Brg1 regulates fibroblast-myofibroblast transition to promote renal fibrosis

Abstract

AbstractExcessive fibrogenesis serves to disrupt the anatomical and functional integrity of the kidneys contributing to renal failure. Renal fibroblast is the major precursor to myofibroblast, the effector cell type of renal fibrosis. How fibroblast-myofibroblast transition (FMyT) is regulated in the kidneys remains incompletely understood. In the present study we investigated the role of Brahma related gene 1 (Brg1), a chromatin remodeling protein, in renal fibrosis focusing on mechanistic insights and translational potential. We report that Brg1 was up-regulated during FMyT bothin vitroandin vivo. Brg1 deletion in fibroblasts partially blocked TGF-β induced FMyTin vitroand attenuated renal fibrosis in three different animal models. Importantly, conditional Brg1 knockout inPostn+mature myofibroblasts mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or ischemia-reperfusion (IR) in mice. Transcriptomic analysis uncovered Prune2 as a potential target for Brg1. Brg1 interacted with E2F1 to activate Prune2 transcription during FMyT. Concordantly, Prune2 knockdown suppressed TGF-β induced FMyTin vitroand dampened renal fibrosis in mice. Mechanistically, Prune2 likely contributed to FMyT by augmenting phosphorylation and activity of the pro-fibrogenic transcription factor PU.1. Finally, small-molecule Brg1 inhibitor PFI-3 exhibited strong antifibrotic potency in established models of renal fibrosis. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of as well as a promising therapeutic target for renal fibrosis.