The hepatocyte growth factor/c-met pathway is a key determinant of the fibrotic kidney local microenvironment

• Published in: iScience Vol. 24; no. 10; p. 103112
• Main Authors: Fu, Haiyan, Gui, Yuan, Liu, Silvia, Wang, Yuanyuan, Bastacky, Sheldon Ira, Qiao, Yi, Zhang, Rong, Bonin, Christopher, Hargis, Geneva, Yu, Yanbao, Kreutzer, Donald L., Biswas, Partha Sarathi, Zhou, Yanjiao, Wang, Yanlin, Tian, Xiao-Jun, Liu, Youhua, Zhou, Dong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22-10-2021; Elsevier
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103112

The kidney local microenvironment (KLM) plays a critical role in the pathogenesis of kidney fibrosis. However, the composition and regulation of a fibrotic KLM remain unclear. Through a multidisciplinary approach, we investigated the roles of the hepatocyte growth factor/c-met signaling pathway in regulating KLM formation in various chronic kidney disease (CKD) models. We performed a retrospective analysis of single-cell RNA sequencing data and determined that tubular epithelial cells and macrophages are two major cell populations in a fibrotic kidney. We then created a mathematical model that predicted loss of c-met in tubular cells would cause greater responses to injury than loss of c-met in macrophages. By generating c-met conditional knockout mice, we validated that loss of c-met influences epithelial plasticity, myofibroblast activation, and extracellular matrix synthesis/degradation, which ultimately determined the characteristics of the fibrotic KLM. Our findings open the possibility of designing effective therapeutic strategies to retard CKD.
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•A fibrotic kidney local microenvironment (KLM) is focal and segmental•C-met is more enriched in the distal tubule and collecting duct than in macrophages•Loss of c-met in tubular cells causes superior quick responses to simulated injury•HGF/c-met pathway determines the characteristics of a formed fibrotic KLM