c-Abl-induced Wnt/ß-catenin activation and Ksp-tdTomato+ PDGFRa+ tubular epithelial cells promote renal fibrosis in mice through epithelial-to-mesenchymal transition
Renal fibrosis is a common pathological manifestation of chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) plays an essential role during renal fibrosis. Here we found the increased expression of c-Abl, a nonreceptor tyrosine kinase, in the tubular epithelial cells (TECs) of patients with CKD and renal fibrosis mouse models. c-Abl deficiency in TECs attenuated kidney fibrosis in mice. c-Abl overexpression in TECs in vitro promoted EMT, accompanied by the activation of the Wnt/ß-catenin signaling which in turn promotes the expression of c-Abl, thereby forming a positive feedback loop. We further found that during renal fibrosis, a group of TECs undergo a partial EMT program, resulting in PDGFRa expression in the Ksp cell lineage. The primary functions of Ksp-tdTomato+ PDGFRa+ cells were to recruit macrophages by secreting chemokines and to create an inflammatory microenvironment by secreting inflammatory factors. c-Abl deletion in TECs reduced the number of Ksp-tdTomato+ PDGFRa+ cells and decelerated EMT progression. In fibrotic mouse models, the c-Abl inhibitors nilotinib and GNF5 ameliorated EMT, inflammation, and fibrosis. Together, our findings suggest that c-Abl-dependent Wnt/ß-catenin signaling activation and Ksp-tdTomato/PDGFRa double-positive cells drive renal fibrosis through partial EMT, providing new insights into the pathogenesis of CKD and a new therapeutic target. Overall design: c-AblloxP/loxP mice were bred with transgenic Ksp-Cre mice to generate a tubular epithelial cell (TEC)-specific knockout c-Abl mouse line. In male mice (8 weeks old; c-Ablflox/flox and c-AblEpi-cKO mice), UUO was maintained for 14 days. The mRNA transcriptome of mouse kidney tissues was examined. Fibrotic kidney tissues from the c-Ablflox/flox group and c-AblEpi-cKO mice kidney tissues were compared. The goal was to identify the effect of c-Abl knockdown in TECs of renal fibrosis on gene expression during kidney fibrosis.