2. Academic Validation
  3. Activation of TGR5 Alleviates Renal Fibrosis by Promoting NEDD4L-Mediated p-Smad2/3 Ubiquitination

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

  • Acta Physiol (Oxf). 2026 Feb;242(2):e70163. doi: 10.1111/apha.70163.
Meng Li 1 2,  Luosha Long 1 2,  Xiaoduo Zhao 3 4,  Xi Yuan 1 2,  Minghui Wang 1 2,  Jinyi Lin 2,  Long Xu 1 2,  Xinyan Wu 1 3,  Ruiqi Bai 5,  Suchun Li 6 7,  Weidong Wang 1 3,  Wei Chen 6 7,  Lihe Lu 3,  Chunling Li 1 2
Affiliations

Affiliations

  • 1 Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 2 Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 4 Department of Pathology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
  • 5 School of Pharmacy, University College London, London, UK.
  • 6 Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 7 NHC Key Laboratory of Clinical Nephrology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
PMID: 41536162 DOI: 10.1111/apha.70163
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.

Keywords

NEDD4L; PI3K‐SGK1 pathway; TGR5; chronic kidney disease; p‐Smad2/3; renal fibrosis; ubiquitination.

Figures
Products