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

Autor:	Kim JJ; 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. Electronic address: jjkim@med.miami.edu., David JM; 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., Wilbon SS; 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., Santos JV; 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., Patel DM; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia., Ahmad A; Department of Radiation Oncology, University of Miami, FL 33136, United States., Mitrofanova A; 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; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, United States., Liu X; 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., Mallela SK; 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., Ducasa GM; 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., Ge M; 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., Sloan AJ; 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., Al-Ali H; 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., Boulina M; Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States., Mendez AJ; Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States., Contreras GN; 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., Prunotto M; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland., Sohail A; Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, United States., Fridman R; Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, United States., Miner JH; Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, United States., Merscher S; 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., Fornoni A; 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. Electronic address: afornoni@med.miami.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2021 Jan; Vol. 63, pp. 103162. Date of Electronic Publication: 2020 Dec 16.
DOI:	10.1016/j.ebiom.2020.103162
Abstrakt:	Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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. Competing Interests: Declaration of Competing Interest A.F., and S.M. are inventors on pending or issued patents (PCT/US11/56272, PCT/US12/62594, PCT/US2019/041730, PCT/US2019/032215, PCT/US13/36484 and PCT 62/674,897) aimed to diagnosing or treating proteinuric kidney diseases. They stand to gain royalties from their future commercialization of these patents. A.F. is Vice-President of L&F Health LLC and is consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin from L&F Research for the treatment of kidney disease. A.F. is founder of LipoNexT LLC. S.M. is a consultant for Kintai Therapeutics, Inc and holds equity interest in L&F Research. AF and SM are supported by Hoffman-La Roche and by Boehringer Ingelheim. (Copyright © 2020. Published by Elsevier B.V.)
Databáze:	MEDLINE
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