Activation of TGR5 Alleviates Renal Fibrosis by Promoting NEDD4L ‐Mediated p‐Smad2/3 Ubiquitination

ABSTRACT Aim Renal fibrosis is a major contributor to chronic kidney disease (CKD) progression and eventual organ failure. G protein‐coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney diseases. The current study aimed to investigate whether TGR5 activation prevents kidney fibrosis and to clarify the underlying mechanism. Methods TGR5 expression was examined in human fibrotic kidneys. Two animal models of renal fibrosis were used: unilateral ureteral obstruction (UUO) and unilateral ischemia–reperfusion injury with contralateral nephrectomy (uIRIx) in wild‐type and TGR5 knockout mice. Renal histology, extracellular matrix (ECM) deposition, and renal function were examined. In vitro studies were performed on human proximal tubular HK2 cells by treating them with transforming growth factor‐β1 and TGR5 agonists/antagonists. Results TGR5 was significantly downregulated in fibrotic human kidneys. In both UUO and uIRIx models, TGR5 activation by lithocholic acid alleviated renal fibrosis, reduced ECM deposition, and improved kidney function. Conversely, Tgr5 knockout in mice exacerbated fibrotic injury. Mechanistically, TGR5 activation prevented fibrosis development, probably by enhancing NEDD4L‐mediated ubiquitination and degradation of phosphorylated Smad2/3 by inhibiting the upstream PI3K–SGK1 pathway. Conclusion TGR5 activation protects against renal fibrosis by inhibiting the PI3K–SGK1–NEDD4L axis and promoting p‐Smad2/3 degradation.