TY - JOUR
T1 - The hepatocyte growth factor/c-met pathway is a key determinant of the fibrotic kidney local microenvironment
AU - Fu, Haiyan
AU - Gui, Yuan
AU - Liu, Silvia
AU - Wang, Yuanyuan
AU - Bastacky, Sheldon Ira
AU - Qiao, Yi
AU - Zhang, Rong
AU - Bonin, Christopher
AU - Hargis, Geneva
AU - Yu, Yanbao
AU - Kreutzer, Donald L.
AU - Biswas, Partha Sarathi
AU - Zhou, Yanjiao
AU - Wang, Yanlin
AU - Tian, Xiao Jun
AU - Liu, Youhua
AU - Zhou, Dong
N1 - Funding Information:
We are grateful to the Center for Biologic Imaging at the University of Pittsburgh for the use of their core facilities. This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. This work was supported by the National Institutes of Health ( NIH ) grants DK064005, DK106049 (to Liu Y.), DK116816, DK128529 (to Zhou D.). Tian X-J is supported by the National Science Foundation grant EF-1921412. Fu H is supported by the National Natural Science Foundation of China Grants 81970587 and 81770737.
Funding Information:
We are grateful to the Center for Biologic Imaging at the University of Pittsburgh for the use of their core facilities. This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. This work was supported by the National Institutes of Health (NIH) grants DK064005, DK106049 (to Liu Y.), DK116816, DK128529 (to Zhou D.). Tian X-J is supported by the National Science Foundation grant EF-1921412. Fu H is supported by the National Natural Science Foundation of China Grants 81970587 and 81770737. Conceptualization, H.F. Y.L. and D.Z.; methodology, H.F. S.L. X.-J.T. and D.Z; investigation, H.F. Y.G. S.L. Y.W. Y.Q. R.Z. Y.Y. B.P. Y.Z. X.-J.T. and D.Z.; writing – original draft, H.F. Y.G. X.-J.T. and D.Z.; writing – review& editing, H.F. Y.G. B.S. B.C. H.G. K.D. Y.W. X.-J.T. Y.L. and D.Z.; funding acquisition, X.-J.T. Y.L. and D.Z.; resources and supervision, Y.L. and D.Z. The authors declare no conflict of interest. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects.
Publisher Copyright:
© 2021 The Authors
PY - 2021/10/22
Y1 - 2021/10/22
N2 - 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.
AB - 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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U2 - 10.1016/j.isci.2021.103112
DO - 10.1016/j.isci.2021.103112
M3 - Article
AN - SCOPUS:85122814164
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 10
M1 - 103112
ER -