW). Liquid chromatography coupled with trapped ion mobility spectrometry-quadrupole-time-of-flight mass spectrometry-based lipidomics was used to determine the lipid profile in the mouse kidneys. Histological and biochemical analyses showed that the mice injected with glyoxylate exhibited crystal precipitation and renal dysfunction. Crystallization decreased significantly in the fenofibrate group, whereas it increased significantly in the GW group. A total of 184 lipids, including fatty acyls, glycerolipids, glycerophospholipids, and sphingolipids differed significantly between the mice in the model and control groups. Peroxisome proliferator-activated receptor alpha activity negatively correlated with glyoxylate-induced kidney stone formation in mice, which may be related to improved fatty acid oxidation, maintenance of ceramide/complex sphingolipids cycle balance, and alleviation of disorder in phospholipid metabolism.
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Affiliation(s)
- Yufan Chao
- School of Medicine, Shanghai University, Shanghai, China
| | - Na Li
- School of Medicine, Shanghai University, Shanghai, China
| | - Shili Xiong
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Clinical Research Center, Shanghai Baoshan Luodian Hospital, Shanghai, China
| | - Guangbo Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Songyan Gao
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Xin Dong
- School of Medicine, Shanghai University, Shanghai, China
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12
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Kong J, Kui H, Tian Y, Kong X, He T, Li Q, Gu C, Guo J, Liu C. Nephrotoxicity assessment of podophyllotoxin-induced rats by regulating PI3K/Akt/mTOR-Nrf2/HO1 pathway in view of toxicological evidence chain (TEC) concept. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 264:115392. [PMID: 37651795 DOI: 10.1016/j.ecoenv.2023.115392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/04/2023] [Accepted: 08/19/2023] [Indexed: 09/02/2023]
Abstract
Adverse reactions to traditional Chinese medicine have hindered the healthy development and internationalization process of the traditional Chinese medicine industry. The critical issue that needs to be solved urgently is to evaluate the safety of traditional Chinese medicine systematically and effectively. Podophyllotoxin (PPT) is a highly active compound extracted from plants of the genus Podophyllum such as Dysosma versipellis (DV). However, its high toxicity and toxicity to multiple target organs affect the clinical application, such as the liver and kidney. Based on the concurrent effects of PPT's medicinal activity and toxicity, it would be a good example to conduct a systematic review of its safety. Therefore, this study revolves around the Toxicological Evidence Chain (TEC) concept. Based on PPT as the main toxic constituent in DV, observe the objective toxicity impairment phenotype of animals. Evaluate the serum biochemical indicators and pathological tissue sections for substantial toxic damage results. Using metabolomics, lipidomics, and network toxicology to evaluate the nephrotoxicity of PPT from multiple perspectives systematically. The results showed that PPT-induced nephrotoxicity manifested as renal tubular damage, mainly affecting metabolic pathways such as glycerophospholipid metabolism and sphingolipid metabolism. PPT inhibits the autophagy process of kidney cells through the PI3K/Akt/mTOR and Nrf2/HO1 pathways and induces the activation of oxidative stress in the body, thereby causing nephrotoxic injury. This study fully verified the feasibility of the TEC concept for the safety and toxicity evaluation of traditional Chinese medicine. Provide a research template for systematically evaluating the safety of traditional Chinese medicine.
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Affiliation(s)
- Jiao Kong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Fangshan District, Beijing 102488, China; Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Hongqian Kui
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Fangshan District, Beijing 102488, China
| | - Yue Tian
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Fangshan District, Beijing 102488, China
| | - Xianbin Kong
- College of Traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Tao He
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Fangshan District, Beijing 102488, China; Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qingbo Li
- College of Traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Chunyu Gu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Fangshan District, Beijing 102488, China
| | - Jinhe Guo
- College of Traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Chuanxin Liu
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Fangshan District, Beijing 102488, China.
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13
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Hirtzel E, Edwards M, Freitas D, Liu Z, Wang F, Yan X. Aziridination-Assisted Mass Spectrometry of Nonpolar Sterol Lipids with Isomeric Resolution. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2023; 34:1998-2005. [PMID: 37523498 PMCID: PMC10863044 DOI: 10.1021/jasms.3c00161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 08/02/2023]
Abstract
Characterization of nonpolar lipids is crucial due to their essential biological functions and ability to exist in various isomeric forms. In this study, we introduce the N-H aziridination method to target carbon-carbon double bonds (C═C bonds) in nonpolar sterol lipids. The resulting fragments are readily dissociated upon collision-induced dissociation, generating specific fragment ions for C═C bond position determination and fingerprint fragments for backbone characterization. This method significantly enhances lipid ionization efficiency, thereby improving the sensitivity and accuracy of nonpolar lipid analysis. We demonstrated that aziridination of sterols leads to distinctive fragmentation pathways for chain and ring C═C bonds, enabling the identification of sterol isomers such as desmosterol and 7-dehydrocholesterol. Furthermore, aziridination can assist in identifying the sterol backbone by providing fingerprint tandem mass spectra. We also demonstrated the quantitative capacity of this approach with a limit of detection of 10 nM in the solvent mixture of methanol and water. To test the feasibility of this method in complex biological samples, we used mouse prostate cancerous tissues and found significant differences in nonpolar lipid profiles between healthy and cancerous samples. The high efficiency and specificity of aziridination-assisted mass spectrometric analysis, as well as its quantitative analysis ability, make it highly suitable for broad applications in nonpolar lipid research.
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Affiliation(s)
- Erin Hirtzel
- Department
of Chemistry, Texas A&M University, College Station, Texas 77843, United States
| | - Madison Edwards
- Department
of Chemistry, Texas A&M University, College Station, Texas 77843, United States
| | - Dallas Freitas
- Department
of Chemistry, Texas A&M University, College Station, Texas 77843, United States
| | - Ziying Liu
- Center
for Translational Cancer Research, Texas
A&M University, Houston, Texas 77030, United States
| | - Fen Wang
- Center
for Translational Cancer Research, Texas
A&M University, Houston, Texas 77030, United States
| | - Xin Yan
- Department
of Chemistry, Texas A&M University, College Station, Texas 77843, United States
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14
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Rietjens RGJ, Wang G, van der Velden AIM, Koudijs A, Avramut MC, Kooijman S, Rensen PCN, van der Vlag J, Rabelink TJ, Heijs B, van den Berg BM. Phosphatidylinositol metabolism of the renal proximal tubule S3 segment is disturbed in response to diabetes. Sci Rep 2023; 13:6261. [PMID: 37069341 PMCID: PMC10110589 DOI: 10.1038/s41598-023-33442-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/12/2023] [Indexed: 04/19/2023] Open
Abstract
Diabetes is a main risk factor for kidney disease, causing diabetic nephropathy in close to half of all patients with diabetes. Metabolism has recently been identified to be decisive in cell fate decisions and repair. Here we used mass spectrometry imaging (MSI) to identify tissue specific metabolic dysregulation, in order to better understand early diabetes-induced metabolic changes of renal cell types. In our experimental diabetes mouse model, early glomerular glycocalyx barrier loss and systemic metabolic changes were observed. In addition, MSI targeted at small molecule metabolites and glycero(phospho)lipids exposed distinct changes upon diabetes in downstream nephron segments. Interestingly, the outer stripe of the outer medullar proximal tubular segment (PT_S3) demonstrated the most distinct response compared to other segments. Furthermore, phosphatidylinositol lipid metabolism was altered specifically in PT_S3, with one of the phosphatidylinositol fatty acid tails being exchanged from longer unsaturated fatty acids to shorter, more saturated fatty acids. In acute kidney injury, the PT_S3 segment and its metabolism are already recognized as important factors in kidney repair processes. The current study exposes early diabetes-induced changes in membrane lipid composition in this PT_S3 segment as a hitherto unrecognized culprit in the early renal response to diabetes.
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Affiliation(s)
- Rosalie G J Rietjens
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Gangqi Wang
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Anouk I M van der Velden
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Angela Koudijs
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - M Cristina Avramut
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Cell and Chemical Biology (Electron Microscopy), Leiden University Medical Center, Leiden, The Netherlands
| | - Sander Kooijman
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Patrick C N Rensen
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine (Endocrinology), Leiden University Medical Center, Leiden, The Netherlands
| | - Johan van der Vlag
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ton J Rabelink
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Bram Heijs
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Bernard M van den Berg
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.
- Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands.
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands.
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15
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Hou Y, Ding T, Guan Z, Wang J, Yao R, Yu Z, Zhao X. Untargeted metabolomics reveals the preventive effect of quercetin on nephrotoxicity induced by four organophosphorus pesticide mixtures. Food Chem Toxicol 2023; 175:113747. [PMID: 36997054 DOI: 10.1016/j.fct.2023.113747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023]
Abstract
This research aimed to explore the protective effect of quercetin against nephrotoxicity induced by four organophosphate pesticide mixtures (PM) using untargeted metabolomics technology in rat kidneys. Sixty male Wistar rats were randomly divided into six groups: control, low-dose quercetin treated (10 mg/kg. bw), high-dose quercetin treated (50 mg/kg. bw), PM-treated, and two dosages of quercetin + PM-treated. Metabolomics results showed that 17 differential metabolites were identified in the PM-treated group, and pathway analysis revealed that renal metabolic disorders include purine metabolism, glycerophospholipid metabolism, and vitamin B6 metabolism. When high-dose quercetin and PM-treated were administered to rats concurrently, the intensities of differential metabolites were substantially restored (p < 0.01), suggesting that quercetin can improve renal metabolic disorders caused by organophosphate pesticides (OPs). Mechanistically, quercetin could regulate the purine metabolism disorder and endoplasmic reticulum stress (ERS)-mediated autophagy induced by OPs by inhibiting XOD activity. Moreover, quercetin inhibits PLA2 activity to regulate glycerophospholipid metabolism and it could also exert antioxidant and anti-inflammatory effects to correct vitamin B6 metabolism in rat kidneys. Taken together, the high dose of quercetin (50 mg/kg.bw) has a certain protective effect on OPs-induced nephrotoxicity in rats, which provides a theoretical basis for quercetin against nephrotoxicity caused by OPs.
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16
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Mohandes S, Doke T, Hu H, Mukhi D, Dhillon P, Susztak K. Molecular pathways that drive diabetic kidney disease. J Clin Invest 2023; 133:165654. [PMID: 36787250 PMCID: PMC9927939 DOI: 10.1172/jci165654] [Citation(s) in RCA: 131] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney disease (DKD) is responsible for close to half of all chronic kidney disease cases. DKD usually develops in a genetically susceptible individual as a result of poor metabolic (glycemic) control. Molecular and genetic studies indicate the key role of podocytes and endothelial cells in driving albuminuria and early kidney disease in diabetes. Proximal tubule changes show a strong association with the glomerular filtration rate. Hyperglycemia represents a key cellular stress in the kidney by altering cellular metabolism in endothelial cells and podocytes and by imposing an excess workload requiring energy and oxygen for proximal tubule cells. Changes in metabolism induce early adaptive cellular hypertrophy and reorganization of the actin cytoskeleton. Later, mitochondrial defects contribute to increased oxidative stress and activation of inflammatory pathways, causing progressive kidney function decline and fibrosis. Blockade of the renin-angiotensin system or the sodium-glucose cotransporter is associated with cellular protection and slowing kidney function decline. Newly identified molecular pathways could provide the basis for the development of much-needed novel therapeutics.
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Affiliation(s)
- Samer Mohandes
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tomohito Doke
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hailong Hu
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Poonam Dhillon
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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17
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Sun ZJ, Chang DY, Chen M, Zhao MH. Deficiency of CFB attenuates renal tubulointerstitial damage by inhibiting ceramide synthesis in diabetic kidney disease. JCI Insight 2022; 7:156748. [PMID: 36546481 PMCID: PMC9869976 DOI: 10.1172/jci.insight.156748] [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: 11/15/2021] [Accepted: 11/09/2022] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence suggests the pathogenic role of immunity and metabolism in diabetic kidney disease (DKD). Herein, we aimed to investigate the effect of complement factor B (CFB) on lipid metabolism in the development of DKD. We found that in patients with diabetic nephropathy, the staining of Bb, CFB, C3a, C5a, and C5b-9 was markedly elevated in renal tubulointerstitium. Cfb-knockout diabetic mice had substantially milder tubulointerstitial injury and less ceramide biosynthesis. The in vitro study demonstrated that cytokine secretion, endoplasmic reticulum stress, oxidative stress, and cell apoptosis were ameliorated in HK-2 cells transfected with siRNA of CFB under high-glucose conditions. Exogenous ceramide supplementation attenuated the protective effect of CFB knockdown in HK-2 cells, while inhibiting ceramide synthases (CERS) with fumonisin B1 in CFB-overexpressing cells rescued the cell injury. CFB knockdown could downregulate the expression of NF-κB p65, which initiates the transcription of CERS3. Furthermore, C3 knockdown abolished CFB-mediated cytokine secretion, NF-κB signaling activation, and subsequently ceramide biosynthesis. Thus, CFB deficiency inhibited activation of the complement alternative pathway and attenuated kidney damage in DKD, especially tubulointerstitial injury, by inhibiting the NF-κB signaling pathway, further blocking the transcription of CERS, which regulates the biosynthesis of ceramide. CFB may be a promising therapeutic target of DKD.
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Affiliation(s)
- Zi-jun Sun
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Dong-yuan Chang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Ming-hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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18
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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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19
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The Contribution of Lipotoxicity to Diabetic Kidney Disease. Cells 2022; 11:cells11203236. [PMID: 36291104 PMCID: PMC9601125 DOI: 10.3390/cells11203236] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/02/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
Lipotoxicity is a fundamental pathophysiologic mechanism in diabetes and non-alcoholic fatty liver disease and is now increasingly recognized in diabetic kidney disease (DKD) pathogenesis. This review highlights lipotoxicity pathways in the podocyte and proximal tubule cell, which are arguably the two most critical sites in the nephron for DKD. The discussion focuses on membrane transporters and lipid droplets, which represent potential therapeutic targets, as well as current and developing pharmacologic approaches to reduce renal lipotoxicity.
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20
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Mallela SK, Merscher S, Fornoni A. Implications of Sphingolipid Metabolites in Kidney Diseases. Int J Mol Sci 2022; 23:ijms23084244. [PMID: 35457062 PMCID: PMC9025012 DOI: 10.3390/ijms23084244] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/08/2022] [Accepted: 04/10/2022] [Indexed: 12/18/2022] Open
Abstract
Sphingolipids, which act as a bioactive signaling molecules, are involved in several cellular processes such as cell survival, proliferation, migration and apoptosis. An imbalance in the levels of sphingolipids can be lethal to cells. Abnormalities in the levels of sphingolipids are associated with several human diseases including kidney diseases. Several studies demonstrate that sphingolipids play an important role in maintaining proper renal function. Sphingolipids can alter the glomerular filtration barrier by affecting the functioning of podocytes, which are key cellular components of the glomerular filtration barrier. This review summarizes the studies in our understanding of the regulation of sphingolipid signaling in kidney diseases, especially in glomerular and tubulointerstitial diseases, and the potential to target sphingolipid pathways in developing therapeutics for the treatment of renal diseases.
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Affiliation(s)
- Shamroop kumar Mallela
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Correspondence: (S.M.); (A.F.); Tel.: +1-305-243-6567 (S.M.); +1-305-243-3583 (A.F.); Fax: +1-305-243-3209 (S.M.); +1-305-243-3506 (A.F.)
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Correspondence: (S.M.); (A.F.); Tel.: +1-305-243-6567 (S.M.); +1-305-243-3583 (A.F.); Fax: +1-305-243-3209 (S.M.); +1-305-243-3506 (A.F.)
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21
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LPCing through the nephron accelerates diabetic kidney disease. Kidney Int 2022; 101:454-456. [DOI: 10.1016/j.kint.2021.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 11/23/2022]
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22
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Hu C, Zhuang X, Zhang J, Wang T, Du S, Wang J, Peng X, Cao Q, Zhang M, Jiang Y. Serum Metabolomics in Patients with Coexisting NAFLD and T2DM Using Liquid Chromatography-Mass Spectrometry. Lab Med 2022; 53:360-368. [PMID: 35075477 DOI: 10.1093/labmed/lmab118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist and can act synergistically to drive adverse outcomes of one another. This study aimed to unravel the metabolomic changes in patients with NAFLD and T2DM, to identify potential noninvasive biomarkers, and to provide insights for understanding the link between NAFLD and T2DM. METHODS Three hundred participants aged 35 to 70 years who were diagnosed with NAFLD (n = 100), T2DM (n = 100), or a comorbidity of NAFLD and T2DM (n = 100) were included in this study. Anthropometrics and routine blood chemistry were assessed after overnight fast. The global serum metabolomic analysis was performed by ultra-performance liquid chromatography-Orbitrap mass spectrometry. Multivariate data analysis methods were utilized to identify the potential biomarkers. RESULTS A set of serum biomarkers that could effectively separate NAFLD from NAFLD + T2DM and T2DM from NAFLD + T2DM were identified. We found that patients with coexisting NAFLD and T2DM had significantly higher levels of total protein (TP), triglycerides (TG), glucose in urine, and gamma-hydroxybutyric acid than those with NAFLD and had significant increased levels of TP, albumin, alanine aminotransferase, aspartate aminotransferase, total cholesterol, cholinesterase, TG, low-density lipoprotein, and apolipoprotein A when compared to patients with T2DM. CONCLUSION The metabolomics results provide evidence that the comorbidity of NAFLD and T2DM considerably altered patients' metabolomics patterns compared to those of patients with only NAFLD or T2DM.
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Affiliation(s)
- Cheng Hu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoyu Zhuang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiaqi Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai TCM-Integrated Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengnan Du
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinping Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xuelian Peng
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qin Cao
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingcai Zhang
- Shuguang Hospital affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanye Jiang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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23
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Iizuka K. Commentary: Comprehensive lipidome profiling of the kidney in early-stage diabetic nephropathy. Front Endocrinol (Lausanne) 2022; 13:1015305. [PMID: 36176464 PMCID: PMC9513222 DOI: 10.3389/fendo.2022.1015305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
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24
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Wang W, Li T, Li Z, Wang H, Liu X. Differential lipidomics of HK-2 cells and exosomes under high glucose stimulation. Int J Med Sci 2022; 19:393-401. [PMID: 35165524 PMCID: PMC8795806 DOI: 10.7150/ijms.67326] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/28/2021] [Indexed: 12/02/2022] Open
Abstract
Abnormal cellular lipid metabolism has a very important role in the occurrence and progression of diabetic kidney disease (DKD). However, the lipid composition and differential expression by high glucose stimulation of renal tubular cells and their exosomes, which is a vital part of the development of DKD, are largely unknown. In this study, based on targeted lipid analysis by isotope labeling and tandem mass spectrometry, a total of 421 and 218 lipid species were quantified in HK-2 cells and exosomes, respectively. More importantly, results showed that GM3 d18:1/22:0, GM3 d18:1/16:0, GM3 d18:0/16:0, GM3 d18:1/22:1 were significantly increased, while LPE18:1, LPE, CL66:4 (16:1), BMP36:3, CL70:7 (16:1), CL74:8 (16:1) were significantly decreased in high glucose-stimulated HK-2 cells. Also, PG36:1, FFA22:5, PC38:3, SM d18:1/16:1, CE-16:1, CE-18:3, CE-20:5, and CE-22:6 were significantly increased, while GM3 d18:1/24:1, GM3 were significantly decreased in exosomes secreted by high glucose-stimulated HK-2 cells. Furthermore, TAG, PC, CL were decreased significantly in the exosomes comparing with the HK-2 cells, and LPA18:2, LPI22:5, PG32:2, FFA16:1, GM3 d18:1/18:1, GM3 d18:1/20:1, GM3 d18:0/20:0, PC40:6p, TAG52:1(18:1), TAG52:0(18:0), CE-20:5, CE-20:4, CE-22:6 were only found in exosomes. In addition, the expression of PI4P in HK-2 cells decreased under a high glucose state. These data may be useful to provide new targets for exploring the mechanisms of DKD.
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Affiliation(s)
- Weidong Wang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, P.R. China, 110001
| | - Tingting Li
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, P.R. China, 110001
| | - Zhijie Li
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, P.R. China, 110001
| | - Hongmiao Wang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, P.R. China, 110001
| | - Xiaodan Liu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, P.R. China, 110001
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25
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Moreno-Gordaliza E, Marazuela MD, Pastor Ó, Lázaro A, Gómez-Gómez MM. Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin. Int J Mol Sci 2021; 22:ijms222212521. [PMID: 34830406 PMCID: PMC8622622 DOI: 10.3390/ijms222212521] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/07/2021] [Accepted: 11/17/2021] [Indexed: 12/02/2022] Open
Abstract
Nephrotoxicity is a major complication of cisplatin-based chemotherapy, leading to acute kidney injury in ca. 30% of patients, with no preventive intervention or treatment available for clinical use. Cilastatin has proved to exert a nephroprotective effect for cisplatin therapies in in vitro and in vivo models, having recently entered clinical trials. A deeper understanding at the molecular level of cisplatin-induced renal damage and the effect of potential protective agents could be key to develop successful nephroprotective therapies and to establish new biomarkers of renal damage and nephroprotection. A targeted lipidomics approach, using LC-MS/MS, was employed for the quantification of 108 lipid species (comprising phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin. Up to 56 and 63 lipid species were found to be altered in the cortex and medulla, respectively, after cisplatin treatment. Co-treatment with cilastatin attenuated many of these lipid changes, either totally or partially with respect to control levels. Multivariate analysis revealed that lipid species can be used to discriminate renal damage and nephroprotection, with cholesterol esters being the most discriminating species, along with sulfatides and phospholipids. Potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were also found.
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Affiliation(s)
- Estefanía Moreno-Gordaliza
- Department of Analytical Chemistry, Faculty of Chemistry, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.D.M.); (M.M.G.-G.)
- Correspondence:
| | - Maria Dolores Marazuela
- Department of Analytical Chemistry, Faculty of Chemistry, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.D.M.); (M.M.G.-G.)
| | - Óscar Pastor
- Servicio de Bioquímica Clínica, UCA-CCM, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
| | - Alberto Lázaro
- Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain;
- Department of Physiology, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Milagros Gómez-Gómez
- Department of Analytical Chemistry, Faculty of Chemistry, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.D.M.); (M.M.G.-G.)
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26
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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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27
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Mitrofanova A, Burke G, Merscher S, Fornoni A. New insights into renal lipid dysmetabolism in diabetic kidney disease. World J Diabetes 2021; 12:524-540. [PMID: 33995842 PMCID: PMC8107981 DOI: 10.4239/wjd.v12.i5.524] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/31/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs, including the kidney. Research suggests that impaired cholesterol metabolism, increased lipid uptake or synthesis, increased fatty acid oxidation, lipid droplet accumulation and an imbalance in biologically active sphingolipids (such as ceramide, ceramide-1-phosphate and sphingosine-1-phosphate) contribute to the development of diabetic kidney disease (DKD). Currently, the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production, oxidative stress, inflammation, or cell death. Therefore, control of renal lipid dysmetabolism is a very important therapeutic goal, which needs to be archived. This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.
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Affiliation(s)
- Alla Mitrofanova
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - George Burke
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - Sandra Merscher
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
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28
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Gu Y, Gao M, Zhang W, Yan L, Shao F, Zhou J. Exposure to phthalates DEHP and DINP May lead to oxidative damage and lipidomic disruptions in mouse kidney. CHEMOSPHERE 2021; 271:129740. [PMID: 33736212 DOI: 10.1016/j.chemosphere.2021.129740] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 05/26/2023]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) has been well acknowledged for its endocrine disruption and associated metabolic diseases, leading to the search for safer industrial alternatives including di-isononyl phthalate (DINP). However, safety data for the latter chemical has been relatively scarce particularly regarding potential damage to the kidney at low doses. Five-week-old ICR male mice were exposed to vehicle, DEHP or DINP (0.05 and 4.8 mg/kg bw) daily via gavage for 5 weeks. We observed increased levels of reactive oxygen species and malondialdehyde, decreased levels of reduced glutathione, in the kidney at higher dose for both chemicals suggestive of oxidative damage. Elevated levels of inflammatory cytokines tumor necrosis factor-α and interleukin-6 of the kidney further suggested inflammatory status as a result of phthalate exposure in both high dose groups. Targeted lipidomics demonstrated greatest changes in the kidney induced by high dose of DEHP, although DINP also induced significant changes in phospholipids diacylglycerides that are associated with lipid accumulation in glomerular podocytes and inflammatory responses. Our data suggest that oxidative stress may be involved in both DEHP- and DINP-induced renal lipidomic disruption and continue to question the suitability of DINP as proper DEHP substitute.
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Affiliation(s)
- Yue Gu
- Department of Nephrology, Henan Provincial People's Hospital and the People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Mei Gao
- Department of Nephrology, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Wenwen Zhang
- Department of Nephrology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Lei Yan
- Department of Nephrology, Henan Provincial People's Hospital and the People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Fengmin Shao
- Department of Nephrology, Henan Provincial People's Hospital and the People's Hospital of Zhengzhou University, Zhengzhou, China.
| | - Jing Zhou
- Department of Health Management, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, China.
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29
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Hirudo Lyophilized Powder Ameliorates Renal Injury in Diabetic Rats by Suppressing Oxidative Stress and Inflammation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6657673. [PMID: 33688363 PMCID: PMC7920712 DOI: 10.1155/2021/6657673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/15/2021] [Accepted: 02/06/2021] [Indexed: 12/25/2022]
Abstract
As diabetic nephropathy (DN) is one of the most common and destructive microvascular complications of diabetes mellitus, the goal of this study, therefore, was to investigate the renal protective effect and latent mechanisms of Hirudo lyophilized powder on diabetic rats. In this study, all rats were randomly assigned into the control group and diabetic group. The rats of diabetic group were injected with low-dose STZ (35 mg/kg) intraperitoneal plus high-fat diet to induce diabetes. Then, the successful diabetic model rats were weighed and randomly assigned into four groups: (1) diabetic model group (DM group); (2) Hirudo lyophilized powder 0.3 g/kg treatment group (SL group); (3) Hirudo lyophilized powder 0.6 g/kg treatment group (SM group); (4) Hirudo lyophilized powder 1.2 g/kg treatment group (SH group). Their fasting blood glucoses (FBG) were measured every 4 weeks. After treatment with Hirudo lyophilized powder at a corresponding dose once a day for 16 weeks, their metabolic and biochemical as well as oxidative stress parameters were tested, and the kidney weight (KW)/body weight (BW) was calculated. The renal tissues were used for histological, mRNA, and protein expression analysis. The results showed that Hirudo lyophilized powder could protect against the structural damages and functional changes of diabetic renal tissue by inhibiting oxidative stress, inflammation, and fibrosis. Furthermore, it was found in the further research that inhibiting the NOX4 expression and JAK2/STAT1/STAT3 pathway activation might be the underlying mechanisms. Collectively, Hirudo lyophilized powder might be a promising therapeutic agent for the treatment of DN.
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30
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Nicholson RJ, Pezzolesi MG, Summers SA. Rotten to the Cortex: Ceramide-Mediated Lipotoxicity in Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2021; 11:622692. [PMID: 33584550 PMCID: PMC7876379 DOI: 10.3389/fendo.2020.622692] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 12/11/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetic kidney disease (DKD) is a prevalent and progressive comorbidity of diabetes mellitus that increases one's risk of developing renal failure. Progress toward development of better DKD therapeutics is limited by an incomplete understanding of forces driving and connecting the various features of DKD, which include renal steatosis, fibrosis, and microvascular dysfunction. Herein we review the literature supporting roles for bioactive ceramides as inducers of local and systemic DKD pathology. In rodent models of DKD, renal ceramides are elevated, and genetic and pharmacological ceramide-lowering interventions improve kidney function and ameliorate DKD histopathology. In humans, circulating sphingolipid profiles distinguish human DKD patients from diabetic controls. These studies highlight the potential for ceramide to serve as a central and therapeutically tractable lipid mediator of DKD.
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Affiliation(s)
- Rebekah J. Nicholson
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, United States
- Diabetes and Metabolism Research Center, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - Marcus G. Pezzolesi
- Diabetes and Metabolism Research Center, University of Utah School of Medicine, Salt Lake City, UT, United States
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Scott A. Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, United States
- Diabetes and Metabolism Research Center, University of Utah School of Medicine, Salt Lake City, UT, United States
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