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

作者：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^*

来源：iScience, 2021, 24(10): 103112.

DOI：10.1016/j.isci.2021.103112

• TO-MESENCHYMAL TRANSITION
• CELL-CYCLE ARREST
• INTERSTITIAL FIBROSIS
• PLASMINOGEN-ACTIVATOR
• MOLECULAR-MECHANISMS
• TENASCIN-C
• PROGRESSION
• MICE
• CONTRIBUTES
• PLASTICITY

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.

• 单位
  南方医科大学