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Li Y, Zhang Y, Cao M, Yuan T, Ou S. Angiopoietin-like protein 4 dysregulation in kidney diseases: a promising biomarker and therapeutic target. Front Pharmacol 2025; 15:1475198. [PMID: 39840089 PMCID: PMC11747783 DOI: 10.3389/fphar.2024.1475198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/20/2024] [Indexed: 01/23/2025] Open
Abstract
The global burden of renal diseases is increasingly severe, underscoring the need for in-depth exploration of the molecular mechanisms underlying renal disease progression and the development of potential novel biomarkers or therapeutic targets. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine involved in the regulation of key biological processes, such as glucose and lipid metabolism, inflammation, vascular permeability, and angiogenesis, all of which play crucial roles in the pathogenesis of kidney diseases. Over the past 2 decades, ANGPTL4 has been regarded as playing a pivotal role in the progression of various kidney diseases, prompting significant interest from the scientific community regarding its potential clinical utility in renal disorders. This review synthesizes the available literature, provides a concise overview of the molecular biological effects of ANGPTL4, and highlights its relationship with multiple renal diseases and recent research advancements. These findings underscore the important gaps that warrant further investigation to develop novel targets for the prediction or treatment of various renal diseases.
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Affiliation(s)
- Yan Li
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephrology, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
| | - Yuxin Zhang
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephrology, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
| | - Mengxia Cao
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephrology, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
| | - Tingting Yuan
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephrology, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
| | - Santao Ou
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephrology, Luzhou, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
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Liu X, Wang S, Liu G, Wang Y, Shang S, Zou G, Jiang S, Wang X, Yang L, Li W. Advancing the clinical assessment of glomerular podocyte pathology in kidney biopsies via super-resolution microscopy and angiopoietin-like 4 staining. Theranostics 2025; 15:784-803. [PMID: 39776814 PMCID: PMC11700855 DOI: 10.7150/thno.101498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 11/15/2024] [Indexed: 01/11/2025] Open
Abstract
Rationale: The tertiary structure of normal podocytes prevents protein from leaking into the urine. However, observing the complexity of podocytes is challenging because of the scale differences in their three-dimensional structure and the close proximity between neighboring cells in space. In this study, we explored podocyte-secreted angiopoietin-like 4 (ANGPTL4) as a potential morphological marker via super-resolution microscopy (SRM). Methods and Results: Specimens from patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), along with normal controls, were analyzed via immunofluorescence and immunohistochemistry to determine the expression and localization of ANGPTL4, confirming its extensive presence in podocytes across both healthy and diseased conditions. Immunoelectron microscopy revealed that ANGPTL4 is distributed throughout the podocyte cell body, primary processes, and foot processes. Compared with conventional podocyte markers such as nephrin and synaptopodin, ANGPTL4 excels in depicting the three-dimensional structure of podocytes via SRM imaging. We then refined a protocol using tyramide signal amplification staining and confocal microscopy to uniformly enhance podocyte fluorescence, facilitating the clinical assessment of biopsies. In patients diagnosed with MCD and FSGS, measurements of slit diaphragm density, primary process width, and foot process width were taken after further co-staining with nephrin to identify patterns of podocyte morphological alterations. Distinctive patterns of foot process effacement were identified in MCD and FSGS patients, with FSGS patients showing more pronounced podocyte injury. Conclusions: ANGPTL4 serves as a reliable morphological marker for podocyte analysis, offering enhanced visualization of their three-dimensional structure and facilitating the identification of distinct pathological changes in nephrotic syndrome patients.
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Affiliation(s)
- Xiaojing Liu
- Department of Nephrology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, 100029, China
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Suxia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, 100034, China
| | - Gang Liu
- Renal Division, Peking University Institute of Nephrology, Key Laboratory of Renal Disease-Ministry of Health of China, Peking University First Hospital, Beijing, 100034, China
| | - Yan Wang
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Shunlai Shang
- Department of Nephrology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, 100029, China
| | - Guming Zou
- Department of Nephrology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, 100029, China
| | - Shimin Jiang
- Department of Nephrology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, 100029, China
| | - Xuliang Wang
- The Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310000, China
| | - Li Yang
- Renal Division, Peking University Institute of Nephrology, Key Laboratory of Renal Disease-Ministry of Health of China, Peking University First Hospital, Beijing, 100034, China
| | - Wenge Li
- Department of Nephrology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, 100029, China
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
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Srivastava SP, Zhou H, Shenoi R, Morris M, Lainez-Mas B, Goedeke L, Rajendran BK, Setia O, Aryal B, Kanasaki K, Koya D, Inoki K, Dardik A, Bell T, Fernández-Hernando C, Shulman GI, Goodwin JE. Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease. SCIENCE ADVANCES 2024; 10:eadn6068. [PMID: 39630889 PMCID: PMC11616692 DOI: 10.1126/sciadv.adn6068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 10/30/2024] [Indexed: 12/07/2024]
Abstract
Angiopoietin-like 4 (ANGPTL4), a key protein involved in lipoprotein metabolism, has diverse effects. There is an association between Angptl4 and diabetic kidney disease; however, this association has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in stimulator of interferon genes pathway activation, expression of pro-inflammatory cytokines, reduced epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, lessened mitochondrial damage, and increased fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Angptl4 interacts with Integrin β1 and influences the association between dipeptidyl-4 with Integrin β1. We demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the kidneys and protects diabetic kidneys from proteinuria and fibrosis. Together, these data demonstrate that podocyte- and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Han Zhou
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
| | - Rachel Shenoi
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Myshal Morris
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Begoña Lainez-Mas
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
| | - Leigh Goedeke
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Medicine (Cardiology), The Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Ocean Setia
- Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT, USA
| | - Binod Aryal
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Keizo Kanasaki
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- The Center for Integrated Kidney Research and Advance, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Ken Inoki
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Alan Dardik
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT, USA
| | | | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Gerald I. Shulman
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
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Wang Y, Li K, Yuan S, Yu C, Yin R, Wang D, Xu Y, Zhang L, Wei L, Cheng Y, Mao L, Zhao D, Yang L. Angiopoietin-like 4 is a potential biomarker for diabetic kidney disease in type 2 diabetes patients. J Diabetes Investig 2024; 15:1763-1772. [PMID: 39264678 PMCID: PMC11615698 DOI: 10.1111/jdi.14304] [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: 04/19/2024] [Revised: 07/01/2024] [Accepted: 08/15/2024] [Indexed: 09/13/2024] Open
Abstract
AIMS/INTRODUCTION The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. METHODS A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. RESULTS Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. CONCLUSIONS ANGPTL4 could be a potential marker and therapeutic target for DKD treatment.
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Affiliation(s)
- Yan Wang
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Kun Li
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Shasha Yuan
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Caiguo Yu
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Ruili Yin
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Di Wang
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Yongsong Xu
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Lijie Zhang
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Lingling Wei
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Yanan Cheng
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Lin Mao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
| | - Longyan Yang
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
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Jiang L, Wang S, Tan Y, Su T. Postpartum Renal Cortical Necrosis: A Case Series. Kidney Med 2024; 6:100892. [PMID: 39314861 PMCID: PMC11417324 DOI: 10.1016/j.xkme.2024.100892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024] Open
Abstract
Rationale & Objective Postpartum renal cortical necrosis (postpartum RCN) is a severe form of obstetric acute kidney injury. This study aimed to identify clinicopathologic features in Chinese postpartum RCN cases to determine how pathologic findings may contribute to the treatment and prognosis. Study Design Single-center, case series. Setting & Participants Twelve patients with postpartum RCN had kidney biopsies at Peking University First Hospital between 2014 and 2021. The diagnosis of postpartum RCN was made according to typical magnetic resonance imaging or pathologic features. Clinical, laboratory, and pathologic data were compared between patients with estimated glomerular filtration rate <30 (poor outcome) and ≥30 mL/min/1.73 m2 after 6 months. Observations All patients with postpartum RCN presented with stage 3 acute kidney injury attributed to a probable atypical hemolytic uremic syndrome. Pregnancy terminations occurred at a median gestational age of 35.5 weeks. Kidney biopsy was performed from 18 days to 4 months from delivery. On biopsy, hemoglobin, platelet count, and lactate dehydrogenase levels had been restored to 137 g/L, 214 × 109/L, and 231.50 ± 65.01 U/L, respectively. Four patients exhibited poor outcome, demonstrating higher schistocyte count, serum creatinine, and mean arterial pressure at onset. Pathologically, glomerular segmental sclerosis was prevalent. The "not otherwise specified" variant was the most common type, followed by collapsing variant, cellular variant, and tip variant. Patients with poor kidney outcome had more glomerular coagulative necrosis, capillary thrombosis, extensive cortical coagulative necrosis, and pronounced arteriole/artery lesions including increased interlobular arteriole intimal edema and fibrin thrombosis, but a lower occurrence of segmental sclerosis. Limitations Limited sample size and retrospective design. Conclusions We identified key pathologic features in patients with postpartum RCN and atypical hemolytic uremic syndrome, highlighting the necessity for more effective therapeutic options. There is a clear demand for noninvasive biomarkers that can accurately track disease progression and inform treatment duration for long-term outcomes improvement.
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Affiliation(s)
- Lei Jiang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, China
| | - Suxia Wang
- Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, China
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Ying Tan
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, China
| | - Tao Su
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, China
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Chen J, Zhao D, Wang Y, Liu M, Zhang Y, Feng T, Xiao C, Song H, Miao R, Xu L, Chen H, Qiu X, Xu Y, Xu J, Cui Z, Wang W, Quan Y, Zhu Y, Huang C, Zheng SG, Zhao J, Zhu T, Sun L, Fan G. Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406333. [PMID: 38981044 PMCID: PMC11481198 DOI: 10.1002/advs.202406333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Indexed: 07/11/2024]
Abstract
Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.
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Affiliation(s)
- Jian Chen
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
- Department of Thoracic Surgery, Shanghai Pulmonary HospitalTongji University507 Zhengmin RoadShanghai200433P. R. China
| | - Deping Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary HospitalTongji University507 Zhengmin RoadShanghai200433P. R. China
| | - Yupeng Wang
- Department of General Surgery, Shanghai Ninth People's HospitalShanghai JiaoTong University School of MedicineShanghai200011P. R. China
| | - Ming Liu
- Department of Thoracic Surgery, Shanghai Pulmonary HospitalTongji University507 Zhengmin RoadShanghai200433P. R. China
| | - Yuan Zhang
- Department of Gastrointestinal SurgeryShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai201620P. R. China
| | - Tingting Feng
- Department of Clinical PharmacyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai201620P. R. China
| | - Chao Xiao
- Department of Gastrointestinal SurgeryShanghai East Hospital, School of MedicineTongji UniversityShanghai200040P. R. China
| | - Huan Song
- Department of Clinical Laboratory MedicineShanghai Pulmonary HospitalTongji University School of MedicineShanghai200433P. R. China
| | - Rui Miao
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
| | - Li Xu
- Department of Thoracic Surgery, Shanghai Pulmonary HospitalTongji University507 Zhengmin RoadShanghai200433P. R. China
| | - Hongwei Chen
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
| | - Xiaoying Qiu
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
| | - Yi Xu
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
| | - Jingxuan Xu
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty MannheimHeidelberg University68167MannheimGermany
| | - Zelin Cui
- Department of Laboratory MedicineShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai201620P. R. China
| | - Wei Wang
- Department of Breast‐thyroid SurgeryShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai201620P. R. China
| | - Yanchun Quan
- Central LaboratoryLinyi People's HospitalShandong273300P. R. China
| | - Yifeng Zhu
- Department of Internal Medicine II, Klinikum rechts der IsarTechnical University of MunichIsmaninger Str. 2281675MunichGermany
| | - Chen Huang
- Department of Gastrointestinal SurgeryShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai201620P. R. China
| | - Song Guo Zheng
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research InstituteShanghai Jiaotong University School of Medicine Affiliated Songjiang HospitalShanghai200080P. R. China
| | - Jian‐yuan Zhao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE‐Shanghai Key Laboratory of Children's Environmental HealthXinhua HospitalShanghai Jiao Tong University School of MedicineShanghai200092P. R. China
| | - Ting Zhu
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
| | - Lianhui Sun
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE‐Shanghai Key Laboratory of Children's Environmental HealthXinhua HospitalShanghai Jiao Tong University School of MedicineShanghai200092P. R. China
| | - Guangjian Fan
- Precision Research Center for Refractory Diseases, Institute for Clinical ResearchShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai200080P. R. China
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Mencarelli F, Azukaitis K, Kirchner M, Bayazit A, Duzova A, Canpolat N, Bulut IK, Obrycki L, Ranchin B, Shroff R, Caliskan S, Candan C, Yilmaz A, Özcakar ZB, Halpay H, Kiyak A, Erdogan H, Gellermann J, Balat A, Melk A, Schaefer F, Querfeld U. Dyslipidemia in children with chronic kidney disease-findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study. Pediatr Nephrol 2024; 39:2759-2772. [PMID: 38720111 PMCID: PMC11272819 DOI: 10.1007/s00467-024-06389-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 07/26/2024]
Abstract
BACKGROUND Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD. METHODS In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis. RESULTS A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure. CONCLUSIONS Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors.
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Affiliation(s)
- Francesca Mencarelli
- Pediatric Nephrology Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Karolis Azukaitis
- Clinic of Pediatrics, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Marietta Kirchner
- Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Aysun Bayazit
- Department of Pediatric Nephrology, Cukurova University, Adana, Turkey
| | - Ali Duzova
- Division of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Nur Canpolat
- Department of Pediatric Nephrology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ipek Kaplan Bulut
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Lukasz Obrycki
- Department of Nephrology and Arterial Hypertension, Children's Memorial Health Institute, Warsaw, Poland
| | - Bruno Ranchin
- Pediatric Nephrology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Université de Lyon, Lyon, France
| | - Rukshana Shroff
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Salim Caliskan
- Division of Pediatric Nephrology, Göztepe Hospital, Istanbul Medeniyet University, Istanbul, Turkey
| | - Cengiz Candan
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Alev Yilmaz
- Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Zeynep Birsin Özcakar
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Ankara University, Ankara, Turkey
| | - Harika Halpay
- Department of Pediatric Nephrology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Aysel Kiyak
- Division of Pediatric Nephrology, Department of Pediatrics, Bakirkoy Children's Hospital, Istanbul, Turkey
| | - Hakan Erdogan
- Division of Pediatric Nephrology, Faculty of Medicine, Uludağ University, Bursa, Turkey
| | - Jutta Gellermann
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité University Hospital, Berlin, Germany
| | - Ayse Balat
- Department of Pediatric Nephrology, Gaziantep University, Gaziantep, Turkey
| | - Anette Melk
- Department of Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Franz Schaefer
- Pediatric Nephrology Division, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany
| | - Uwe Querfeld
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité University Hospital, Berlin, Germany.
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8
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Cortés-Camacho F, Zambrano-Vásquez OR, Aréchaga-Ocampo E, Castañeda-Sánchez JI, Gonzaga-Sánchez JG, Sánchez-Gloria JL, Sánchez-Lozada LG, Osorio-Alonso H. Sodium-Glucose Cotransporter Inhibitors: Cellular Mechanisms Involved in the Lipid Metabolism and the Treatment of Chronic Kidney Disease Associated with Metabolic Syndrome. Antioxidants (Basel) 2024; 13:768. [PMID: 39061837 PMCID: PMC11274291 DOI: 10.3390/antiox13070768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
Metabolic syndrome (MetS) is a multifactorial condition that significantly increases the risk of cardiovascular disease and chronic kidney disease (CKD). Recent studies have emphasized the role of lipid dysregulation in activating cellular mechanisms that contribute to CKD progression in the context of MetS. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated efficacy in improving various components of MetS, including obesity, dyslipidemia, and insulin resistance. While SGLT2i have shown cardioprotective benefits, the underlying cellular mechanisms in MetS and CKD remain poorly studied. Therefore, this review aims to elucidate the cellular mechanisms by which SGLT2i modulate lipid metabolism and their impact on insulin resistance, mitochondrial dysfunction, oxidative stress, and CKD progression. We also explore the potential benefits of combining SGLT2i with other antidiabetic drugs. By examining the beneficial effects, molecular targets, and cytoprotective mechanisms of both natural and synthetic SGLT2i, this review provides a comprehensive understanding of their therapeutic potential in managing MetS-induced CKD. The information presented here highlights the significance of SGLT2i in addressing the complex interplay between metabolic dysregulation, lipid metabolism dysfunction, and renal impairment, offering clinicians and researchers a valuable resource for developing improved treatment strategies and personalized approaches for patients with MetS and CKD.
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Affiliation(s)
- Fernando Cortés-Camacho
- Doctorado en Ciencias Biologicas y de la Salud, Universidad Autónoma Metropolitana, Mexico City 04960, Mexico; (F.C.-C.); (O.R.Z.-V.)
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico; (J.G.G.-S.); (L.G.S.-L.)
| | - Oscar René Zambrano-Vásquez
- Doctorado en Ciencias Biologicas y de la Salud, Universidad Autónoma Metropolitana, Mexico City 04960, Mexico; (F.C.-C.); (O.R.Z.-V.)
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico; (J.G.G.-S.); (L.G.S.-L.)
| | - Elena Aréchaga-Ocampo
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, Mexico City 05348, Mexico;
| | | | - José Guillermo Gonzaga-Sánchez
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico; (J.G.G.-S.); (L.G.S.-L.)
| | - José Luis Sánchez-Gloria
- Department of Internal Medicine, Division of Nephrology, Rush University Medical Center, Chicago, IL 60612, USA;
| | - Laura Gabriela Sánchez-Lozada
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico; (J.G.G.-S.); (L.G.S.-L.)
| | - Horacio Osorio-Alonso
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico; (J.G.G.-S.); (L.G.S.-L.)
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9
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Chugh SS, Clement LC. "Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end. Am J Physiol Renal Physiol 2023; 325:F685-F694. [PMID: 37795536 PMCID: PMC10878723 DOI: 10.1152/ajprenal.00219.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/11/2023] [Accepted: 10/02/2023] [Indexed: 10/06/2023] Open
Abstract
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
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Affiliation(s)
- Sumant S Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
| | - Lionel C Clement
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
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10
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Salfi G, Casiraghi F, Remuzzi G. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Front Immunol 2023; 14:1247606. [PMID: 37795085 PMCID: PMC10546017 DOI: 10.3389/fimmu.2023.1247606] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/05/2023] [Indexed: 10/06/2023] Open
Abstract
The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential "circulating factors" contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS.
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Affiliation(s)
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
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11
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Morris AD, Floyd L, Woywodt A, Dhaygude A. Rituximab in the treatment of primary FSGS: time for its use in routine clinical practice? Clin Kidney J 2023; 16:1199-1205. [PMID: 37529639 PMCID: PMC10387384 DOI: 10.1093/ckj/sfad122] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Indexed: 08/03/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and whilst advances have been made in the pathophysiology, diagnostics and management of other podocytopathies, primary FSGS remains the most elusive. It has been assumed for a long time that a circulatory permeability factor exists that mediates podocyte injury, and the potential for autoantibody-mediated disease therefore raises the question as to whether patients may benefit from targeted B-cell therapy with rituximab. The prospective case series of seven patients by Roccatello et al. adds to the limited but growing evidence suggesting that B-cell depletion therapy can be safe and effective in the treatment of primary FSGS. In this editorial we explore the available evidence that suggests how and in whom rituximab may play a role in the management of primary FSGS, as well as the limitations and other potential future treatments. Further research and randomized controlled trials are needed to include larger numbers of patients, feature genetic screening and incorporate data on B-cell kinetics as a potential guide for dosing and frequency of rituximab.
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Affiliation(s)
| | - Lauren Floyd
- Department of Nephrology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Alexander Woywodt
- Department of Nephrology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Ajay Dhaygude
- Department of Nephrology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
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12
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Zuo Y, He Z, Chen Y, Dai L. Dual role of ANGPTL4 in inflammation. Inflamm Res 2023:10.1007/s00011-023-01753-9. [PMID: 37300585 DOI: 10.1007/s00011-023-01753-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Angiopoietin-like 4 (ANGPTL4) belongs to the angiopoietin-like protein family and mediates the inhibition of lipoprotein lipase activity. Emerging evidence suggests that ANGPTL4 has pleiotropic functions with anti- and pro-inflammatory properties. METHODS A thorough search on PubMed related to ANGPTL4 and inflammation was performed. RESULTS Genetic inactivation of ANGPTL4 can significantly reduce the risk of developing coronary artery disease and diabetes. However, antibodies against ANGPTL4 result in several undesirable effects in mice or monkeys, such as lymphadenopathy and ascites. Based on the research progress on ANGPTL4, we systematically discussed the dual role of ANGPTL4 in inflammation and inflammatory diseases (lung injury, pancreatitis, heart diseases, gastrointestinal diseases, skin diseases, metabolism, periodontitis, and osteolytic diseases). This may be attributed to several factors, including post-translational modification, cleavage and oligomerization, and subcellular localization. CONCLUSION Understanding the potential underlying mechanisms of ANGPTL4 in inflammation in different tissues and diseases will aid in drug discovery and treatment development.
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Affiliation(s)
- Yuyue Zuo
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Department of Dermatology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhen He
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan, 430030, Hubei, China
| | - Yu Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan, 430030, Hubei, China
| | - Lei Dai
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan, 430030, Hubei, China.
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13
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Del Nogal Avila M, Das R, Kharlyngdoh J, Molina-Jijon E, Donoro Blazquez H, Gambut S, Crowley M, Crossman DK, Gbadegesin RA, Chugh SS, Chugh SS, Avila-Casado C, Macé C, Clement LC, Chugh SS. Cytokine storm-based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection. JCI Insight 2023; 8:e166012. [PMID: 37040185 PMCID: PMC10322692 DOI: 10.1172/jci.insight.166012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 04/05/2023] [Indexed: 04/12/2023] Open
Abstract
Viral illnesses like SARS-CoV-2 have pathologic effects on nonrespiratory organs in the absence of direct viral infection. We injected mice with cocktails of rodent equivalents of human cytokine storms resulting from SARS-CoV-2/COVID-19 or rhinovirus common cold infection. At low doses, COVID-19 cocktails induced glomerular injury and albuminuria in zinc fingers and homeoboxes 2 (Zhx2) hypomorph and Zhx2+/+ mice to mimic COVID-19-related proteinuria. Common Cold cocktail induced albuminuria selectively in Zhx2 hypomorph mice to model relapse of minimal change disease, which improved after depletion of TNF-α, soluble IL-4Rα, or IL-6. The Zhx2 hypomorph state increased cell membrane to nuclear migration of podocyte ZHX proteins in vivo (both cocktails) and lowered phosphorylated STAT6 activation (COVID-19 cocktail) in vitro. At higher doses, COVID-19 cocktails induced acute heart injury, myocarditis, pericarditis, acute liver injury, acute kidney injury, and high mortality in Zhx2+/+ mice, whereas Zhx2 hypomorph mice were relatively protected, due in part to early, asynchronous activation of STAT5 and STAT6 pathways in these organs. Dual depletion of cytokine combinations of TNF-α with IL-2, IL-13, or IL-4 in Zhx2+/+ mice reduced multiorgan injury and eliminated mortality. Using genome sequencing and CRISPR/Cas9, an insertion upstream of ZHX2 was identified as a cause of the human ZHX2 hypomorph state.
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Affiliation(s)
- Maria Del Nogal Avila
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ranjan Das
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Joubert Kharlyngdoh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Eduardo Molina-Jijon
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Hector Donoro Blazquez
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Stéphanie Gambut
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Michael Crowley
- Genomics Core Lab, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - David K. Crossman
- Genomics Core Lab, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rasheed A. Gbadegesin
- Division of Nephrology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
| | - Sunveer S. Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Sunjeet S. Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Carmen Avila-Casado
- Department of Anatomical Pathology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
- Instituto Nacional de Cardiología, Mexico City, Mexico
| | - Camille Macé
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Lionel C. Clement
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Sumant S. Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
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14
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Onwuzo SS, Hitawala AA, Boustany A, Kumar P, Almomani A, Onwuzo C, Monteiro JM, Asaad I. Prevalence of non-alcoholic fatty liver disease in patients with nephrotic syndrome: A population-based study. World J Hepatol 2023; 15:265-273. [PMID: 36926242 PMCID: PMC10011912 DOI: 10.4254/wjh.v15.i2.265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a global health concern with a prevalence of about 25% amongst United States adults. Its increased prevalence is attributed to increase in patients with obesity and metabolic syndrome, partly due to similar mechanisms of injury. Nephrotic syndrome (NS) is a clinical entity resulting from extensive proteinuria leading to hypoalbuminemia, hyperlipidemia, edema, and other complications. Given its association with hyperlipidemia, there is concern that patients with NS may be at increased risk of NAFLD.
AIM To perform a cross-sectional population-based study to investigate the prevalence and risk factors of NAFLD in patients with NS.
METHODS A large multicenter database (Explorys Inc., Cleveland, OH, United States) was utilized for this retrospective cohort study. A cohort of 49700 patients with a diagnosis of “Non-Alcoholic fatty liver disease” using the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) between 1999-2022 was identified. Inclusion criteria were age ≥ 18 years, presence of NAFLD, presence of NS. There were no specific exclusion criteria. Univariate and multivariate analysis were performed to adjust for multiple risk factors including age, gender, Caucasian race, NS, type II diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease. Statistical analysis was conducted using R, and for all analyses, a 2-sided P value of < 0.05 was considered statistically significant.
RESULTS Among the 78734750 individuals screened in this database, there were a total of 49700 subjects with NAFLD. In univariate analysis, the odds of having NAFLD in patients with NS, type 2 diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease were 14.84 [95% confidence interval (95%CI) 13.67-16.10], 17.05 (95%CI 16.78-17.32), 6.99 (95%CI 6.87-7.11), 13.61 (95%CI 13.38-13.84), 19.19 (95%CI 18.89-19.50), 29.09 (95%CI 28.26--29.95), and 9.05 (95%CI 8.88-9.22), respectively. In multivariate analysis, the odds of having NAFLD amongst patients with NS were increased to 1.85 (95%Cl 1.70-2.02), while the odds were also remained high in patients that have type 2 diabetes mellitus [odds ratio (OR) 3.84], hypothyroidism (OR 1.57), obesity (OR 5.10), hyperlipidemia (OR 3.09), metabolic syndrome (OR 3.42) and chronic kidney disease (OR 1.33).
CONCLUSION Patients with NS are frequently found to have NAFLD, even when adjusting for common risk factors. Hence, clinicians should maintain a high index of suspicion regarding presence of NAFLD in patients with NS.
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Affiliation(s)
| | - Asif Ali Hitawala
- Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Antoine Boustany
- Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Prabhat Kumar
- Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Ashraf Almomani
- Digestive Disease and Hepatology, Cleveland Clinic Foundation Florida, Weston, FI 33331, United States
| | - Chidera Onwuzo
- Department of Medicine & Surgery, General Hospital Lagos Island, Lagos Island 101223, Lagos, Nigeria
| | | | - Imad Asaad
- Digestive Disease and Hepatology, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
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15
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ANGPTL4 promotes nephrotic syndrome by downregulating podocyte expression of ACTN4 and podocin. Biochem Biophys Res Commun 2023; 639:176-182. [PMID: 36495766 DOI: 10.1016/j.bbrc.2022.11.081] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND lipopolysaccharide (LPS) can induce nephrotic syndrome-like features such as massive proteinuria, hyperlipidemia, and fusion of glomerular podocytes with foot processes (FPs) in mice. Angiopoietin-like protein 4 (ANGPTL4) neutralized the negative charge of glomerular basement membrane charge and aggravated renal injury. The mechanism of ANGPTL4 aggravating podocyte injury has not been well clarified. In this study, we aimed to investigate the potential role of ANGPTL4 on podocyte FPs fusion and podocyte signal molecules. METHODS We built angptl4 gene knocked out in C57BL6 mice using CRISPR/Cas9 technique. Nephrotic model was built by LPS in wild type and angptl4-/- mice. Expression of ACTN4, podocin and TRPC6 in the glomerulus were determined by immunohistochemistry. RESULTS In physical condition, the wild type and angptl4-/- mice showed no significant differences in biochemical indicators and kidney pathology. But in nephrotic condition, compared with wild type mice hyperlipidemia and proteinuria with the angptl4-/- mice was significantly relieved. Moreover, the degree of FPs fusion was notably improved in the nephrotic mice knocked out angptl4 gene. Expression of ACTN4 and podocin decreased drastically in the glomerulus of wild-type nephrotic mice. Different from wild-type, the ACTN4 and podocin expression showed slight weakening in angptl4-/- nephrotic mice. As transient receptor potential cation channel subfamily member, TRPC6 expression had no visible change in glomerulus of each group. CONCLUSIONS ANGPTL4 induces hyperlipidemia and podocyte injury in nephrotic mice, thereby promoting the formation of proteinuria. Its molecular mechanism may be related to ANGPTL4 down-regulating actin cytoskeletal regulatory signals ACTN4 and podocin.
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16
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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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17
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Cara-Fuentes G, Andres-Hernando A, Bauer C, Banks M, Garcia GE, Cicerchi C, Kuwabara M, Shimada M, Johnson RJ, Lanaspa MA. Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood. iScience 2022; 25:104694. [PMID: 35847557 PMCID: PMC9284382 DOI: 10.1016/j.isci.2022.104694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 05/23/2022] [Accepted: 06/24/2022] [Indexed: 01/21/2023] Open
Abstract
Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.
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Affiliation(s)
| | - Ana Andres-Hernando
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA,Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA
| | - Colin Bauer
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Mindy Banks
- Rocky Mountain Pediatric Kidney Center, Denver, CO, USA
| | - Gabriela E. Garcia
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Christina Cicerchi
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Masanari Kuwabara
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Michiko Shimada
- Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Richard J. Johnson
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Miguel A. Lanaspa
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA,Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA,Corresponding author
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18
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Kim JH, Yang H, Kim MW, Cho KS, Kim DS, Yim HE, Atala Z, Ko IK, Yoo JJ. The Delivery of the Recombinant Protein Cocktail Identified by Stem Cell-Derived Secretome Analysis Accelerates Kidney Repair After Renal Ischemia-Reperfusion Injury. Front Bioeng Biotechnol 2022; 10:848679. [PMID: 35646873 PMCID: PMC9130839 DOI: 10.3389/fbioe.2022.848679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/27/2022] [Indexed: 12/14/2022] Open
Abstract
Recent advances in cell therapy have shown the potential to treat kidney diseases. As the treatment effects of the cell therapies are mainly attributed to secretomes released from the transplanted cells, the delivery of secretomes or conditioned medium (CM) has emerged as a promising treatment option for kidney disease. We previously demonstrated that the controlled delivery of human placental stem cells (hPSC)-derived CM using platelet-rich plasma (PRP) ameliorated renal damages and restored kidney function in an acute kidney injury (AKI) model in rats. The proteomics study of the hPSC-CM revealed that hPSC secrets several proteins that contribute to kidney tissue repair. Based on our results, this study proposed that the proteins expressed in the hPSC-CM and effective for kidney repair could be used as a recombinant protein cocktail to treat kidney diseases as an alternative to CM. In this study, we analyzed the secretome profile of hPSC-CM and identified five proteins (follistatin, uPAR, ANGPLT4, HGF, VEGF) that promote kidney repair. We investigated the feasibility of delivering the recombinant protein cocktail to improve structural and functional recovery after AKI. The pro-proliferative and anti-apoptotic effects of the protein cocktail on renal cells are demonstrated in vitro and in vivo. The intrarenal delivery of these proteins with PRP ameliorates the renal tubular damage and improved renal function in the AKI-induced rats, yielding similar therapeutic effects compared to the CM delivery. These results indicate that our strategy may provide a therapeutic solution to many challenges associated with kidney repair resulting from the lack of suitable off-the-shelf regenerative medicine products.
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Affiliation(s)
- Ji Hyun Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Heejo Yang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Urology, Soonchunhyang University College of Medicine, Cheonan, South Korea
| | - Michael W Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Kang Su Cho
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Doo Sang Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Urology, Soonchunhyang University College of Medicine, Cheonan, South Korea
| | - Hyung Eun Yim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Pediatrics, Korea University College of Medicine, Seoul, South Korea
| | - Zachary Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - In Kap Ko
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
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19
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Al-Waili K, Al-Rasadi K, Al-Bulushi M, Habais M, Al-Mujaini A, Al-Yaarubi S, Rimbert A, Zadjali R, Khaniabadi PM, Al-Barwani H, Hasary S, Al-Dahmani ZM, Al-Badi H, Al-Maawali A, Zadjali F. The Genetic Spectrum of Familial Hypertriglyceridemia in Oman. Front Genet 2022; 13:886182. [PMID: 35669187 PMCID: PMC9163817 DOI: 10.3389/fgene.2022.886182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/11/2022] [Indexed: 11/15/2022] Open
Abstract
Familial hypertriglyceridemia (F-HTG) is an autosomal disorder that causes severe elevation of serum triglyceride levels. It is caused by genetic alterations in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. The mutation spectrum of F-HTG in Arabic populations is limited. Here, we report the genetic spectrum of six families of F-HTG of Arab ancestry in Oman. Methods: six Omani families affected with triglyceride levels >11.2 mmol/L were included in this study. Ampli-Seq sequencing of the selected gene panels was performed. Whole-exome sequencing and copy number variant analysis were also performed in cases with negative exome results. Three novel pathogenic missense variants in the LPL gene were identified, p.M328T, p.H229L, and p.S286G, along with a novel splice variant c.1322+15T > G. The LPL p.H229L variant existed in double heterozygous mutation with the APOA5 gene p.V153M variant. One family had a homozygous mutation in the LMF1 gene (c.G107A; p.G36D) and a heterozygous mutation in the LPL gene (c.G106A; p.D36N). All affected subjects did not have a serum deficiency of LPL protein. Genetic analysis in one family did not show any pathogenic variants even after whole-exome sequencing. These novel LPL and APOA5 mutations are not reported in other ethnic groups. This suggests that patients with F-HTG in Oman have a founder effect and are genetically unique. This warrants further analysis of patients of F-HTG in the Middle East for preventative and counseling purposes to limit the spread of the disease in a population of high consanguinity.
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Affiliation(s)
- Khalid Al-Waili
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Khalid Al-Rasadi
- Medical Research Centre, College of Medicine and Health Sciences, Department of Biochemistry, Sultan Qaboos University, Muscat, Oman
| | - Muna Al-Bulushi
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Mohammed Habais
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Abdullah Al-Mujaini
- Department of Ophthalmology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Saif Al-Yaarubi
- Department of Child Health, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman
| | - Antoine Rimbert
- Nantes Université, CHU Nantes, CNRS, INSERM, L’institut du Thorax, Nantes, France
| | - Razan Zadjali
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Pegah Moradi Khaniabadi
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | | | - Sana Hasary
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Zayana M. Al-Dahmani
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Hala Al-Badi
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Almundher Al-Maawali
- Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Fahad Zadjali
- Department of Clinical Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
- *Correspondence: Fahad Zadjali,
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20
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Huang JK, Lee HC. Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL). Int J Mol Sci 2022; 23:4300. [PMID: 35457118 PMCID: PMC9031540 DOI: 10.3390/ijms23084300] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 12/18/2022] Open
Abstract
Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.
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Affiliation(s)
- Jih-Kai Huang
- Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Hsiang-Chun Lee
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80708, Taiwan
- Graduate Institute of Animal Vaccine Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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21
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Srivastava SP, Kanasaki K. Editorial: Receptor Biology and Cell Signaling in Diabetes. Front Pharmacol 2022; 13:864117. [PMID: 35370643 PMCID: PMC8965761 DOI: 10.3389/fphar.2022.864117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/24/2022] [Indexed: 11/28/2022] Open
Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States.,Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, United States
| | - Keizo Kanasaki
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo, Japan
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22
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Zou X, Nie L, Liao Y, Liu Z, Zheng W, Qu X, Xu X, Qin H, Wang H, Liu J, He G, Jing T. Effects of statin therapy and treatment duration on cardiovascular disease risk in patients with nephrotic syndrome: A nested case-control study. Pharmacotherapy 2022; 42:311-319. [PMID: 35184315 PMCID: PMC9314031 DOI: 10.1002/phar.2675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/06/2022] [Accepted: 02/08/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND Although statins are the cornerstone of lipid management, hardly any of the existing studies on statin treatment of dyslipidemia in nephrotic syndrome (NS) addressed patient-centered outcomes of cardiovascular events. OBJECTIVE To evaluate whether statin treatment impacts the outcomes of cardiovascular events in patients with NS. DESIGN A single-center, retrospective, nested case-control study analyzed data from the First Affiliated Hospital of Army Medical University. PATIENTS Patients diagnosed with NS from January 1, 1999, to November 30, 2014, were selected and followed up for 5 years. MEASUREMENTS AND MAIN RESULTS A total of 2706 patients with NS were enrolled in this study cohort. Among these, 115 patients diagnosed with cardiovascular disease (CVD) at the end of the observational period and 235 CVD-free controls enrolled by 1:2 matching with gender, age, and index time were included in the study. Propensity score matching was used to match (1:1) the baseline characteristics of the cases and controls. The chi-square test was performed based on whether the patient used a statin as an exposure factor, and binary logistic regression analysis of the association between cardiovascular events and statin therapy duration was conducted. Subgroup analyses for relevant variables were also performed. The chi-square test showed that statin therapy was significantly associated with a reduction in CVD risk in patients with NS (p = 0.002). Furthermore, the risk of cardiovascular events in patients with NS decreased as the length of statin treatment increased (OR = 0.82 [95% CI 0.73-0.89], p < 0.001). CONCLUSIONS For NS patients with dyslipidemia, statin therapy may be used to decrease CVD risk, and extended treatment was associated with more significant risk reduction.
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Affiliation(s)
- Xinliang Zou
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Li Nie
- Department of Internal Medicine, Central Hospital of Wandong, Wansheng, Chongqing, China
| | - Yi Liao
- Department of Thoracic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhihui Liu
- Department of Burn Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wanxiang Zheng
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaolong Qu
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiang Xu
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Haoran Qin
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Haidong Wang
- Department of Thoracic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jianping Liu
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Guoxiang He
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Department of Cardiology, Guiqian International General Hospital, Guiyang, China
| | - Tao Jing
- Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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23
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Li Y, Gong W, Liu J, Chen X, Suo Y, Yang H, Gao X. Angiopoietin-like protein 4 promotes hyperlipidemia-induced renal injury by down-regulating the expression of ACTN4. Biochem Biophys Res Commun 2022; 595:69-75. [PMID: 35101665 DOI: 10.1016/j.bbrc.2022.01.061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/05/2022] [Accepted: 01/15/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVE The molecular mechanism of in hyperlipidemia-induced renal injury has not been elucidated. Angiogenin-like protein 4 (ANGPTL4) is a key regulator of lipid metabolism. The role of ANGPTL4 hyperlipidemia-induced renal injury has not been reported. METHODS Wild type C57 mice and gene angptl4 knockout mice were fed with 60% high fat diet or normal diet respectively. The serum lipid, urinary albumin and renal pathology were tested at the 9th, 13th, 17th and 21st week with high fat diet. RESULTS Elevated blood lipids in the wild-type mice with high-fat diet were found at 9th week. At the 17th week, the level of urinary albumin in high-fat fed wild type mice were significantly higher than which with normal diet, correspondingly, segmental fusion of podocyte foot process in kidney could be observed in these hyperlipidemia mice. IHC showed that the expression of ANGPTL4 in glomeruli of high-fat fed wild type mice began significant elevated since the 9th week. When given high fat diet, compared to the wild type, the gene angptl4 knockout mice showed significantly alleviated the levels of hyperlipidemia, proteinuria and effacement of podocyte foot process. Finally, the expression of ACTN4 showed remarkably lower in glomeruli podocyte of wild type mice fed high fat diet than that of wild type mice with normal diet at each time-point (P < 0.01). Differently, the expression of ACTN4 in gene angptl4 knockout mice did not happen significantly weaken when given the same dose of high fat diet. CONCLUSION ANGPTL4 could play a role in hyperlipidemic-induced renal injury via down-regulating the expression of ACTN4 in kidney podocyte.
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Affiliation(s)
- Yue Li
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, 510000, China
| | - Wangqiu Gong
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, 510000, China
| | - Jing Liu
- Pediatric Department, Gansu Province People's Hospital, Lanzhou City, 730000, China
| | - Xingxing Chen
- Pediatric Department, Gansu Province People's Hospital, Lanzhou City, 730000, China
| | - Yanhong Suo
- Pediatric Department, Gansu Province People's Hospital, Lanzhou City, 730000, China
| | - Huabing Yang
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, 510000, China
| | - Xia Gao
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, 510000, China.
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24
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Abstract
Nephrotic syndrome (NS) encompasses a variety of disease processes leading to heavy proteinuria and edema. Minimal change disease (MCD) remains the most common primary cause of NS, as well as the most responsive to pharmacologic treatment with often minimal to no chronic kidney disease. Other causes of NS include focal segmental glomerulosclerosis, which follows MCD, and secondary causes, including extrarenal or systemic diseases, infections, and drugs. Although initial diagnosis relies on clinical findings as well as urine and blood chemistries, renal biopsy and genetic testing are important diagnostic tools, especially when considering non-MCD NS. Moreover, biomarkers in urine and serum have become important areas for research in this disease. NS progression and prognosis are variable and depend on etiology, with corticosteroids being the mainstay of treatment. Other alternative therapies found to be successful in inducing and maintaining remission include calcineurin inhibitors and rituximab. Disease course can range from recurrent disease relapse with or without acute kidney injury to end-stage renal disease in some cases. Given the complex pathogenesis of NS, which remains incompletely understood, complications are numerous and diverse and include infections, electrolyte abnormalities, acute kidney injury, and thrombosis. Pediatricians must be aware of the presentation, complications, and overall long-term implications of NS and its treatment.
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25
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Purohit S, Piani F, Ordoñez FA, de Lucas-Collantes C, Bauer C, Cara-Fuentes G. Molecular Mechanisms of Proteinuria in Minimal Change Disease. Front Med (Lausanne) 2022; 8:761600. [PMID: 35004732 PMCID: PMC8733331 DOI: 10.3389/fmed.2021.761600] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/15/2021] [Indexed: 11/13/2022] Open
Abstract
Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury.
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Affiliation(s)
- Shrey Purohit
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Federica Piani
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Flor A Ordoñez
- Division of Pediatric Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Colin Bauer
- Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Gabriel Cara-Fuentes
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
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26
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Hackl A, Zed SEDA, Diefenhardt P, Binz-Lotter J, Ehren R, Weber LT. The role of the immune system in idiopathic nephrotic syndrome. Mol Cell Pediatr 2021; 8:18. [PMID: 34792685 PMCID: PMC8600105 DOI: 10.1186/s40348-021-00128-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.
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Affiliation(s)
- Agnes Hackl
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. .,Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
| | - Seif El Din Abo Zed
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.,Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Paul Diefenhardt
- Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Julia Binz-Lotter
- Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Rasmus Ehren
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Lutz Thorsten Weber
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
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27
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van de Wouw J, Joles JA. Albumin is an interface between blood plasma and cell membrane, and not just a sponge. Clin Kidney J 2021; 15:624-634. [PMID: 35371452 PMCID: PMC8967674 DOI: 10.1093/ckj/sfab194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Indexed: 12/16/2022] Open
Abstract
Albumin is the most abundant protein in blood plasma and acts as a carrier for many circulating molecules. Hypoalbuminaemia, mostly caused by either renal or liver disease or malnutrition, can perturb vascular homeostasis and is involved in the development of multiple diseases. Here we review four functions of albumin and the consequences of hypoalbuminaemia on vascular homeostasis. (i) Albumin is the main determinant of plasma colloid osmotic pressure. Hypoalbuminaemia was therefore thought to be the main mechanism for oedema in nephrotic syndrome (NS), however, experimental studies showed that intrarenal mechanisms rather than hypoalbuminaemia determine formation and, in particular, maintenance of oedema. (ii) Albumin functions as an interface between lysophosphatidylcholine (LPC) and circulating factors (lipoproteins and erythrocytes) and the endothelium. Consequently, hypoalbuminaemia results in higher LPC levels in lipoproteins and erythrocyte membrane, thereby increasing atherosclerotic properties of low-density lipoprotein and blood viscosity, respectively. Furthermore, albumin dose-dependently restores LPC-induced inhibition of vasodilation. (iii) Hypoalbuminaemia impacts on vascular nitric oxide (NO) signalling by directly increasing NO production in endothelial cells, leading to reduced NO sensitivity of vascular smooth muscle cells. (iv) Lastly, albumin binds free fatty acids (FFAs). FFAs can induce vascular smooth muscle cell apoptosis, uncouple endothelial NO synthase and decrease endothelium-dependent vasodilation. Unbound FFAs can increase the formation of reactive oxygen species by mitochondrial uncoupling in multiple cell types and induce hypertriglyceridemia in NS. In conclusion, albumin acts as an interface in the circulation and hypoalbuminaemia impairs multiple aspects of vascular function that may underlie the association of hypoalbuminaemia with adverse outcomes. However, hypoalbuminaemia is not a key to oedema in NS. These insights have therapeutic implications.
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Affiliation(s)
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands
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28
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Dong L, Wei W, Han M, Xu G. Utility of non-HDL-C in predicting proteinuria remission of idiopathic membranous nephropathy: a retrospective cohort study. Lipids Health Dis 2021; 20:122. [PMID: 34587945 PMCID: PMC8482680 DOI: 10.1186/s12944-021-01558-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/14/2021] [Indexed: 11/10/2022] Open
Abstract
Background Idiopathic membranous nephropathy (IMN) may have various clinical outcomes. Hyperlipidemia is quite common in IMN. However, the utility of the lipid profile in predicting outcomes remains unknown. This study aimed to explore the correlation between hyperlipidemia and proteinuria remission in IMN. Methods 256 patients who diagnosed with IMN confirmed by renal biopsy in Wuhan Tongji Hospital from January 2016 to October 2020 were included in this study. The end point was defined as a combination of partial and complete remission. Cox proportional-hazards regression analysis and Kaplan–Meier curve were applied to assess the prognostic value of the lipid profile for proteinuria remission. Results A total of 153 (59.8%) patients achieved remission and 103 (40.2%) did not. The levels of total cholesterol, low-density lipoprotein, and non-high-density lipoprotein were significantly lower in the remission group than in the non-remission group. Non-high-density lipoprotein level revealed the strongest correlation with proteinuria (Spearman’s rho = 0.42; P < 0.001). The multivariate analysis demonstrated that serum total cholesterol [hazard ratio (HR): 0.883; 95% confidence interval (CI): 0.813–0.958; P = 0.003] and non-high-density lipoprotein cholesterol (HR: 0.892; 95% CI: 0.820–0.970; P = 0.007) levels were independent markers to predict proteinuria remission in IMN. Conclusions Among the lipid profile, the non-high-density lipoprotein level exhibited the strongest correlation with proteinuria in IMN. Moreover, elevated serum cholesterol and non-high-density lipoprotein cholesterol concentrations at baseline predicted probability of proteinuria non-remission in IMN.
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Affiliation(s)
- Lei Dong
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, D-430030, Hubei, China
| | - Wang Wei
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, D-430030, Hubei, China
| | - Min Han
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, D-430030, Hubei, China.
| | - Gang Xu
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, D-430030, Hubei, China.
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29
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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30
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Clinical Management of Hypertriglyceridemia in the Prevention of Cardiovascular Disease and Pancreatitis. Curr Atheroscler Rep 2021; 23:72. [PMID: 34515873 PMCID: PMC8436578 DOI: 10.1007/s11883-021-00962-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2021] [Indexed: 02/07/2023]
Abstract
Purpose of Review Hypertriglyceridemia (HTG) is common and is a significant contributor to atherosclerosis and pancreatitis risk. Specific HTG treatments have had variable success in reducing atherosclerosis risk. Novel therapies for severe HTG treatment and pancreatitis risk reduction are likely to be available soon. These novel therapies are expected to have broader applications for more moderate HTG and atherosclerosis risk reduction as well. Recent Findings NHANES 2012 data has confirmed a reduction in average triglyceride (TG) levels in the US population. Dietary modification and weight reduction when needed remain the core treatment elements for all individuals with HTG, while statin therapy is a foundational pharmacologic care for atherosclerotic cardiovascular disease (ASCVD) event risk reduction. In addition, the REDUCE-IT study provides evidence for additional benefit from the use of high-dose icosapent ethyl (IPE) on top of background medical therapy in adults with moderate HTG and ASCVD or type 2 diabetes mellitus (T2D) and additional ASCVD risk factors. However, treatment with eicosapentaenoic acid (EPA) combined with docosahexanoic acid (DHA) did not reduce ASCVD in a similar population studied in the STRENGTH trial. Furthermore, novel therapeutics targeting PPAR-ɑ, as well as ApoC-III and AngPTL3, effectively lower TG levels in individuals with moderate and severe HTG, respectively. These treatments may have applicability for reducing risk from ASCVD among individuals with chylomicronemia; in addition, ApoC-III and AngPTL3 treatments may have a role in treating individuals with the rare monogenic familial chylomicronemia syndrome (FCS) at risk for acute pancreatitis (AP). Summary Residual ASCVD risk in individuals treated with contemporary care may be due in part to non-LDL lipid abnormalities including HTG. The findings from REDUCE-IT, but not STRENGTH, confirm that consumption of high-dose EPA may reduce ASCVD risk, while combination therapy of EPA plus DHA does not reduce ASCVD in a similar population. TG lowering likely reduces ASCVD risk in individuals with HTG, but ASCVD risk is multifactorial; the added benefit of IPE to contemporary preventive therapy is the consequence of differential non-TG biologic properties between the two fatty acids. Acute pancreatitis is more difficult to study prospectively since it is less common; however, TG lowering is likely critical for the care of at-risk individuals. Additional benefit from novel therapy that has an impact on this otherwise refractory condition is anticipated.
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31
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Cara-Fuentes G, Smoyer WE. Biomarkers in pediatric glomerulonephritis and nephrotic syndrome. Pediatr Nephrol 2021; 36:2659-2673. [PMID: 33389089 DOI: 10.1007/s00467-020-04867-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/16/2020] [Accepted: 11/18/2020] [Indexed: 12/21/2022]
Abstract
Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome.
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Affiliation(s)
- Gabriel Cara-Fuentes
- Department of Pediatrics, Division of Pediatric Nephrology, University of Colorado, 12700 E 19th Ave, R2 building, Room 7420D, Aurora, CO, 80045, USA.
| | - William E Smoyer
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
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C Thambiah S, Lai LC. Diabetic dyslipidaemia. Pract Lab Med 2021; 26:e00248. [PMID: 34368411 PMCID: PMC8326412 DOI: 10.1016/j.plabm.2021.e00248] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 05/16/2021] [Accepted: 07/14/2021] [Indexed: 12/22/2022] Open
Abstract
Diabetes mellitus (DM) is an escalating pandemic and an established cardiovascular risk factor. An important aspect of the interaction between DM and atherosclerotic cardiovascular disease (ASCVD) is diabetic dyslipidaemia, an atherogenic dyslipidaemia encompassing quantitative [hypertriglyceridaemia (hyperTG) and decreased high density lipoprotein cholesterol (HDL)] and qualitative [increased small dense low density lipoprotein cholesterol (sdLDL) particles, large very low density lipoprotein cholesterol (VLDL) subfraction (VLDL1) and dysfunctional HDL] modifications in lipoproteins. Much of the pathophysiology linking DM and dyslipidaemia has been elucidated. This paper aims to review the pathophysiology and management of diabetic dyslipidaemia with respect to ASCVD. Briefly, the influence of diabetic kidney disease on lipid profile and lipid changes causing type 2 diabetes mellitus are highlighted. Biomarkers of diabetic dyslipidaemia, including novel markers and clinical trials that have demonstrated that non-lipid and lipid lowering therapies can lower cardiovascular risk in diabetics are discussed. The stands of various international guidelines on lipid management in DM are emphasised. It is important to understand the underlying mechanisms of diabetic dyslipidaemia in order to develop new therapeutic strategies against dyslipidaemia and diabetes. The various international guidelines on lipid management can be used to tailor a holistic approach specific to each patient with diabetic dyslipidaemia.
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Affiliation(s)
- Subashini C Thambiah
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
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Li W, Duan A, Xing Y, Xu L, Yang J. Transcription-Based Multidimensional Regulation of Fatty Acid Metabolism by HIF1α in Renal Tubules. Front Cell Dev Biol 2021; 9:690079. [PMID: 34277635 PMCID: PMC8283824 DOI: 10.3389/fcell.2021.690079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022] Open
Abstract
Lipid metabolism plays a basic role in renal physiology, especially in tubules. Hypoxia and hypoxia-induced factor (HIF) activation are common in renal diseases; however, the relationship between HIF and tubular lipid metabolism is poorly understood. Using prolyl hydroxylase inhibitor roxadustat (FG-4592), we verified and further explored the relationship between sustained HIF1α activation and lipid accumulation in cultured tubular cells. A transcriptome and chromatin immunoprecipitation sequencing analysis revealed that HIF1α directly regulates the expression of a number of genes possibly affecting lipid metabolism, including those associated with mitochondrial function. HIF1α activation suppressed fatty acid (FA) mobilization from lipid droplets (LDs) and extracellular FA uptake. Moreover, HIF1α decreased FA oxidation and ATP production. A lipidomics analysis showed that FG-4592 caused strong triglyceride (TG) accumulation and increased some types of phospholipids with polyunsaturated fatty acyl (PUFA) chains, as well as several proinflammatory lipids. Nevertheless, the overall FA level was maintained. Thus, our study indicated that HIF1α reduced the FA supply and utilization and reconstructed the composition of lipids in tubules, which is likely a part of hypoxic adaptation but could also be involved in pathological processes in the kidney.
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Affiliation(s)
- Wenju Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Aiping Duan
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yuexian Xing
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Li Xu
- Department of Otorhinolaryngology-Head and Neck Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jingping Yang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Medical School of Nanjing University, Nanjing, China
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34
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Zou H, Xu Y, Meng X, Li D, Chen X, Du T, Yang Y, Chen Y, Shao S, Yuan G, Zhou X, Hu S, He W, Ma D, Xie J, Zhang B, Zhang J, Li W, Liu Z, Yu X. Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C Study. Cardiovasc Diabetol 2021; 20:127. [PMID: 34167540 PMCID: PMC8223309 DOI: 10.1186/s12933-021-01317-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/07/2021] [Indexed: 12/18/2022] Open
Abstract
Background ANGPTL8, an important regulator of lipid metabolism, was recently proven to have additional intracellular and receptor-mediated functions. This study aimed to investigate circulating levels of ANGPTL8 and its potential association with the risk of kidney function decline in a cohort study. Methods We analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Kidney function decline was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 m2 of body surface area, a decrease in eGFR of ≥ 30% from baseline, chronic kidney disease (CKD)-related hospitalization or death, or end-stage renal disease. The association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models, and inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting. Results There were 136 (5.9%) cases of kidney function decline over a median of 3.8 years of follow-up. We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to those without kidney function decline during follow-up (718.42 ± 378.17 vs. 522.04 ± 283.07 pg/mL, p < 0.001). Compared with the first quartile, multivariable-adjusted hazard ratio (95% confidence intervals [CIs]) for kidney function decline was 2.59 (95% CI, 1.41–4.77) for the fourth ANGPTL8 quartile. Furthermore, compared with patients in the first ANGPTL8 quartile, those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD (relative risk: 1.33; 95% CI, 1.01–1.74). The conclusions of the regression analyses were not altered in the IPTW models. Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline (p for nonlinear trend = 0.66, p for linear trend < 0.001). Conclusions Participants with higher circulating ANGPTL8 levels were at increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01317-3.
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Affiliation(s)
- Huajie Zou
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yongping Xu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xiaoyu Meng
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Danpei Li
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xi Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Tingting Du
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yan Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yong Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Shiying Shao
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Gang Yuan
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xinrong Zhou
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Shuhong Hu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Wentao He
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Delin Ma
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Junhui Xie
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Benping Zhang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Jianhua Zhang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Wenjun Li
- Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhelong Liu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China. .,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China.
| | - Xuefeng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China. .,Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China.
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Gu X, Zhang S, Zhang T. Abnormal Crosstalk between Endothelial Cells and Podocytes Mediates Tyrosine Kinase Inhibitor (TKI)-Induced Nephrotoxicity. Cells 2021; 10:cells10040869. [PMID: 33921219 PMCID: PMC8070074 DOI: 10.3390/cells10040869] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/04/2021] [Accepted: 04/09/2021] [Indexed: 12/12/2022] Open
Abstract
Vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2 are the main targets of antiangiogenic therapies, and proteinuria is one of the common adverse events associated with the inhibition of the VEGFA/VEGFR2 pathway. The proteinuric kidney damage induced by VEGFR2 tyrosine kinase inhibitors (TKIs) is characterized by podocyte foot process effacement. TKI therapy promotes the formation of abnormal endothelial‒podocyte crosstalk, which plays a key role in TKI-induced podocyte injury and proteinuric nephropathy. This review article summarizes the underlying mechanism by which the abnormal endothelial‒podocyte crosstalk mediates podocyte injury and discusses the possible molecules and signal pathways involved in abnormal endothelial‒podocyte crosstalk. What is more, we highlight the molecules involved in podocyte injury and determine the essential roles of Rac1 and Cdc42; this provides evidence for exploring the abnormal endothelial‒podocyte crosstalk in TKI-induced nephrotoxicity.
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Affiliation(s)
| | | | - Ti Zhang
- Correspondence: ; Tel.: +86-21-6417-5590
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36
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Barbagallo CM, Cefalù AB, Giammanco A, Noto D, Caldarella R, Ciaccio M, Averna MR, Nardi E. Lipoprotein Abnormalities in Chronic Kidney Disease and Renal Transplantation. Life (Basel) 2021; 11:life11040315. [PMID: 33916487 PMCID: PMC8067409 DOI: 10.3390/life11040315] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease (CKD) is one of the most important risk factors for cardiovascular disease (CVD). Despite the kidney having no direct implications for lipoproteins metabolism, advanced CKD dyslipidemia is usually present in patients with CKD, and the frequent lipid and lipoprotein alterations occurring in these patients play a role of primary importance in the development of CVD. Although hypertriglyceridemia is the main disorder, a number of lipoprotein abnormalities occur in these patients. Different enzymes pathways and proteins involved in lipoprotein metabolism are impaired in CKD. In addition, treatment of uremia may modify the expression of lipoprotein pattern as well as determine acute changes. In renal transplantation recipients, the main lipid alteration is hypercholesterolemia, while hypertriglyceridemia is less pronounced. In this review we have analyzed lipid and lipoprotein disturbances in CKD and also their relationship with progression of renal disease. Hypolipidemic treatments may also change the natural history of CVD in CKD patients and may represent important strategies in the management of CKD patients.
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Affiliation(s)
- Carlo Maria Barbagallo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
| | - Angelo Baldassare Cefalù
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
| | - Antonina Giammanco
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
| | - Davide Noto
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
| | - Rosalia Caldarella
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
| | - Marcello Ciaccio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), Section of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, 90127 Palermo, Italy;
| | - Maurizio Rocco Averna
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
| | - Emilio Nardi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties—University of Palermo, Via del Vespro, 127, 90127 Palermo, Italy; (C.M.B.); (A.B.C.); (A.G.); (D.N.); (R.C.); (M.R.A.)
- Correspondence: ; Tel.: +39-916-554-316
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Chen J, Qiao XH, Mao JH. Immunopathogenesis of idiopathic nephrotic syndrome in children: two sides of the coin. World J Pediatr 2021; 17:115-122. [PMID: 33660135 DOI: 10.1007/s12519-020-00400-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Idiopathic nephrotic syndrome is a common form of glomerular nephropathy in children, with an incidence rate of 1.15-16.9/100,000 depending on different nationalities and ethnicities. The etiological factors and mechanisms of childhood idiopathic nephrotic syndrome have not yet been fully elucidated. This review summarizes the progress of the immunopathogenesis of idiopathic nephrotic syndrome in children. DATA SOURCES We review the literature on the immunopathogenesis of idiopathic nephrotic syndrome in children. Databases including Medline, Scopus, and Web of Science were searched for studies published in any language with the terms "children", "idiopathic nephrotic syndrome", "immunopathogenesis", "T cells", "circulating permeability factors", and "B cells". RESULTS Dysfunction in T lymphocytes and pathogenic circulatory factors were indicated to play key roles in the pathogenesis of idiopathic nephrotic syndrome. Recently, some studies have shown that cellular immune dysfunction may also be involved in the pathogenesis of idiopathic nephrotic syndrome. CONCLUSIONS Both T- and B-cell dysfunction may play significant roles in the pathogenesis of idiopathic nephrotic syndrome, like two sides of one coin, but the role of B cell seems more important than T cells.
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Affiliation(s)
- Jing Chen
- Department of Nephrology, Ningbo Women and Children's Hospital, 339 LiutingRd, Ningbo, 315012, China
| | - Xiao-Hui Qiao
- Department of Nephrology, Ningbo Women and Children's Hospital, 339 LiutingRd, Ningbo, 315012, China.
| | - Jian-Hua Mao
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, 57 Zhuganxiang, Hangzhou, 310003, China
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Curtis LM, George J, Vallon V, Barnes S, Darley-Usmar V, Vaingankar S, Cutter GR, Gutierrez OM, Seifert M, Ix JH, Mehta RL, Sanders PW, Agarwal A. UAB-UCSD O'Brien Center for Acute Kidney Injury Research. Am J Physiol Renal Physiol 2021; 320:F870-F882. [PMID: 33779316 DOI: 10.1152/ajprenal.00661.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Acute kidney injury (AKI) remains a significant clinical problem through its diverse etiologies, the challenges of robust measurements of injury and recovery, and its progression to chronic kidney disease (CKD). Bridging the gap in our knowledge of this disorder requires bringing together not only the technical resources for research but also the investigators currently endeavoring to expand our knowledge and those who might bring novel ideas and expertise to this important challenge. The University of Alabama at Birmingham-University of California-San Diego O'Brien Center for Acute Kidney Injury Research brings together technical expertise and programmatic and educational efforts to advance our knowledge in these diverse issues and the required infrastructure to develop areas of novel exploration. Since its inception in 2008, this O'Brien Center has grown its impact by providing state-of-the-art resources in clinical and preclinical modeling of AKI, a bioanalytical core that facilitates measurement of critical biomarkers, including serum creatinine via LC-MS/MS among others, and a biostatistical resource that assists from design to analysis. Through these core resources and with additional educational efforts, our center has grown its investigator base to include >200 members from 51 institutions. Importantly, this center has translated its pilot and catalyst funding program with a $37 return per dollar invested. Over 500 publications have resulted from the support provided with a relative citation ratio of 2.18 ± 0.12 (iCite). Through its efforts, this disease-centric O'Brien Center is providing the infrastructure and focus to help the development of the next generation of researchers in the basic and clinical science of AKI. This center creates the promise of the application at the bedside of the advances in AKI made by current and future investigators.
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Affiliation(s)
- Lisa M Curtis
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - James George
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Volker Vallon
- Division of Nephrology, Department of Medicine, University of California-San Diego, San Diego, California
| | - Stephen Barnes
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Victor Darley-Usmar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Sucheta Vaingankar
- Division of Pediatric Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Gary R Cutter
- School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
| | - Orlando M Gutierrez
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Michael Seifert
- Division of Pediatric Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joachim H Ix
- Division of Nephrology, Department of Medicine, University of California-San Diego, San Diego, California
| | - Ravindra L Mehta
- Division of Nephrology, Department of Medicine, University of California-San Diego, San Diego, California
| | - Paul W Sanders
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.,Department of Veterans Affairs, Birmingham, Alabama
| | - Anupam Agarwal
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.,Department of Veterans Affairs, Birmingham, Alabama
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Jia S, Peng X, Liang L, Zhang Y, Li M, Zhou Q, Shen X, Wang Y, Wang C, Feng S, Chen J, Ren P, Jiang H. The Study of Angptl4-Modulated Podocyte Injury in IgA Nephropathy. Front Physiol 2021; 11:575722. [PMID: 33643055 PMCID: PMC7905042 DOI: 10.3389/fphys.2020.575722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/20/2020] [Indexed: 11/16/2022] Open
Abstract
Background Increasing evidence shows that Angptl4 affects proteinuria in podocytes injured kidney disease, however, whether there is a relationship between Angptl4 and IgA nephropathy (IgAN) has not been studied yet. Methods Plasma and urine samples were obtained from 71 patients with IgAN and 61 healthy controls. Glomeruli from six renal biopsy specimens (three IgAN patients and three healthy controls) were separated by RNA-Seq. Differentially expressed genes (DEGs) related to podocytes and Angptl4 between IgAN patients and healthy controls were performed using the Limma package. Gene set enrichment analysis was used to determine whether there was a statistically significant difference between the two groups. STRING was used to create a protein-protein interaction network of DEGs. Association analysis between Angptl4 levels and clinical features of IgAN was performed. Results Thirty-three podocyte-related and twenty-three Angpt4-related DEGs were found between IgAN patients and healthy controls. By overlapping the genes, FOS and G6PC were found to be upregulated in IgAN patients, while MMP9 was downregulated in IgAN patients. Plasma and urine Angptl4 levels were closely related to the degree of podocyte injury and urine protein, but not to the protein-creatine ratio. Conclusion Our findings show that Angptl4 levels in plasma and urine are related to podocyte damage and, therefore, may be a promising tool for assessing the severity of IgAN patients to identify and reverse the progression to ESRD.
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Affiliation(s)
- Sha Jia
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China.,Dongyang Women & Children Hospital, Dongyang, China
| | - Xiaofeng Peng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Ludan Liang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Ying Zhang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Meng Li
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Qin Zhou
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Xiujin Shen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Yucheng Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Cuili Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Shi Feng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Pingping Ren
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Hong Jiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Nephropathy, Hangzhou, China.,Kidney Disease Immunology Laboratory, The Third-Grade Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Beijing, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
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MicroRNAs as Biomarkers for Nephrotic Syndrome. Int J Mol Sci 2020; 22:ijms22010088. [PMID: 33374848 PMCID: PMC7795691 DOI: 10.3390/ijms22010088] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.
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Zhao Y, Goto M, Vaziri ND, Khazaeli M, Liu H, Farahanchi N, Khanifar E, Farzaneh T, Haslett PA, Moradi H, Soundarapandian MM. RNA Interference Targeting Liver Angiopoietin-Like Protein 3 Protects from Nephrotic Syndrome in a Rat Model Via Amelioration of Pathologic Hypertriglyceridemia. J Pharmacol Exp Ther 2020; 376:428-435. [PMID: 33443084 DOI: 10.1124/jpet.120.000257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/04/2020] [Indexed: 11/22/2022] Open
Abstract
Nephrotic syndrome (NS) is associated with metabolic perturbances including profound dyslipidemia characterized by hypercholesterolemia and hypertriglyceridemia. A major underlying mechanism of hypertriglyceridemia in NS is lipoprotein lipase (LPL) deficiency and dysfunction. There is emerging evidence that elevated angiopoietin-like protein 3 (ANGPTL3), an LPL inhibitor that is primarily expressed and secreted by hepatocytes, may be in part responsible for these findings. Furthermore, there is evidence pointing to the contribution of ANGPTL3 to the pathogenesis of proteinuria in NS. Therefore, we hypothesized that inhibition of hepatic ANGPTL3 by RNA interference will ameliorate dyslipidemia and other symptoms of NS and pave the way for a new therapeutic strategy. To this end, we used a subcutaneously delivered, GalNAc (N-Acetylgalactosamine)-conjugated small interfering RNA (siRNA) to selectively target and suppress liver Angptl3 in rats with puromycin-induced NS, which exhibits clinical features of NS including proteinuria, hypoalbuminemia, hyperlipidemia, and renal histologic abnormalities. The study demonstrated that siRNA-mediated knockdown of the liver Angptl3 relieved its inhibitory effect on LPL and significantly reduced hypertriglyceridemia in nephrotic rats. This was accompanied by diminished proteinuria and hypoalbuminemia, which are the hallmarks of NS, and significant attenuation of renal tissue inflammation and oxidative stress. Taken together, this study confirmed the hypothesis that suppression of Angptl3 is protective in NS and points to the possibility that the use of RNA interference to suppress hepatic Angptl3 can serve as a novel therapeutic strategy for NS. SIGNIFICANCE STATEMENT: The current standard of care for mitigating nephrotic dyslipidemia in nephrotic syndrome is statins therapy. However, the efficacy of statins and its safety in the context of impaired kidney function is not well established. Here, we present an alternate therapeutic approach by using siRNA targeting Angptl3 expressed in hepatocytes. As the liver is the major source of circulating Angptl3, siRNA treatment reduced the profound hypertriglyceridemia in a rat model of nephrotic syndrome and was also effective in improving kidney and cardiac function.
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Affiliation(s)
- Yitong Zhao
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Masaki Goto
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Mahyar Khazaeli
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Han Liu
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Nazli Farahanchi
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Elham Khanifar
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Ted Farzaneh
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Patrick A Haslett
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Hamid Moradi
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
| | - Mangala M Soundarapandian
- Division of Nephrology and Hypertension, University of California, Irvine, California (Y.Z., M.G., N.D.V., M.K., H.L., N.F., H.M.); Long Beach Memorial Pathology Group, Long Beach, California (E.K.); Department of Pathology and Laboratory Medicine, University of California, Irvine, California (T.F.); Tibor Rubin VA Medical Center, Department of Medicine, Nephrology Section, Long Beach, California (H.M.); and Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts (P.A.H., M.M.S.)
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Alteration of the Fatty Acid Metabolism in the Rat Kidney Caused by the Injection of Serum from Patients with Collapsing Glomerulopathy. Biomedicines 2020; 8:biomedicines8100388. [PMID: 33003345 PMCID: PMC7601944 DOI: 10.3390/biomedicines8100388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/23/2020] [Accepted: 09/28/2020] [Indexed: 01/10/2023] Open
Abstract
Patients with collapsing glomerulopathy (CG) have marked proteinuria that rapidly progresses to chronic renal failure. In this study, we investigated if the nephropathy produced in a rat model by the injection of serum from CG patients induced alterations in fatty acid (FA) metabolism. Twenty-four female Sprague-Dawley rats were divided into four groups of six rats each: Group I, control rats (C); Group II, rats that received injections of 1 mL of 0.9% NaCl saline solution (SS); Group III, rats injected with 25 mg/mL of serum from healthy subjects (HS); and Group IV, rats injected with 25 mg/mL of serum from CG patients. In all groups, the systolic blood pressure (SBP), proteinuria, creatinine clearance (CC), cholesterol and total FA composition in the kidney and serum were evaluated. The administration of serum from CG patients to rats induced glomerular collapse, proteinuria, reduced CC and elevated SBP (p ≤ 0.01) in comparison with the C, SS and HS rats. The FA composition of the serum of rats that received the CG serum showed an increase in palmitic acid (PA) and a decrease in arachidonic acid (AA) when compared to serum from HS (p ≤ 0.02). In rats receiving the CG serum, there was also a decrease in the AA in the kidney but there was an increase in the PA in the serum and kidney (p ≤ 0.01). These results suggest that the administration of serum from CG patients to rats induces alterations in FA metabolism including changes in PA and in AA, which are precursors for the biosynthesis of the prostaglandins that are involved in the elevation of SBP and in renal injury. These changes may contribute to collapsing glomerulopathy disease.
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Shen X, Zhang Y, Lin C, Weng C, Wang Y, Feng S, Wang C, Shao X, Lin W, Li B, Wang H, Chen J, Jiang H. Calcineurin inhibitors ameliorate PAN-induced podocyte injury through the NFAT-Angptl4 pathway. J Pathol 2020; 252:227-238. [PMID: 32686149 DOI: 10.1002/path.5512] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 06/29/2020] [Accepted: 07/13/2020] [Indexed: 12/31/2022]
Abstract
Podocyte injury plays a vital role in proteinuria and nephrotic syndrome. Calcineurin (CaN) inhibitors are effective in reducing proteinuria. However, their molecular mechanism is still not fully understood. Angiopoietin-like-4 (ANGPTL4) is a secreted protein that mediates proteinuria in podocyte-related nephropathy. In this study, we established a puromycin aminonucleoside (PAN)-induced minimal-change disease (MCD) rat model and a cultured podocyte injury model. We found that CaN inhibitors protected against PAN-induced podocyte injury, accompanied by an inhibition of Nfatc1 and Angptl4 both in vivo and in vitro. Nfatc1 overexpression and knockdown experiments indicated that Angptl4 was regulated by Nfatc1 in podocytes. ChIP assays further demonstrated that Nfatc1 increased Angptl4 expression by binding to the Angptl4 promoter. In addition, overexpression and knockdown of Angptl4 revealed that Angptl4 directly induced rearrangement of the cytoskeleton of podocytes, reduced the expression of synaptopodin, and enhanced PAN-induced podocyte apoptosis. Furthermore, in a cohort of 83 MCD and 94 membranous nephropathy (MN) patients, we found increased expression of serum ANGPTL4 compared to 120 healthy controls, and there were close correlations between serum ANGPTL4 and Alb, urinary protein, urinary Alb, eGFR, Scr, and BUN in MCD patients. No obvious correlation was found in MN patients. Immunofluorescence studies indicated that increased ANGPTL4 in MCD and MN patients was located mostly in podocytes. In conclusion, our results demonstrate that CaN inhibitors ameliorate PAN-induced podocyte injury by targeting Angptl4 through the NFAT pathway, and Angptl4 plays a vital role in podocyte injury and is involved in human podocyte-related nephropathy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Xiujin Shen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Ying Zhang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Chuan Lin
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Chunhua Weng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Yucheng Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Shi Feng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Cuili Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Xue Shao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Weiqiang Lin
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Bingjue Li
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Haibing Wang
- Central Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
| | - Hong Jiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, PR China
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Hari P, Khandelwal P, Smoyer WE. Dyslipidemia and cardiovascular health in childhood nephrotic syndrome. Pediatr Nephrol 2020; 35:1601-1619. [PMID: 31302760 DOI: 10.1007/s00467-019-04301-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/11/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022]
Abstract
Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.
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Affiliation(s)
- Pankaj Hari
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.
| | - Priyanka Khandelwal
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - William E Smoyer
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
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Abstract
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.
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Molina-Jijon E, Gambut S, Macé C, Avila-Casado C, Clement LC. Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome. Kidney Int 2020; 98:1449-1460. [PMID: 32750454 DOI: 10.1016/j.kint.2020.06.045] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 06/08/2020] [Accepted: 06/29/2020] [Indexed: 01/08/2023]
Abstract
The proprotein PCSK9 functions as a chaperone for the epithelial sodium channel in the cortical collecting duct (CCD), is highly expressed in the liver, and plays a significant role in the pathogenesis of hypercholesterolemia. Lower levels of PCSK9 expression also occur in the normal kidney and intestine. Here, we found increased PCSK9 expression in the CCD of biopsies of patients with primary glomerular disease and explored a possible relationship with hypercholesterolemia of nephrotic syndrome. Significantly elevated serum PCSK9 and cholesterol levels were noted in two models of focal and segmental glomerulosclerosis, the Rrm2b-/- mouse and the Buffalo/Mna rat. Increased expression of PCSK9 in the kidney occurred when liver expression was reduced in both models. The impact of reduced or increased PCSK9 in the CCD on hypercholesterolemia in nephrotic syndrome was next studied. Mice with selective deficiency of PCSK9 expression in the collecting duct failed to develop hypercholesterolemia after injection of nephrotoxic serum. Blocking epithelial sodium channel activity with Amiloride in Rrm2b-/- mice resulted in increased expression of its chaperone PCSK9 in the CCD, followed by elevated plasma levels and worsening hypercholesterolemia. Thus, our data suggest that PCSK9 in the kidney plays a role in the initiation of hypercholesterolemia in nephrotic syndrome and make a case for depletion of PCSK9 early in patients with nephrotic syndrome to prevent the development of hypercholesterolemia.
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Affiliation(s)
- Eduardo Molina-Jijon
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Stéphanie Gambut
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Camille Macé
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Carmen Avila-Casado
- Department of Pathology, Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Lionel C Clement
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
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Shen CJ, Chang KY, Lin BW, Lin WT, Su CM, Tsai JP, Liao YH, Hung LY, Chang WC, Chen BK. Oleic acid-induced NOX4 is dependent on ANGPTL4 expression to promote human colorectal cancer metastasis. Am J Cancer Res 2020; 10:7083-7099. [PMID: 32641980 PMCID: PMC7330862 DOI: 10.7150/thno.44744] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Colorectal cancer (CRC) progression and related mortality are highly associated with metabolic disorders. However, the molecular mechanism involved in the regulation of hyperlipidemia-associated CRC metastasis remains unclear. This study aimed to investigate the effects of angiopoietin-like 4 (ANGPTL4) on NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) production, which might provide new targets for improving outcomes in patients with hyperlipidemia-associated CRC metastasis. Methods: The clinical relevance of relationship between NOX4 expression and ANGPTL4 was examined in CRC patients by the Oncomine and TCGA data set. Expressions of NOX4, epithelial-mesenchymal transition (EMT) markers, and gene regulation of NOX4 in free fatty acids (FFAs)-treated CRC cells were determined. The FFAs-triggered metastatic ability of CRC cells under treatments of antioxidants or knockdown of NOX4, ANGPTL4, and MMPs was evaluated in vitro and in vivo. In addition, effects of antioxidants and depletion of metastasis-associated molecules on the correlation between ROS production and FFAs-promoted CRC metastasis were also clarified. Results: In this study, we found that the induction of NOX4, followed by the increased ROS was essential for oleic acid (OA)-promoted CRC cell metastasis. The depletion of ANGPTL4 significantly inhibited c-Jun-mediated transactivation of NOX4 expression, accompanied with reduced levels of ROS, MMP-1, and MMP-9, resulting in the disruption of OA-promoted CRC cell metastasis. Moreover, knockdown of ANGPTL4, NOX4, MMP-1, and MMP-9 or the treatment of antioxidants dramatically inhibited circulating OA-enhanced tumor cell extravasation and metastatic seeding of tumor cells in lungs, indicating that the ANGPTL4/NOX4 axis was critical for dyslipidemia-associated tumor metastasis. Conclusion: The coincident expression of NOX4 and ANGPTL4 in CRC tumor specimens provides the insight into the potential therapeutic targets for the treatment of dyslipidemia-associated CRC metastasis.
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Ward RA, Beck W, Bernardo AA, Alves FC, Stenvinkel P, Lindholm B. Hypoalbuminemia: a price worth paying for improved dialytic removal of middle-molecular-weight uremic toxins? Nephrol Dial Transplant 2020; 34:901-907. [PMID: 30102329 DOI: 10.1093/ndt/gfy236] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Indexed: 01/17/2023] Open
Abstract
Hemodiafiltration (HDF) increases the removal of middle-molecular-weight uremic toxins and may improve outcomes in patients with end-stage kidney disease (ESKD), but it requires complex equipment and comes with risks associated with infusion of large volumes of substitution solution. New high-flux hemodialysis membranes with improved diffusive permeability profiles do not have these limitations and offer an attractive alternative to HDF. However, both strategies are associated with increased albumin loss into the dialysate, raising concerns about the potential for decreased serum albumin concentrations that have been associated with poor outcomes in ESKD. Many factors can contribute to hypoalbuminemia in ESKD, including protein energy wasting, inflammation, volume expansion, renal loss and loss into the dialysate; of these factors, loss into the dialysate is not necessarily the most important. Furthermore, recent studies suggest that mild hypoalbuminemia per se is not an independent predictor of increased mortality in dialysis patients, but in combination with inflammation it is a poor prognostic sign. Thus, whether hypoalbuminemia predisposes to increased morbidity and mortality may depend on the presence or absence of inflammation. In this review we summarize recent findings on the role of dialysate losses in hypoalbuminemia and the importance of concomitant inflammation on outcomes in patients with ESKD. Based on these findings, we discuss whether hypoalbuminemia may be a price worth paying for increased dialytic removal of middle-molecular-weight uremic toxins.
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Affiliation(s)
| | - Werner Beck
- R&D, Baxter International Inc., Hechingen, Germany
| | | | - Filipa C Alves
- Department of Nephrology, Hospital Espírito Santo, Évora, Portugal.,Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Peter Stenvinkel
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Bengt Lindholm
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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Guo K, Pan P, Wu M, Ma Y, Lu J, Chen H. Hyposialylated angiopoietin-like-4 induces apoptosis of podocytes via β1 Integrin/FAK signaling in diabetic nephropathy. Mol Cell Endocrinol 2020; 505:110730. [PMID: 31981598 DOI: 10.1016/j.mce.2020.110730] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 01/18/2020] [Accepted: 01/20/2020] [Indexed: 12/12/2022]
Abstract
Angiopoietin-like-4 (ANGPTL4) is reported to mediate proteinuria in some types of glomerulonephropathy. However, the mechanism underlying the effect on podocytes of ANGPTL4 under pathologic conditions in diabetic nephropathy (DN) is unclear. We investigated the role of ANGPTL4 in the pathogenesis of DN. In DN rats, elevated ANGPTL4 expression was associated with increased proteinuria, glomerular hypertrophy, and ultrastructural changes in podocytes. In vitro, hyperglycemia induced the upregulation of ANGPTL4, which led to activation of integrin-β1/FAK signaling with increased apoptosis of podocytes and actin cytoskeleton derangement. These pathological changes were reversed by transfection with a lentivirus expressing short hairpin RNA against integrin-β1 or an ANGPTL4-neutralizing antibody in vitro. Furthermore, supplementation with the sialic acid precursor ManNAc reversed these pathological changes and conferred renoprotection in a mouse model of DN. Our findings suggest that ANGPTL4 mediates high glucose-induced loss of podocytes by modulating their detachment and apoptosis in vivo and in vitro. This study deepens our understanding of the mechanisms of podocyte loss in DN and shows targeting ANGPTL4-related signaling has therapeutic potential for DN.
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Affiliation(s)
- Kaifeng Guo
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China; Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University; Minhang Branch, Zhongshan Hospital, Fudan University; Central Hospital of Minhang District, Shanghai, 201199, China
| | - Pan Pan
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Mian Wu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yiwen Ma
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Junxi Lu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Haibing Chen
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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Alteration of Angiopoietin-Like Protein 4 Levels in Serum or Urine Correlate with Different Biochemical Markers in Hyperlipidemia-Related Proteinuria. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5281251. [PMID: 32280690 PMCID: PMC7125447 DOI: 10.1155/2020/5281251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 01/26/2020] [Accepted: 02/29/2020] [Indexed: 01/28/2023]
Abstract
Angiopoietin-like protein 4 (ANGPTL4) is widely known as a key regulator of lipid metabolism. We investigated the relationship between ANGPTL4 expression in serum or urine and blood lipid or urine protein levels of patients with hyperlipidemia- (HL-) related proteinuria. Sixty-eight patients with HL-related proteinuria (HL-Pro group), 68 patients with HL without proteinuria (HL-NPro group), 46 patients with non-HL-related proteinuria (NHL-Pro group), and 50 healthy control (Con) subjects were selected. There were no significant differences in serum ANGPTL4 levels between the Con group (36.82 ± 17.03 ng/ml) and the HL-Pro group (27.94 (18.90, 53.72) ng/ml). Additionally, the serum ANGPTL4 levels in the HL-Pro group were significantly lower than those in the HL-NPro group (53.32 ± 24.01 ng/ml) (P < 0.001). The urine ANGPTL4/Cr levels in the HL-Pro group (52.01 (45.25, 79.79) μg/g) were significantly higher than those in the HL-NPro group (9.96 (8.35, 12.43) ng/ml) (P < 0.05). A significant alteration in urine ANGPTL4/Cr levels was observed in the NHL-Pro group (69.41 ± 55.36 μg/g) and the Con group (10.08 ± 2.38 μg/g) as well. There was no correlation between serum and urine ANGPTL4 levels of the four groups (P > 0.05). Serum ANGPTL4 levels (HL-Pro/HL-NPro group) were positively correlated with total cholesterol (TC) and triglyceride (TG) levels in hyperlipidemia patients. However, there was no correlation between urinary ANGPTL4 levels and TC or TG (P > 0.05). Urine ANGPTL4 levels were positively correlated with 24hUPro in patients with renal impairment (HL-Pro/NHL-Pro group). To summarize, ANGPTL4 may be considered an accurate predictor of proteinuria with HL. Notably, serum or urine ANGPTL4 levels indicated the degree of proteinuria or hyperlipidemia, respectively, in HL patients.
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