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Published on: September 12, 2019
Activation of TGR5 Alleviates Renal Fibrosis by Promoting NEDD4L-Mediated p-Smad2/3 Ubiquitination
Meng Li1,2, Luosha Long1,2, Xiaoduo Zhao3,4
1Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
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.
Insights
G protein-coupled bile acid receptor 1 (TGR5) activation protects kidneys from fibrosis by reducing extracellular matrix deposition. This mechanism involves inhibiting the PI3K-SGK1-NEDD4L pathway and promoting the degradation of phosphorylated Smad2/3.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Signaling
Background:
- Renal fibrosis is a key driver of chronic kidney disease (CKD) progression.
- G protein-coupled bile acid receptor 1 (TGR5) has demonstrated protective effects in kidney disease models.
Purpose of the Study:
- To investigate the protective role of TGR5 activation against kidney fibrosis.
- To elucidate the underlying molecular mechanisms of TGR5 in preventing renal fibrosis.
Main Methods:
- Examined TGR5 expression in human fibrotic kidneys.
- Utilized unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (uIRIx) models in wild-type and Tgr5 knockout mice.
- Conducted in vitro studies on human proximal tubular HK2 cells.
Main Results:
- TGR5 expression was significantly reduced in fibrotic human kidneys.
- TGR5 activation alleviated renal fibrosis, reduced extracellular matrix deposition, and improved kidney function in UUO and uIRIx models.
- Tgr5 knockout exacerbated fibrotic injury, while activation inhibited fibrosis by promoting p-Smad2/3 degradation via the PI3K-SGK1-NEDD4L pathway.
Conclusions:
- TGR5 activation demonstrates a protective effect against renal fibrosis.
- The mechanism involves the inhibition of the PI3K-SGK1-NEDD4L axis, leading to enhanced degradation of phosphorylated Smad2/3.
- TGR5 represents a potential therapeutic target for mitigating kidney fibrosis in CKD.
