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

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.

SUBMITTER: Fu H

PROVIDER: S-EPMC8479790 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Fu Haiyan H Gui Yuan Y Liu Silvia S Wang Yuanyuan Y Bastacky Sheldon Ira SI Qiao Yi Y Zhang Rong R Bonin Christopher C Hargis Geneva G Yu Yanbao Y Kreutzer Donald L DL Biswas Partha Sarathi PS Zhou Yanjiao Y Wang Yanlin Y Tian Xiao-Jun XJ Liu Youhua Y Zhou Dong D

iScience 20210909 10

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 macrop ...[more]

PMID: 34622165

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Project description:MET, the receptor for hepatocyte growth factor (HGF), is involved in wide variety of biological events and its aberrant activation is implicated in the pathogenesis of cancer. Especially, MET signaling is associated with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), key drugs in therapy of non-small cell lung cancer. MET has 11 potential N-glycosylation sites, however, the site-specific roles of N-glycans have not been elucidated. Here, we report that N-glycans regulate proteolytic processing of MET and HGF induced MET signaling, site specifically. N-glycosylation inhibitors suppressed processing and trafficking of endogenous MET in H1975 and EBC-1 lung cancer cells and exogenous MET in CHO cells. We purified the recombinant extracellular domain of human MET and determined the site-specific N-glycan structures and occupancy using nanoflow liquid chromatography-electrospray ionization mass spectrometry. The results indicated that most sites were fully glycosylated and the dominant population were complex-type which were rich in sialic acids and core fucoses. To examine the effects of N-glycan deletion of MET, we prepared endogenous-MET-knockout Flp-In CHO cells and transfected with series of N-glycan deletion mutants of MET. It was found that several N-glycans are implicated in processing of MET. It was also suggested that the N-glycans of -subunit of MET positively regulate HGF signaling, and the N-glycans of β-subunit negatively regulate HGF signaling. In all-N-glycan deletion mutant, processing and signaling were significantly suppressed. It was observed that the cell proliferation rate was suppressed in all-N-glycan deletion mutant, although the cell surface expression levels of MET were not completely diminished. We examined the HGF biding affinity for the recombinant extracellular domain of MET and found that peptide N-glycosidase F treatment did not affect the ligand binding affinity. It was suggested that N-glycans of MET affect the status and the function of the receptor site-specifically.

Dataset Information

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

Publications

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

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