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Bhatia D, Srivastava SP. Editorial: Diabetic kidney disease: routes to drug development, pharmacology and underlying molecular mechanisms, volume II. Front Pharmacol 2025; 16:1609100. [PMID: 40351438 PMCID: PMC12061879 DOI: 10.3389/fphar.2025.1609100] [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: 04/09/2025] [Accepted: 04/17/2025] [Indexed: 05/14/2025] Open
Affiliation(s)
- Divya Bhatia
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, United States
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Robinson CH, Smoyer WE, Cara-Fuentes G. Unraveling the Immunogenetic Mechanisms of Childhood Idiopathic Nephrotic Syndrome. J Pediatr 2025; 282:114595. [PMID: 40252964 DOI: 10.1016/j.jpeds.2025.114595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/16/2025] [Accepted: 04/14/2025] [Indexed: 04/21/2025]
Affiliation(s)
- Cal H Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada; Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.
| | - William E Smoyer
- The Center for Clinical and Translational Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH; Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
| | - Gabriel Cara-Fuentes
- Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
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Liu S, Meng M, Huang C, He L, Wang P, Tang Z, Ran X, Gao H, Guo Y, He Y, Chen J, Hu H, He S, Zhao Y, Hou Z, Li L, Li W, Wang W, Wang X. Umbilical Cord Mesenchymal Stem Cells Attenuate Podocyte Injury in Diabetic Nephropathy Rats by Inhibiting Angpltl4/Integrin β3 in the Glomerulus. J Diabetes Res 2025; 2025:6683126. [PMID: 40256245 PMCID: PMC12008490 DOI: 10.1155/jdr/6683126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 03/19/2025] [Indexed: 04/22/2025] Open
Abstract
In this study, we investigated the therapeutic effects and mechanisms of umbilical cord mesenchymal stem cells (UCMSCs) in diabetic nephropathy (DN) ZDF (FA/FA) rats. The therapeutic effects were assessed by renal function tests, the urinary albumin-creatinine ratio, PAS staining, electron microscopy, and TGF-β1 expression in renal tissue. Subsequently, podocyte injury in renal tissue was detected by immunofluorescence staining for podocin. To further explore the underlying mechanism, serum Angptl4 levels were measured, and Angptl4, integrin β3, fibronectin, and podocin levels in renal tissue were analysed by Western blotting. In vitro, podocytes are stimulated with high glucose and then treated with UCMSCs, and podocyte activity and the expression of synaptopodin, Angptl4, and integrin β3 were observed. UCMSC significantly improve renal function, pathological injury, and podocyte injury in the ZDF (FA/FA) rats. Western blot revealed increased expression of Angptl4, integrin β3, and fibronectin in renal tissues of the DN group, and UCMSC treatment significantly downregulated those proteins. However, UCMSC showed no effects on serum Angptl4 concentration. Podocin expression in renal tissues was significantly restored by UCMSC treatment. In vitro, podocyte activity was decreased after high glucose stimulation and improved by UCMSC treatment. UCMSC restored the expression of synaptopodin, and Angptl4 and downstream integrin β3 were also inhibited. Our study suggested that UCMSC therapy could improve renal function and renal pathological changes in ZDF (FA/FA) rats. In addition, inhibition of the Angptl4/integrin β3 pathway is the potential mechanism by which UCMSC attenuates podocyte injury in the DN model.
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Affiliation(s)
- Shiyuan Liu
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Mingyao Meng
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Chunkai Huang
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Lijia He
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Pu Wang
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Zhe Tang
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Xi Ran
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Hui Gao
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Yangfan Guo
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Yan He
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Jian Chen
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Haiyan Hu
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Shan He
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Yiyi Zhao
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Zongliu Hou
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Lin Li
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Wenhong Li
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Wenju Wang
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
| | - Xiaodan Wang
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
- Yunnan stem cell Clinical transformation Engineering Research Center, Kunming, China
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Yang S, Su X, Lai M, Liu X, Cheng Y. Angiopoietin-Like Protein Family-Mediated Functions in Modulating Triglyceride Metabolism and Related Metabolic Diseases. FRONT BIOSCI-LANDMRK 2025; 30:25862. [PMID: 40302331 DOI: 10.31083/fbl25862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/24/2024] [Accepted: 01/21/2025] [Indexed: 05/02/2025]
Abstract
Hypertriglyceridemia, characterized by increased triglyceride (TG) concentrations, is considered the most important risk factor for cardiometabolic disorders, including dyslipidemia, atherosclerotic cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Recently, the angiopoietin-like protein (ANGPTL) family, which comprises ANGPTL1 to ANGPTL8, was confirmed to play an important role in modulating lipoprotein lipase (LPL) activity. However, understanding of the underlying mechanisms remains limited. Importantly, emerging evidence has linked several transcriptional and post-transcriptional factors to the potential alteration of TG metabolism via ANGPTL proteins. This review focused on the similarities and differences in the expression, structural features, and modulatory profile of three ANGPTLs: ANGPTL3, ANGPTL4, and ANGPTL8. In addition, the regulatory functions of those three ANGPTLs in modulating LPL were summarized to provide potential therapeutic and clinical strategies for hypertriglyceridemia and its related cardiometabolic disorders.
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Affiliation(s)
- Sen Yang
- Department of Anesthesia Surgery Center, The West China Xiamen Hospital of Sichuan University, 361021 Xiamen, Fujian, China
| | - Xin Su
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, 361000 Xiamen, Fujian, China
| | - Min Lai
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, 361000 Xiamen, Fujian, China
| | - Xiaoxi Liu
- Department of Anesthesia Surgery Center, The West China Xiamen Hospital of Sichuan University, 361021 Xiamen, Fujian, China
| | - Ye Cheng
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, 361000 Xiamen, Fujian, China
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Gong W, Li G, Lu D, Liu M, Gao X. Serum angiopoietin-like protein 4 levels correlate with hypertriglyceridemia and renal function decline in pediatric patients with lupus nephritis. Eur J Intern Med 2025:S0953-6205(25)00087-1. [PMID: 40102075 DOI: 10.1016/j.ejim.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/17/2024] [Accepted: 03/02/2025] [Indexed: 03/20/2025]
Affiliation(s)
- Wangqiu Gong
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China
| | - Guanyu Li
- Maoming Maternal and Child Health Hospital, Maoming, 525000, China
| | - Di Lu
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China
| | - Ming Liu
- School of Pediatrics, Guangzhou Medical University, 510180, China
| | - Xia Gao
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China.
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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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Jefferson JA, Chen K, Hingorani S, Malik AB, Tykodi SS, Keller KH, Huang Y, Smith KD, Reed RC, Weins A, Akilesh S. Genetic and Iatrogenic Defects in Peripheral Tolerance Associated with Anti-Nephrin Antibody-Associated Minimal Change Disease. GLOMERULAR DISEASES 2025; 5:74-83. [PMID: 39991196 PMCID: PMC11845169 DOI: 10.1159/000543334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/19/2024] [Indexed: 02/25/2025]
Abstract
Introduction Minimal change disease (MCD) is a common cause of nephrotic syndrome in children and adults. Immune dysregulation is a contributor, but the relative roles of individual components of the immune system in MCD pathogenesis remain unclear. Case Presentation Here, we present 2 patients with defects in immune tolerance mechanisms that developed MCD associated with anti-nephrin antibodies. The first patient had a pathogenic deletion in FOXP3, leading to reduced regulatory T cells. Serum could not be obtained from this patient during the active phase of MCD to directly establish the presence of anti-nephrin antibodies. However, this patient demonstrated IgG dusting over podocyte cell bodies by immunofluorescence microscopy, as well as colocalization of IgG with nephrin in confocal microscopy. The second patient developed MCD in the context of immune checkpoint inhibitor treatment for metastatic carcinoma. Anti-nephrin antibodies were detected in this patient during active disease. The patient's kidney biopsy also showed evidence of binding of anti-nephrin antibodies within the glomeruli. Conclusion These cases demonstrate that genetic and iatrogenic mechanisms of breakdown in peripheral tolerance can lead to MCD.
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Affiliation(s)
- J. Ashley Jefferson
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Karin Chen
- Division of Immunology, Department of Pediatrics, University of Washington, Seattle, WA, USA
- Seattle Chilidren’s Research Institute, Seattle, WA, USA
| | - Sangeeta Hingorani
- Division of Immunology, Department of Pediatrics, University of Washington, Seattle, WA, USA
- Seattle Chilidren’s Research Institute, Seattle, WA, USA
| | - A. Bilal Malik
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Scott S. Tykodi
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | | | - Yuan Huang
- Robert J. Tomsich Department of Pathology and Laboratory Medicine, Diagnostics Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Kelly D. Smith
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Robyn C. Reed
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
- Department of Laboratory Medicine and Pathology, Seattle Children’s Hospital, Seattle, WA, USA
| | - Astrid Weins
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
| | - Shreeram Akilesh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
- Kidney Research Institute, Seattle, WA, USA
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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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11
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Chebotareva NV, Charionovskaya EA, Biryukova EA, Vinogradov AA, Alentov II, Sergeeva NS, Kononikhin AS, Nikolaev EN, Moiseev SV. Increased levels of antibodies to synaptopodin and annexin 1 in patients with primary podocytopathies. FRONTIERS IN NEPHROLOGY 2024; 4:1471078. [PMID: 39544697 PMCID: PMC11560892 DOI: 10.3389/fneph.2024.1471078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 11/17/2024]
Abstract
Introduction Circulating anti-podocyte antibodies have been proposed as potential factors contributing to increased permeability in primary podocytopathies, such as Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS). The aim of the study was to to assess the levels of antibodies targeting synaptopodin and annexin 1 in the blood serum of patients diagnosed with nephrotic syndrome, with the aim of evaluating their potential utility in diagnosing primary podocytopathies and predicting therapeutic response. Methods The study included a total of 72 patients diagnosed with nephrotic syndrome, alongside 21 healthy subjects for comparison. Among the patients, 38 were diagnosed with FSGS, 12 with MCD, and 22 with MN. The levels of anti-synaptopodin and anti-annexin-1 antibodies were quantified using Enzyme-Linked Immunosorbent Assay. Results The levels of antibodies to annexin 1 and anti-synaptopodin in the blood were found to be higher in patients diagnosed with MCD and FSGS compared to those with MN and healthy individuals. The elevated levels of antibodies to annexin 1 and synaptopodin showed area under the curve values of 0.826 (95% CI 0.732-0.923) and 0.827 (95% CI 0.741-0.879), respectively. However, a model incorporating both antibodies demonstrated higher sensitivity (80.9%) and specificity (81.3%) with an AUC of 0.859 (95% CI 0.760-0.957). Notably, serum levels of annexin 1 and anti-synaptopodin antibodies did not predict the response to prednisolone and/or CNI therapy. Discussion Levels of antibodies targeting synaptopodin and annexin 1 were notably elevated in patients diagnosed with MCD and FSGS compared to those with MN and healthy controls. A panel comprising both antibodies demonstrated moderate to high sensitivity and specificity for diagnosis MCD or FSGS.
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Affiliation(s)
- Natalia V. Chebotareva
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Evgenia A. Biryukova
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Igor I. Alentov
- Department of Prediction of Conservative Treatment Efficiency, Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Natalia S. Sergeeva
- Department of Prediction of Conservative Treatment Efficiency, Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Alexey S. Kononikhin
- Project Center of Advanced Mass, Spectrometry Technologies, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Evgeny N. Nikolaev
- Project Center of Advanced Mass, Spectrometry Technologies, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Sergey V. Moiseev
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
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12
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Meliambro K, He JC, Campbell KN. Podocyte-targeted therapies - progress and future directions. Nat Rev Nephrol 2024; 20:643-658. [PMID: 38724717 DOI: 10.1038/s41581-024-00843-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2024] [Indexed: 09/14/2024]
Abstract
Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney failure worldwide. Seminal experimental and clinical studies have established a causative link between podocyte depletion and the magnitude of proteinuria in progressive glomerular disease. However, no substantial advances have been made in glomerular disease therapies, and the standard of care for podocytopathies relies on repurposed immunosuppressive drugs. The past two decades have seen a remarkable expansion in understanding of the mechanistic basis of podocyte injury, with prospects increasing for precision-based treatment approaches. Dozens of disease-causing genes with roles in the pathogenesis of clinical podocytopathies have been identified, as well as a number of putative glomerular permeability factors. These achievements, together with the identification of novel targets of podocyte injury, the development of potential approaches to harness the endogenous podocyte regenerative potential of progenitor cell populations, ongoing clinical trials of podocyte-specific pharmacological agents and the development of podocyte-directed drug delivery systems, contribute to an optimistic outlook for the future of glomerular disease therapy.
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Affiliation(s)
- Kristin Meliambro
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John C He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kirk N Campbell
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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13
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Suresh V, Stillman IE, Campbell KN, Meliambro K. Focal Segmental Glomerulosclerosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:275-289. [PMID: 39084753 DOI: 10.1053/j.akdh.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 08/02/2024]
Abstract
Focal segmental glomerular sclerosis (FSGS) is a histological lesion characterized by sclerosis in sections (segmental) of some glomeruli (focal) in association with podocyte injury. Historically, FSGS has often been characterized as a disease, but it is a heterogeneous entity based on etiology, clinical course, and therapeutic approach. A unifying feature is podocyte injury and loss, which can be primary or the result of secondary maladaptive responses to glomerular stressors. FSGS has been demonstrated over time to carry a large health burden and remains a leading glomerular cause of ESRD globally. Recent clinical practice guidelines highlight the unmet scientific need for better understanding of disease pathogenesis, particularly for immunologic etiologies, as well as more targeted therapeutic drug development. In this review, we will discuss the current FSGS classification scheme, pathophysiologic mechanisms of injury, and treatment guidelines, along with emerging and investigational therapeutics.
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Affiliation(s)
- Varsha Suresh
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isaac E Stillman
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Kirk N Campbell
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
| | - Kristin Meliambro
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
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14
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Wang X, Chang HC, Gu X, Han W, Mao S, Lu L, Jiang S, Ding H, Han S, Qu X, Bao Z. Renal lipid accumulation and aging linked to tubular cells injury via ANGPTL4. Mech Ageing Dev 2024; 219:111932. [PMID: 38580082 DOI: 10.1016/j.mad.2024.111932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 04/02/2024] [Indexed: 04/07/2024]
Abstract
Renal tubular epithelial cells are vulnerable to stress-induced damage, including excessive lipid accumulation and aging, with ANGPTL4 potentially playing a crucial bridging role between these factors. In this study, RNA-sequencing was used to identify a marked increase in ANGPTL4 expression in kidneys of diet-induced obese and aging mice. Overexpression and knockout of ANGPTL4 in renal tubular epithelial cells (HK-2) was used to investigate the underlying mechanism. Subsequently, ANGPTL4 expression in plasma and kidney tissues of normal young controls and elderly individuals was analyzed using ELISA and immunohistochemical techniques. RNA sequencing results showed that ANGPTL4 expression was significantly upregulated in the kidney tissue of diet-induced obesity and aging mice. In vitro experiments demonstrated that overexpression of ANGPTL4 in HK-2 cells led to increased lipid deposition and senescence. Conversely, the absence of ANGPTL4 appears to alleviate the impact of free fatty acids (FFA) on aging in HK-2 cells. Additionally, aging HK-2 cells exhibited elevated ANGPTL4 expression, and stress response markers associated with cell cycle arrest. Furthermore, our clinical evidence revealed dysregulation of ANGPTL4 expression in serum and kidney tissue samples obtained from elderly individuals compared to young subjects. Our study findings indicate a potential association between ANGPTL4 and age-related metabolic disorders, as well as injury to renal tubular epithelial cells. This suggests that targeting ANGPTL4 could be a viable strategy for the clinical treatment of renal aging.
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Affiliation(s)
- Xiaojun Wang
- Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Hung-Chen Chang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Xuchao Gu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Wanlin Han
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shihang Mao
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, China
| | - Lili Lu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shuai Jiang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Haiyong Ding
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Urologic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Shisheng Han
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinkai Qu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Zhijun Bao
- Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
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15
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Mantovani A, Csermely A, Cappelli D, Taverna A, Sani E, Shtembari E, Pagani M, Targher G. Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study. Acta Diabetol 2024; 61:281-288. [PMID: 37853295 DOI: 10.1007/s00592-023-02198-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 10/04/2023] [Indexed: 10/20/2023]
Abstract
AIMS Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). METHODS We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12 mL/min/1.73 m2 and a median serum NEFA concentration of 662 uEq/L (interquartile range 524-842 uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262 uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. CONCLUSIONS The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy.
| | - Alessandro Csermely
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Davide Cappelli
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Antonio Taverna
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Elena Sani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Emigela Shtembari
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Micol Pagani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
- IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
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16
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Bhayana S, Dougherty JA, Kamigaki Y, Agrawal S, Wijeratne S, Fitch J, Waller AP, Wolfgang KJ, White P, Kerlin BA, Smoyer WE. Glucocorticoid- and pioglitazone-induced proteinuria reduction in experimental NS both correlate with glomerular ECM modulation. iScience 2024; 27:108631. [PMID: 38188512 PMCID: PMC10770536 DOI: 10.1016/j.isci.2023.108631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 10/31/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.
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Affiliation(s)
- Sagar Bhayana
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Julie A. Dougherty
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Yu Kamigaki
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Shipra Agrawal
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Saranga Wijeratne
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - James Fitch
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Amanda P. Waller
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Katelyn J. Wolfgang
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Peter White
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Bryce A. Kerlin
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - William E. Smoyer
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
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17
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Jiang H, Shen Z, Zhuang J, Lu C, Qu Y, Xu C, Yang S, Tian X. Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy. Front Immunol 2024; 14:1335936. [PMID: 38288116 PMCID: PMC10822972 DOI: 10.3389/fimmu.2023.1335936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 12/29/2023] [Indexed: 01/31/2024] Open
Abstract
The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.
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Affiliation(s)
- Hong Jiang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Zhirang Shen
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jing Zhuang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Chen Lu
- Division of Nephrology, Department of Internal Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yue Qu
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Chengren Xu
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Shufen Yang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xuefei Tian
- Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
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18
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Thorin E, Labbé P, Lambert M, Mury P, Dagher O, Miquel G, Thorin-Trescases N. Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases. Can J Cardiol 2023; 39:1736-1756. [PMID: 37295611 DOI: 10.1016/j.cjca.2023.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/27/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathologic functions; they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis, and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs-particularly the triad ANGPTL3, 4, and 8-have an established role in lipid metabolism through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTL expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed, and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the current review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTL family in the cardiovascular system, their contribution to CVD, and the therapeutic potential of manipulating some of them.
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Affiliation(s)
- Eric Thorin
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.
| | - Pauline Labbé
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
| | - Mélanie Lambert
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Pauline Mury
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Olina Dagher
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada; Department of Cardiac Sciences, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | - Géraldine Miquel
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
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19
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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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20
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Wang Z, Nie X, Gao F, Tang Y, Ma Y, Zhang Y, Gao Y, Yang C, Ding J, Wang X. Increasing brain N-acetylneuraminic acid alleviates hydrocephalus-induced neurological deficits. CNS Neurosci Ther 2023; 29:3183-3198. [PMID: 37222223 PMCID: PMC10580356 DOI: 10.1111/cns.14253] [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: 07/04/2022] [Revised: 03/27/2023] [Accepted: 04/01/2023] [Indexed: 05/25/2023] Open
Abstract
AIMS This metabolomic study aimed to evaluate the role of N-acetylneuraminic acid (Neu5Ac) in the neurological deficits of normal pressure hydrocephalus (NPH) and its potential therapeutic effect. METHODS We analyzed the metabolic profiles of NPH using cerebrospinal fluid with multivariate and univariate statistical analyses in a set of 42 NPH patients and 38 controls. We further correlated the levels of differential metabolites with severity-related clinical parameters, including the normal pressure hydrocephalus grading scale (NPHGS). We then established kaolin-induced hydrocephalus in mice and treated them using N-acetylmannosamine (ManNAc), a precursor of Neu5Ac. We examined brain Neu5Ac, astrocyte polarization, demyelination, and neurobehavioral outcomes to explore its therapeutic effect. RESULTS Three metabolites were significantly altered in NPH patients. Only decreased Neu5Ac levels were correlated with NPHGS scores. Decreased brain Neu5Ac levels have been observed in hydrocephalic mice. Increasing brain Neu5Ac by ManNAc suppressed the activation of astrocytes and promoted their transition from A1 to A2 polarization. ManNAc also attenuated the periventricular white matter demyelination and improved neurobehavioral outcomes in hydrocephalic mice. CONCLUSION Increasing brain Neu5Ac improved the neurological outcomes associated with the regulation of astrocyte polarization and the suppression of demyelination in hydrocephalic mice, which may be a potential therapeutic strategy for NPH.
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Affiliation(s)
- Zhangyang Wang
- Department of Neurology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Xiaoqun Nie
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant SciencesChinese Academy of Sciences (CAS)ShanghaiChina
| | - Fang Gao
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant SciencesChinese Academy of Sciences (CAS)ShanghaiChina
| | - Yanmin Tang
- Department of Neurology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yuanyuan Ma
- Department of Neurology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yiying Zhang
- Department of Neurology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Yanqin Gao
- Department of the State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain ScienceFudan UniversityShanghaiChina
| | - Chen Yang
- CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant SciencesChinese Academy of Sciences (CAS)ShanghaiChina
| | - Jing Ding
- Department of Neurology, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Xin Wang
- Department of Neurology, Zhongshan HospitalFudan UniversityShanghaiChina
- Department of the State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain ScienceFudan UniversityShanghaiChina
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21
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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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22
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Vincenti F, Angeletti A, Ghiggeri GM. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 2023; 14:1167741. [PMID: 37503337 PMCID: PMC10368981 DOI: 10.3389/fimmu.2023.1167741] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2-7 per 100,000 children aged below 18 years old yearly and is classified, based on the response to drugs, into steroid sensitive (SSNS), steroid dependent, (SDNS), multidrug dependent (MDNS), and multidrug resistant (MRNS). Forms of NS that are more difficult to treat are associated with a worse outcome with respect to renal function. In particular, MRNS commonly progresses to end stage renal failure requiring renal transplantation, with recurrence of the original disease in half of the cases. Histological presentations of NS may vary from minimal glomerular lesions (MCD) to focal segmental glomerulosclerosis (FSGS) and, of relevance, the histological patterns do not correlate with the response to treatments. Moreover, around half of MRNS cases are secondary to causative pathogenic variants in genes involved in maintaining the glomerular structure. The pathogenesis of NS is still poorly understood and therapeutic approaches are mostly based on clinical experience. Understanding of pathogenetic mechanisms of NS is one of the 'unmet needs' in nephrology and represents a significant challenge for the scientific community. The scope of the present review includes exploring relevant findings, identifying unmet needs, and reviewing therapeutic developments that characterize NS in the last decades. The main aim is to provide a basis for new perspectives and mechanistic studies in NS.
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Affiliation(s)
- Flavio Vincenti
- Division of Nephrology, Department of Medicine and Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Andrea Angeletti
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
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23
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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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24
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Bano G, Imam MT, Bajpai R, Alem G, Kashyap VK, Habib A, Najmi AK. Expression of Angiopoetin-Like Protein-4 and Kidney Injury Molecule-1 as Preliminary Diagnostic Markers for Diabetes-Related Kidney Disease: A Single Center-Based Cross-Sectional Study. J Pers Med 2023; 13:jpm13040577. [PMID: 37108963 PMCID: PMC10146969 DOI: 10.3390/jpm13040577] [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: 02/09/2023] [Revised: 03/11/2023] [Accepted: 03/21/2023] [Indexed: 04/29/2023] Open
Abstract
The purpose of the study was to examine the urinary levels of kidney injury molecule-1 (KIM-1) and angiopoietin-like protein-4 (ANGPTL-4) in individuals with diabetic kidney disease (DKD) and their association with established DKD diagnostic markers such as albuminuria and estimated glomerular filtration rate (eGFR). Levels of ANGPTL-4 and KIM-1 were estimated in urine samples. A total of 135 participants were recruited into three groups: 45 diabetes type 2 patients in the control group and 90 DKD patients in two disease groups. Concentrations of ANGPTL-4 and KIM-1 were conclusively related to the urinary albumin-creatinine ratio (UACR). Also, the levels of both ANGPTL-4 and KIM-1 were negatively associated with the eGFR. Multivariable Poisson regression analysis showed that urinary ANGPTL-4 (PR: 3.40; 95% CI: 2.32 to 4.98; p < 0.001) and KIM-1 (PR: 1.25; 95% CI: 1.14 to 1.38; p < 0.001) were prevalent in DKD patients. Receiver operating characteristic (ROC) analysis of urinary ANGPTL-4 and KIM-1 in the combined form resulted in an area under curve (AUC) of 0.967 (95%CI: 0.932-1.000; p < 0.0001) in the microalbuminuria group and 1 (95%CI: 1.000-1.000; p < 0.0001) in the macroalbuminuria group. The association of urinary levels of ANGPTL-4 and KIM-1 with UACR and eGFR and significant prevalence in the diabetic kidney disease population illustrates the diagnostic potential of these biomarkers.
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Affiliation(s)
- Gulnaz Bano
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Tarique Imam
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdul Aziz University, Al-Kharj 11942, Saudi Arabia
| | - Ram Bajpai
- School of Medicine, Keele University, Staffordshire ST5 5BG, UK
| | - Ghada Alem
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdul Aziz University, Al-Kharj 11942, Saudi Arabia
| | - Varun Kumar Kashyap
- Department of Community Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi 10062, India
| | - Anwar Habib
- Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi 10062, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
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25
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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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26
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Lin J, Lv J, Yu S, Chen Y, Wang H, Chen J. Transcript Engineered Extracellular Vesicles Alleviate Alloreactive Dynamics in Renal Transplantation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202633. [PMID: 36073846 PMCID: PMC9631077 DOI: 10.1002/advs.202202633] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 08/06/2022] [Indexed: 06/15/2023]
Abstract
Direct contact of membrane molecules and cytokine interactions orchestrate immune homeostasis. However, overcoming the threshold of distance and velocity barriers, and achieving adhesion mediated immune interaction remain difficult. Here, inspired by the natural chemotaxis of regulatory T cells, multifunctionalized FOXP3 genetic engineered extracellular vesicles, termed Foe-TEVs, are designed, which display with adhesive molecules, regulatory cytokines, and coinhibitory contact molecules involving CTLA-4 and PD-1, by limited exogenous gene transduction. Foe-TEVs effectively adhere to the tubular, endothelial, and glomerular regions of allogeneic injury in the renal allograft, mitigating cell death in situ and chronic fibrosis transition. Remarkably, transcript engineering reverses the tracking velocity of vesicles to a retained phenotype and enhanced arrest coefficient by a factor of 2.16, directly interacting and attenuating excessive allosensitization kinetics in adaptive lymphoid organs. In murine allogeneic transplantation, immune adhesive Foe-TEVs alleviate pathological responses, restore renal function with well ordered ultrastructure and improved glomerular filtration rate, and prolong the survival period of the recipient from 30.16 to 92.81 days, demonstrating that the delivery of extracellular vesicles, genetically engineered for immune adhesive, is a promising strategy for the treatment of graft rejection.
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Affiliation(s)
- Jinwen Lin
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineKey Laboratory of Kidney Disease Prevention and Control TechnologyNational Key Clinical Department of Kidney DiseasesInstitute of NephrologyZhejiang University, and Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhouZhejiang Province310003P. R. China
- Zhejiang University‐University of Edinburgh InstituteSchool of MedicineZhejiang UniversityHangzhouZhejiang Province310003P. R. China
| | - Junhao Lv
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineKey Laboratory of Kidney Disease Prevention and Control TechnologyNational Key Clinical Department of Kidney DiseasesInstitute of NephrologyZhejiang University, and Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhouZhejiang Province310003P. R. China
| | - Shiping Yu
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineKey Laboratory of Kidney Disease Prevention and Control TechnologyNational Key Clinical Department of Kidney DiseasesInstitute of NephrologyZhejiang University, and Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhouZhejiang Province310003P. R. China
| | - Ying Chen
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineKey Laboratory of Kidney Disease Prevention and Control TechnologyNational Key Clinical Department of Kidney DiseasesInstitute of NephrologyZhejiang University, and Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhouZhejiang Province310003P. R. China
| | - Huiping Wang
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineKey Laboratory of Kidney Disease Prevention and Control TechnologyNational Key Clinical Department of Kidney DiseasesInstitute of NephrologyZhejiang University, and Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhouZhejiang Province310003P. R. China
| | - Jianghua Chen
- Kidney Disease CenterThe First Affiliated HospitalZhejiang University School of MedicineKey Laboratory of Kidney Disease Prevention and Control TechnologyNational Key Clinical Department of Kidney DiseasesInstitute of NephrologyZhejiang University, and Zhejiang Clinical Research Center of Kidney and Urinary System DiseaseHangzhouZhejiang Province310003P. R. China
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27
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Li Y, Liu H, Wang J, Gong W, Gao X. Serum and urine angiopoietin-like protein 4 levels correlate with different degrees of dislipidemea and proteinuria in patients with primary nephrotic syndrome. Eur J Intern Med 2022; 104:131-132. [PMID: 35760660 DOI: 10.1016/j.ejim.2022.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022]
Affiliation(s)
- Yue Li
- Department of Nephrology, Guangzhou Women and Children's Medical Center, No. 318 Renmin Middle Road, Guangzhou 510623, China
| | - Huajie Liu
- Department of Neonatology, Children's Hospital of Shanxi, Taiyuan 030000, China
| | - Jingzhi Wang
- Department of Nephrology, Guangzhou Women and Children's Medical Center, No. 318 Renmin Middle Road, Guangzhou 510623, China
| | - Wangqiu Gong
- Department of Nephrology, Guangzhou Women and Children's Medical Center, No. 318 Renmin Middle Road, Guangzhou 510623, China
| | - Xia Gao
- Department of Nephrology, Guangzhou Women and Children's Medical Center, No. 318 Renmin Middle Road, Guangzhou 510623, China.
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28
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Study on the Mechanism of circRNA Regulating the miRNA Level in Nephrotic Syndrome. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3729995. [PMID: 35859997 PMCID: PMC9293565 DOI: 10.1155/2022/3729995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/10/2022] [Accepted: 06/17/2022] [Indexed: 12/02/2022]
Abstract
Background Nephrotic syndrome is an enormous public healthy threaten, which causes a variety of complications and secondary disease; however, the molecular mechanism of nephrotic syndrome remains unclear. Methods In our study, RNA-seq were used to test the transcription level of patients with nephrotic syndrome, in order to investigate the interaction of circRNA-miRNA-mRNA in nephrotic syndrome patients. Results Consistent with our hypothesis, miRNAs were confirmed to be associated with nephrotic syndrome, majority of their targeting circRNAs downregulated in nephrotic syndrome patients and at the same time, the KEGG pathway analysis found that target genes of the circRNAs bonding miRNAs was highly correlated with the occurrence of kidney diseases. Conclusion Thus, we can draw a conclusion that downregulated circRNAs cause miRNA expressing aberrant and then affect the expression level of mRNA, finally leading to the generation of nephrotic syndrome.
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29
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Salvadori M, Tsalouchos A. How immunosuppressive drugs may directly target podocytes in glomerular diseases. Pediatr Nephrol 2022; 37:1431-1441. [PMID: 34244853 DOI: 10.1007/s00467-021-05196-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/07/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022]
Abstract
Podocytes are the direct target of immunologic injury in many immune-mediated glomerular diseases, leading to proteinuria and subsequent kidney failure. Immunosuppressive agents such as steroids, calcineurin inhibitors, and rituximab are the commonly used treatment strategies in this context for their immunotherapeutic or anti-inflammatory properties. However, in recent years, studies have demonstrated that immunosuppressive agents can have a direct effect on podocytes, introducing the concept of the non-immunologic mechanism of kidney protection by immunomodulators. In this review, we focus on the mechanisms by which these agents may directly target the podocyte independent of their systemic effects and examine their clinical significance.
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Affiliation(s)
- Maurizio Salvadori
- Department of Transplantation Renal Unit, Careggi University Hospital, 50139, Florence, Italy
| | - Aris Tsalouchos
- Department of Medicine, Division of Nephrology, Santa Maria Annunziata Hospital, Via Antella, 58, 50012 Ponte a Niccheri, Bagno a Ripoli, Florence, Italy.
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30
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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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31
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Liu F, Chen J, Luo C, Meng X. Pathogenic Role of MicroRNA Dysregulation in Podocytopathies. Front Physiol 2022; 13:948094. [PMID: 35845986 PMCID: PMC9277480 DOI: 10.3389/fphys.2022.948094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) participate in the regulation of various important biological processes by regulating the expression of various genes at the post-transcriptional level. Podocytopathies are a series of renal diseases in which direct or indirect damage of podocytes results in proteinuria or nephrotic syndrome. Despite decades of research, the exact pathogenesis of podocytopathies remains incompletely understood and effective therapies are still lacking. An increasing body of evidence has revealed a critical role of miRNAs dysregulation in the onset and progression of podocytopathies. Moreover, several lines of research aimed at improving common podocytopathies diagnostic tools and avoiding invasive kidney biopsies have also identified circulating and urine miRNAs as possible diagnostic and prognostic biomarkers for podocytopathies. The present review mainly aims to provide an updated overview of the recent achievements in research on the potential applicability of miRNAs involved in renal disorders related to podocyte dysfunction by laying particular emphasis on focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), diabetic kidney disease (DKD) and IgA nephropathy (IgAN). Further investigation into these dysregulated miRNAs will not only generate novel insights into the mechanisms of podocytopathies, but also might yield novel strategies for the diagnosis and therapy of this disease.
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Affiliation(s)
- Feng Liu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiefang Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changqing Luo
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Changqing Luo, ; Xianfang Meng,
| | - Xianfang Meng
- Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Changqing Luo, ; Xianfang Meng,
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32
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Chen CH, Wu YC, Li YC, Tsai FA, Li JY, Wang JS, Lee CH. Factors Associated with Postoperative Lipiduria and Hypoxemia in Patients Undergoing Surgery for Orthopedic Fractures. Front Surg 2022; 9:814229. [PMID: 35574529 PMCID: PMC9096020 DOI: 10.3389/fsurg.2022.814229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
We investigated factors associated with postoperative lipiduria and hypoxemia in patients undergoing surgery for orthopedic fractures. We enrolled patients who presented to our emergency department due to traumatic fractures between 2016 and 2017. We collected urine samples within 24 h after the patients had undergone surgery to determine the presence of lipiduria. Hypoxemia was defined as an SpO2 <95% determined with a pulse oximeter during the hospitalization. Patients’ anthropometric data, medical history, and laboratory test results were collected from the electronic medical record. Logistic regression analyses were used to determine the associations of clinical factors with postoperative lipiduria and hypoxemia with multivariate adjustments. A total of 144 patients were analyzed (mean age 51.3 ± 22.9 years, male 50.7%). Diabetes (odd ratio 3.684, 95% CI, 1.256–10.810, p = 0.018) and operation time (odd ratio 1.005, 95% CI, 1.000–1.009, p = 0.029) were independently associated with postoperative lipiduria, while age (odd ratio 1.034, 95% CI, 1.003–1.066, p = 0.029), body mass index (odd ratio 1.100, 95% CI, 1.007–1.203, p = 0.035), and operation time (odd ratio 1.005, 95% CI, 1.000–1.010, p = 0.033) were independently associated with postoperative hypoxemia. We identified several factors independently associated with postoperative lipiduria and hypoxemia in patients with fracture undergoing surgical intervention. Operation time was associated with both postoperative lipiduria and hypoxemia, and we recommend that patients with prolonged operation for fractures should be carefully monitored for clinical signs related to fat embolism syndrome.
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Affiliation(s)
- Chih-Hui Chen
- Department of Orthopedics, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Orthopedic surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yun-Che Wu
- Department of Orthopedics, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yu-Cheng Li
- Department of Pathology & Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Feng-An Tsai
- Department of Pathology & Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jen-Ying Li
- Department of Pathology & Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jun-Sing Wang
- Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Correspondence: Jun-Sing Wang Cheng-Hung Lee
| | - Cheng-Hung Lee
- Department of Orthopedics, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Food Science and Technology, Hung Kuang University, Taichung, Taiwan
- Correspondence: Jun-Sing Wang Cheng-Hung Lee
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33
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Lin S, Miao Y, Zheng X, Dong Y, Yang Q, Yang Q, Du S, Xu J, Zhou S, Yuan T. ANGPTL4 negatively regulates the progression of osteosarcoma by remodeling branched-chain amino acid metabolism. Cell Death Dis 2022; 8:225. [PMID: 35461343 PMCID: PMC9035178 DOI: 10.1038/s41420-022-01029-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 01/18/2023]
Abstract
Angiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly known as a regulator in lipid metabolism, now, is also indicated to be involved in the regulation of cancer progression and metastasis. However, little is known about not only biological functions, but also underlying mechanism of ANGPTL4 in the progression of osteosarcoma (OS). Here, we discovered that ANGPTL4 is downregulated in OS, and is associated with branched-chain amino acid (BCAA) metabolism. The BCAAs (valine, leucine, and isoleucine) are essential amino acids that play an important role in metabolic regulation. Aberrant BCAA metabolism is also found in various cancers and is associated with tumor progression, including proliferation, invasion, and metastasis. In this study, we indicated that the negative relation between the expression of ANGPTL4 and BCAA catabolism in OS samples and cell lines. The knockdown of ANGPTL4 in OS cells resulted in the accumulation of BCAAs, which in turn activated the mTOR signaling pathway, enhancing OS cell proliferation. Thus, reduced expression of ANGPTL4 is associated with the progression of OS. Taken together, our results demonstrated that the ANGPTL4/BCAA/mTOR axis is an important pathway in OS progression and may be a potential therapeutic target to slow OS progression.
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Second and Third Generational Advances in Therapies of the Immune-Mediated Kidney Diseases in Children and Adolescents. CHILDREN 2022; 9:children9040536. [PMID: 35455580 PMCID: PMC9030090 DOI: 10.3390/children9040536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 11/17/2022]
Abstract
Therapy of immune-mediated kidney diseases has evolved during recent decades from the non-specific use of corticosteroids and antiproliferative agents (like cyclophosphamide or azathioprine), towards the use of more specific drugs with measurable pharmacokinetics, like calcineurin inhibitors (cyclosporine A and tacrolimus) and mycophenolate mofetil, to the treatment with biologic drugs targeting detailed specific receptors, like rituximab, eculizumab or abatacept. Moreover, the data coming from a molecular science revealed that several drugs, which have been previously used exclusively to modify the upregulated adaptive immune system, may also exert a local effect on the kidney microstructure and ameliorate the functional instability of podocytes, reducing the leak of protein into the urinary space. The innate immune system also became a target of new therapies, as its specific role in different kidney diseases has been de novo defined. Current therapy of several immune kidney diseases may now be personalized, based on the detailed diagnostic procedures, including molecular tests. However, in most cases there is still a space for standard therapies based on variable protocols including usage of steroids with the steroid-sparing agents. They are used as a first-line treatment, while modern biologic agents are selected as further steps in cases of lack of the efficacy or toxicity of the basic therapies. In several clinical settings, the biologic drugs are effective as the add-on therapy.
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35
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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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36
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Gao Y, Ma Y, Xie D, Jiang H. ManNAc protects against podocyte pyroptosis via inhibiting mitochondrial damage and ROS/NLRP3 signaling pathway in diabetic kidney injury model. Int Immunopharmacol 2022; 107:108711. [PMID: 35338958 DOI: 10.1016/j.intimp.2022.108711] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/05/2022] [Accepted: 03/14/2022] [Indexed: 12/31/2022]
Abstract
Podocyte pyroptosis is an inflammatory form of cell death associated with Diabetic nephropathy (DN). It is reported that hyposialylated Angiopoietin-like-4 (Angptl4) secreted by glomerular podocytes plays an important role in the formation of proteinuria. Previous study indicated that supplementation of sialic acid precursor N-acetylmannosamine (ManNAc) could inhibit podocyte apoptosis and actin cytoskeleton rearrangement. Nevertheless, whether ManNAc could improve diabetic kidney damage by inhibiting podocyte pyroptosis remains unclear. This study aimed to explore the effect of ManNAc therapy on alleviating diabetic renal injury and podocyte pyroptosis, and its possible mechanism was also figured out. The male 8-week-old C57BL/6 mice were divided into three groups: control group, Streptozocin (STZ)-induced DN group, and ManNAc treated diabetic group. Then, the changes in renal function, renal histopathology, podocyte pyroptosis, reactive oxygen species (ROS), and mitochondrial dysfunction were measured. Herein, we observed that the upregulated expression of Angptl4 was involved in podocyte injury. ManNAc treatment ameliorated podocyte ultrastructure, renal function, and renal histopathology in STZ-induced DN mice. In addition, ManNAc administration attenuated podocyte cell death and suppressed the activation of Nucleotide leukin-rich polypeptide 3 (NLRP3), caspase-1, and interleukin-1β (IL-1β), and the cleavage of gasdermin-D (GSDMD). Moreover, ManNAc inhibited ROS production and restored mitochondrial morphology in vivo and vitro. Further, ManNAc administration significantly alleviated podocyte pyroptosis through inhibiting ROS/NLRP3 signaling pathway. Therefore, these results elucidated that the upregulated expression of Angptl4 was involved in podocyte injury and ManNAc treatment protected against podocyte pyroptosis via inhibiting mitochondrial injury and ROS/NLRP3 signaling pathway in DN mice.
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Affiliation(s)
- Yanmin Gao
- Department of General Practice, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; Department of General Practice, Kongjiang Community Health Service Center, Yangpu District, Shanghai 200093, China
| | - Yanli Ma
- Department of Pediatrics, Fourth People's Hospital Affiliated to Tongji University, Shanghai 200434, China
| | - Di Xie
- Emergency Department, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Hua Jiang
- Department of General Practice, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
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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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38
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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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39
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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: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 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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40
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Sylvers-Davie KL, Davies BSJ. Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8. Am J Physiol Endocrinol Metab 2021; 321:E493-E508. [PMID: 34338039 PMCID: PMC8560382 DOI: 10.1152/ajpendo.00195.2021] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/14/2021] [Accepted: 07/26/2021] [Indexed: 01/28/2023]
Abstract
Triglyceride-rich lipoproteins deliver fatty acids to tissues for oxidation and for storage. Release of fatty acids from circulating lipoprotein triglycerides is carried out by lipoprotein lipase (LPL), thus LPL serves as a critical gatekeeper of fatty acid uptake into tissues. LPL activity is regulated by a number of extracellular proteins including three members of the angiopoietin-like family of proteins. In this review, we discuss our current understanding of how, where, and when ANGPTL3, ANGPTL4, and ANGPTL8 regulate lipoprotein lipase activity, with a particular emphasis on how these proteins interact with each other to coordinate triglyceride metabolism and fat partitioning.
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Affiliation(s)
- Kelli L Sylvers-Davie
- Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center, and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa
| | - Brandon S J Davies
- Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center, and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa
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41
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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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42
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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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43
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Sharma I, Liao Y, Zheng X, Kanwar YS. New Pandemic: Obesity and Associated Nephropathy. Front Med (Lausanne) 2021; 8:673556. [PMID: 34268323 PMCID: PMC8275856 DOI: 10.3389/fmed.2021.673556] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
Incidence of obesity related renal disorders have increased 10-folds in recent years. One of the consequences of obesity is an increased glomerular filtration rate (GFR) that leads to the enlargement of the renal glomerulus, i.e., glomerulomegaly. This heightened hyper-filtration in the setting of type 2 diabetes irreparably damages the kidney and leads to progression of end stage renal disease (ESRD). The patients suffering from type 2 diabetes have progressive proteinuria, and eventually one third of them develop chronic kidney disease (CKD) and ESRD. For ameliorating the progression of CKD, inhibitors of renin angiotensin aldosterone system (RAAS) seemed to be effective, but on a short-term basis only. Long term and stable treatment strategies like weight loss via restricted or hypo-caloric diet or bariatric surgery have yielded better promising results in terms of amelioration of proteinuria and maintenance of normal GFR. Body mass index (BMI) is considered as a traditional marker for the onset of obesity, but apparently, it is not a reliable indicator, and thus there is a need for more precise evaluation of regional fat distribution and amount of muscle mass. With respect to the pathogenesis, recent investigations have suggested perturbation in fatty acid and cholesterol metabolism as the critical mediators in ectopic renal lipid accumulation associated with inflammation, increased generation of ROS, RAAS activation and consequential tubulo-interstitial injury. This review summarizes the renewed approaches for the obesity assessment and evaluation of the pathogenesis of CKD, altered renal hemodynamics and potential therapeutic targets.
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Affiliation(s)
- Isha Sharma
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States
| | - Yingjun Liao
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States.,Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoping Zheng
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States.,Department of Urology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yashpal S Kanwar
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States
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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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Suzuki T, Ishii S, Shinohara M, Kawano Y, Wakahashi K, Kawano H, Sada A, Minagawa K, Hamada M, Takahashi S, Furuyashiki T, Tan NS, Matsui T, Katayama Y. Mobilization efficiency is critically regulated by fat via marrow PPARδ. Haematologica 2021; 106:1671-1683. [PMID: 33538151 PMCID: PMC8168511 DOI: 10.3324/haematol.2020.265751] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Indexed: 12/21/2022] Open
Abstract
The mobilization efficiency of hematopoietic stem/progenitor cells from bone marrow (BM) to circulation by granulocyte colony-stimulating factor (G-CSF) is dramatically dispersed in humans and mice with no mechanistic lead for poor mobilizers. The regulatory mechanism for mobilization efficiency by dietary fat was assessed in mice. Fat-free diet (FFD) for 2 weeks greatly increased mobilization compared to normal diet (ND). The BM mRNA level of peroxisome proliferator-activated receptor δ (PPARδ), a receptor for lipid mediators, was markedly up-regulated by G-CSF in mice fed with ND and displayed strong positive correlation with widely scattered mobilization efficiency. It was hypothesized that BM fat ligand for PPARδ might inhibit mobilization. The PPARδ agonist inhibited mobilization in mice fed with ND and enhanced mobilization by FFD. Treatment with the PPARδ antagonist and chimeric mice with PPARδ+/- BM showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that BM PPARδ expression was enhanced by G-CSF mainly in mature/immature neutrophils. BM lipid mediator analysis revealed that G-CSF treatment and FFD resulted in the exhaustion of ω3-polyunsaturated fatty acids such as eicosapentaenoic acid (EPA). EPA induced the up-regulation of genes downstream of PPARδ, such as carnitine palmitoyltransferase-1α and angiopoietin-like protein 4 (Angptl4), in mature/immature neutrophils in vitro and inhibited enhanced mobilization in mice fed with FFD in vivo. Treatment of wild-type mice with the anti-Angptl4 antibody enhanced mobilization together with BM vascular permeability. Collectively, PPARδ signaling in BM mature/immature neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.
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Affiliation(s)
- Tomohide Suzuki
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Shinichi Ishii
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Masakazu Shinohara
- Division of Epidemiology; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Yuko Kawano
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Kanako Wakahashi
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Hiroki Kawano
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Akiko Sada
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Kentaro Minagawa
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Michito Hamada
- Department of Anatomy and Embryology, Faculty of Medicine,
| | - Satoru Takahashi
- Department of Anatomy and Embryology, Faculty of Medicine; Transborder Medical Research Center (TMRC),; International Institute for Integrative Sleep Medicine (WPI-IIIS); Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8576
| | - Tomoyuki Furuyashiki
- Division of Pharmacology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232; School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551
| | - Toshimitsu Matsui
- Department of Hematology, Nishiwaki Municipal Hospital, 652-1 Shimotoda, Nishiwaki 677-0043
| | - Yoshio Katayama
- Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017.
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Li Y, Liu Q, Kang C, Cui W, Xu Z, Zhong F, Gao X. Serum and urine ANGPTL8 expression levels are associated with hyperlipidemia and proteinuria in primary nephrotic syndrome. BMC Nephrol 2021; 22:130. [PMID: 33853533 PMCID: PMC8045271 DOI: 10.1186/s12882-021-02350-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/06/2021] [Indexed: 11/24/2022] Open
Abstract
Background This study aimed to investigate the expression characteristics of ANGPTL8 in patients with primary nephrotic syndrome and its possible correlation with hyperlipidemia and proteinuria. Methods ANGPTL8 levels were determined using an enzyme-linked immunosorbent assay in 133 subjects with PNS and 60 healthy controls. Results Compared with healthy controls, subjects with primary nephrotic syndrome had higher levels of serum and urine ANGPTL8 (P < 0.001). In primary nephrotic syndrome patients, serum ANGPTL8 was positively correlated with cholesterol (r = 0.209, P < 0.05) and triglycerides (r = 0.412, P < 0.001), while there was no correlation with 24 hUTP. Urine ANGPTL8 was positively correlated with high-density lipoprotein cholesterol (r = 0.181, P < 0.05) and was significantly negatively correlated with creatinine (r = − 0.323, P < 0.001), eGFR (r = − 0, P < 0.001) and 24 hUTP (r = − 0.268, P = 0.002). Interestingly, the urine ANGPTL8 concentrations in membranous nephropathy and mesangial proliferative glomerulonephritis pathological types were different. Conclusions Serum and urine ANGPTL8 levels in primary nephrotic syndrome patients were correlated with blood lipid levels and proteinuria, respectively, suggesting that ANGPTL8 may play a role in the development of primary nephrotic syndrome hyperlipidemia and proteinuria.
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Affiliation(s)
- Yue Li
- Graduate School, Gansu University of Chinese Medicine, Lanzhou city, 730000, China
| | - Qingju Liu
- Graduate School, Gansu University of Chinese Medicine, Lanzhou city, 730000, China.,Departmentof Pediatrics, the Fifth People's Hospital of Chengdu, Chengdu city, 611130, China
| | - Chengdong Kang
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou city, 510623, China
| | - Weijing Cui
- Pediatric Department, Gansu Provincial Hospital, Lanzhou city, 730000, China
| | - Zichuan Xu
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou city, 510623, China
| | - Fu Zhong
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou city, 510623, China
| | - Xia Gao
- Department of Nephrology, Guangzhou Women and Children's Medical Center, Guangzhou city, 510623, China.
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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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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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Walther CP, Ix JH, Biggs ML, Kizer JR, Navaneethan SD, Djoussé L, Mukamal KJ. Nonesterified Fatty Acids and Kidney Function Decline in Older Adults: Findings From the Cardiovascular Health Study. Am J Kidney Dis 2021; 78:259-267. [PMID: 33548344 DOI: 10.1053/j.ajkd.2020.11.030] [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: 07/24/2020] [Accepted: 11/30/2020] [Indexed: 11/11/2022]
Abstract
RATIONALE & OBJECTIVE Circulating nonesterified fatty acids (NEFAs) make up a small portion of circulating lipids but are a metabolically important energy source. Excessive circulating NEFAs may contribute to lipotoxicity in many tissues, including the kidneys. We investigated the relationship between total circulating NEFA concentration and kidney outcomes in older, community-dwelling adults. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS 4,698 participants≥65 years of age in the Cardiovascular Health Study who underwent total fasting serum NEFA concentration measurements in 1992-1993. EXPOSURE Fasting serum NEFA concentration at one time point. OUTCOME Three primary outcomes: estimated glomerular filtration rate (eGFR) decline of≥30%, the composite of eGFR decline≥30% or kidney failure with replacement therapy, and change in eGFR. These outcomes were assessed over 4- and 13-year periods. ANALYTICAL APPROACH Logistic regression for the dichotomous outcomes and mixed effects models for the continuous outcome, with sequential adjustment for baseline covariates. Inverse probability of attrition weighting was implemented to account for informative attrition during the follow-up periods. RESULTS Serum NEFA concentrations were not independently associated with kidney outcomes. In unadjusted and partially adjusted analyses, the highest quartile of serum NEFA concentration (compared with lowest) was associated with a higher risk of≥30% eGFR decline at 4 years and faster rate of decline of eGFR. No associations were evident after adjustment for comorbidities, lipid levels, insulin sensitivity, medications, and vital signs: the odds ratio for the eGFR decline outcome was 1.33 (95% CI, 0.83-2.13), and the difference in eGFR slope in the highest versus lowest quartile of serum NEFA concentration was-0.15 (95% CI, -0.36 to 0.06) mL/min/1.73m2 per year. LIMITATIONS Single NEFA measurements, no measurements of post-glucose load NEFA concentrations or individual NEFA species, no measurement of baseline urine albumin. CONCLUSIONS A single fasting serum NEFA concentration was not independently associated with long-term adverse kidney outcomes in a cohort of older community-living adults.
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Affiliation(s)
- Carl P Walther
- Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX.
| | - Joachim H Ix
- Nephrology Section, Veterans Affairs San Diego Healthcare System, and Division of Nephrology-Hypertension, University of California-San Diego, La Jolla, CA
| | - Mary L Biggs
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA
| | - Jorge R Kizer
- Cardiology Section, San Francisco Veterans Affairs Healthcare System, and Departments of Medicine, Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA
| | - Sankar D Navaneethan
- Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX; Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Luc Djoussé
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, and Boston Veterans Affairs Healthcare System, Boston, MA
| | - Kenneth J Mukamal
- Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA
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50
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van den Broek M, Smeets B, Schreuder MF, Jansen J. The podocyte as a direct target of glucocorticoids in nephrotic syndrome. Nephrol Dial Transplant 2021; 37:1808-1815. [PMID: 33515261 DOI: 10.1093/ndt/gfab016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Indexed: 12/14/2022] Open
Abstract
Nephrotic syndrome (NS) is characterized by massive proteinuria; podocyte loss or altered function is a central event in its pathophysiology. Treatment with glucocorticoids is the mainstay of therapy. However, many patients experience one or multiple relapses and prolonged use may be associated with severe adverse effects. Recently, the beneficial effects of glucocorticoids have been attributed to a direct effect on podocytes in addition to the well-known immunosuppressive effects. The molecular effects of glucocorticoid action have been studied using animal and cell models of NS. This review provides a comprehensive overview of different molecular mediators regulated by glucocorticoids including an overview of the model systems that were used to study them. Glucocorticoids are described to stimulate podocyte recovery by restoring pro-survival signaling of slit diaphragm related proteins and limiting inflammatory responses. Of special interest is the effect of glucocorticoids on stabilizing the cytoskeleton of podocytes, since these effects are also described for other therapeutic agents used in NS, such as cyclosporin. Current models provide much insight, but do not fully recapitulate the human condition since the pathophysiology underlying NS is poorly understood. New and promising models include the glomerulus-on-a-chip and kidney organoids, which have the potential to be further developed into functional NS models in the future.
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Affiliation(s)
- Martijn van den Broek
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.,Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Bart Smeets
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Michiel F Schreuder
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Jitske Jansen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.,Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Amalia Children's Hospital, Nijmegen, The Netherlands
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