期刊
EBIOMEDICINE
卷 63, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2020.103162
关键词
Alport syndrome; Discoidin domain receptor; Podocyte lipotoxicity; Glomerular basement membrane
资金
- NIH (Miami Clinical Translational Science Institute, National Center for Advancing Translational Sciences) [R01DK117599, R01DK104753, R01CA227493, U54DK083912, UM1DK100846, U01DK116101, UL1TR000460]
- National Institute on Minority Health and Health Disparities
- Hoffmann-La Roche
- Alport Syndrome Foundation
- NIH/NIDDK [F32DK115109]
DDR1 activation mediated by Col I induces CD36-mediated podocyte lipotoxic injury in Alport Syndrome mice. Ezetimibe interferes with the CD36/DDR1 interaction, thus protecting renal function. Targeting the Col I/DDR1 pathway may represent a new therapeutic strategy for patients with AS and CKD associated with Col4 mutations.
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. (C) 2020 Published by Elsevier B.V.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据