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

作者：Jin-Ju Kim, J. M. David, Sydney S. Wilbon, J. Santos, Devang M. Patel, Anis Ahmad, A. Mitrofanova, Xiaochen Liu, S. Mallela, G. Ducasa, M. Ge, A. Sloan, H. Al-Ali, Maria Boulina, A. Mendez, G. Contreras, M. Prunotto, Anjum Sohail, R. Fridman, J. Miner, S. Merscher, A. Fornoni · 发表于：EBioMedicine · 年份：2020 · DOI：10.1016/j.ebiom.2020.103162 · 被引用次数：49 · 研究领域：Medicine

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) associa...