Activation of TGR5 Attenuates Renal Fibrosis after Renal Ischemia Reperfusion Injury
10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20230508.001
- VernacularTitle:激活TGR5缓解肾缺血再灌注后肾脏纤维化损伤
- Author:
Meng LI
1
;
Luo-sha LONG
1
;
Bai-en LIANG
2
;
Long XU
1
;
Xiao-duo ZHAO
2
;
Wei-dong WANG
2
;
Chun-ling LI
1
Author Information
1. Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
2. Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
- Publication Type:Journal Article
- Keywords:
TGR5;
uIRIx;
renal fibrosis;
lithcholic acid
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2023;44(4):617-624
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate the role of bile acid receptor TGR5 activation in renal fibrosis induced by unilateral ischemia reperfusion injury and contralateral nephrectomy (uIRIx) model. MethodsIn vivo: C57BL/6J mice were randomly divided into Sham group, uIRIx group and uIRIx+ lithcholic acid (LCA) group with 6 mice in each group. Kidney fibrosis was induced by uIRIx model, kidney function was evaluated by blood and urine biochemical indexes, and the degree of kidney injury was evaluated by HE staining. Masson staining and immunohistochemistry were used to evaluate the degree of renal fibrosis, and Western Blotting was used to detect the expression of related index proteins of renal cortical fibrosis. Sham group and uIRIx group were set in TGR5+/+ mice and TGR5-/- mice respectively, with 6 mice in each group. The degree of renal fibrosis in each group was detected by Western Blotting. In vitro: TGF-β1 was administered to induce pro-fibrosis response in human renal tubular epithelial cell line (HK2 cells), LCA was used for drug intervention, cytoskeleton was labeled with phalloidin-FITC staining and the expression of fibrosis related indicator protein in HK2 cells was detected by Western Blotting. ResultsIn vivo: Compared with the Sham group, plasma creatinine level (P=0.007) and urinary albumin/creatinine ratio (P=0.041) in uIRIx group were significantly increased, renal cortical protein TGR5 expression (P=0.002) was decreased, Fibronectin expression (P=0.020) and COL1A1 expression (P<0.001) were increased. At the same time, the kidney structure was damaged and collagen deposition was aggravated. LCA intervention effectively improved the kidney function and alleviated the degree of kidney injury and fibrosis. TGR5 gene knockout increased uIRIx-induced Fibronectin expression (P<0.001) and COL1A1 expression (P=0.001) compared with TGR5+/+ mice. In vitro: TGF-β1 induced morphological changes of HK2 cells, cytoskeletal depolymerization and recombination, and promoted the up-regulation of fibrosis index protein. LCA effectively inhibited the morphological changes and skeletal depolymerization induced by TGF-β1, and down-regulated the expression of fibrosis related indicator proteins. ConclusionsLCA alleviated renal fibrosis induced by uIRIx model, and knockout of TGR5 gene aggravated uIRIx induced renal fibrosis; In HK2 cells, LCA alleviated fibrogenic reaction induced by TGF-β1. This indicates that activation of TGR5 alleviates renal fibrosis induced by uIRIx.