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

Haiyan Fu, Yuan Gui, Silvia Liu, Yuanyuan Wang, Sheldon Ira Bastacky, Yi Qiao, Rong Zhang, Christopher Bonin, Geneva Hargis, Yanbao Yu, Donald L. Kreutzer, Partha Sarathi Biswas, Yanjiao Zhou, Yanlin Wang, Xiao Jun Tian, Youhua Liu, Dong Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number103112
JournaliScience
Volume24
Issue number10
DOIs
StatePublished - Oct 22 2021

ASJC Scopus subject areas

  • General

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