Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome

Jin-Ju Kim; Judith M David; Sydney S Wilbon; Javier V Santos; Devang M Patel; Anis Ahmad; Alla Mitrofanova; Xiaochen Liu; Shamroop K Mallela; Gloria M Ducasa; Mengyuan Ge; Alexis J Sloan; Hassan Al-Ali; Marcia Boulina; Armando J Mendez; Gabriel N Contreras; Marco Prunotto; Anjum Sohail; Rafael Fridman; Jeffrey H Miner; Sandra Merscher; Alessia Fornoni

doi:10.1016/j.ebiom.2020.103162

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Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome

Journal article

Open access

Peer reviewed

Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome

Jin-Ju Kim, Judith M David, Sydney S Wilbon, Javier V Santos, Devang M Patel, Anis Ahmad, Alla Mitrofanova, Xiaochen Liu, Shamroop K Mallela, Gloria M Ducasa, …

EBioMedicine, Vol.63, pp.103162-103162

2021-01

DOI: https://doi.org/10.1016/j.ebiom.2020.103162

PMID: 33340991

Abstract

Glomerular basement membrane

Discoidin domain receptor

Podocyte lipotoxicity

Alport syndrome

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is activated by collagens that is involved in the pathogenesis of fibrotic disorders. Interestingly, de novo production of the collagen type I (Col I) has been observed in Col4a3 knockout mice, a mouse model of Alport Syndrome (AS mice). Deletion of the DDR1 in AS mice was shown to improve survival and renal function. However, the mechanisms driving DDR1-dependent fibrosis remain largely unknown. Podocyte pDDR1 levels, Collagen and cluster of differentiation 36 (CD36) expression was analyzed by Real-time PCR and Western blot. Lipid droplet accumulation and content was determined using Bodipy staining and enzymatic analysis. CD36 and DDR1 interaction was determined by co-immunoprecipitation. Creatinine, BUN, albuminuria, lipid content, and histological and morphological assessment of kidneys harvested from AS mice treated with Ezetimibe and/or Ramipril or vehicle was performed. We demonstrate that Col I-mediated DDR1 activation induces CD36-mediated podocyte lipotoxic injury. We show that Ezetimibe interferes with the CD36/DDR1 interaction in vitro and prevents lipotoxicity in AS mice thus preserving renal function similarly to ramipril. Our study suggests that Col I/DDR1-mediated lipotoxicity contributes to renal failure in AS and that targeting this pathway may represent a new therapeutic strategy for patients with AS and with chronic kidney diseases (CKD) associated with Col4 mutations. This study is supported by the NIH grants R01DK117599, R01DK104753, R01CA227493, U54DK083912, UM1DK100846, U01DK116101, UL1TR000460 (Miami Clinical Translational Science Institute, National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities), F32DK115109, Hoffmann-La Roche and Alport Syndrome Foundation.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.132 Extracellular Matrix & Cell Differentiation; 1.132.1373 Alport Syndrome
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine

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Title: Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome
Creators: Jin-Ju Kim - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Judith M David - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Sydney S Wilbon - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Javier V Santos - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Devang M Patel - Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
Anis Ahmad - Department of Radiation Oncology, University of Miami, FL 33136, United States
Alla Mitrofanova - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Xiaochen Liu - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Shamroop K Mallela - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Gloria M Ducasa - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Mengyuan Ge - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Alexis J Sloan - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Hassan Al-Ali - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Marcia Boulina - Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
Armando J Mendez - Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
Gabriel N Contreras - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Marco Prunotto - Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
Anjum Sohail - Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, United States
Rafael Fridman - Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, United States
Jeffrey H Miner - Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, United States
Sandra Merscher - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Alessia Fornoni - Katz Family Division of Nephrology and Hypertension, Drug Discovery center, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL 33136, United States
Publication Details: EBioMedicine, Vol.63, pp.103162-103162
Publisher: Elsevier B.V
Academic Unit: Miller School of Medicine; Diabetes Research Institute (DRI); Miami Project to Cure Paralysis; Peggy and Harold Katz Family Drug Discovery Center; UMMG Dept of Medicine - Nephrology & Hypertension Div; UMMG Dept of Neurological Surgery; UMMG Dept of Radiation Oncology
Language: English
Resource Type: Journal article
PMID: 33340991
Record Identifier: 991031578789602976