TGR5 activation suppressed S1P/S1P2 signaling and resisted high glucose-induced fibrosis in glomerular mesangial cells

Yang, Zhao; Xiong, Fengxiao; Wang, Yu; Gong, Wenyan; Huang, Junying; Chen, Cheng; Liu, Peiqing; Huang, Heqing

doi:10.1016/j.phrs.2016.05.035

Cited by 36 publications

(27 citation statements)

References 36 publications

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“…10). So far, several studies on the association between S1P and renal fibrosis have demonstrated that S1P may possess profibrotic properties through S1P2 (55)(56)(57)(58)(59). In fact, we observed that the pharmacological blockade of S1P2 signaling with JTE suppressed fibrotic changes (Fig.…”

Section: Discussionmentioning

confidence: 60%

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

et al. 2019

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Because the association between sphingosine 1‐phosphate (S1P)/apolipoprotein M (ApoM) and chronic kidney diseases has not been established, we investigated the involvement of S1P/ApoM in the phenotypes of IgA nephropathy in hyper‐IgA (HIGA) mice. The overexpression of ApoM in adenoviral gene transfer ameliorated the phenotypes of IgA nephropathy in HIGA mice, whereas the knockdown of ApoM with siRNA caused deterioration. When ApoM‐overexpressing HIGA mice were treated with VPC23019, an antagonist against S1P receptor 1 (S1P1) and 3 (S1P3), we observed that the protective effects of ApoM were reversed, whereas JTE013, an antagonist against S1P2, did not inhibit the effects. We also found that S1P bound to albumin accelerated the proliferation of MES13 cells and the fibrotic changes of HK2 cells, which were inhibited by JTE013, whereas S1P bound to ApoM suppressed these changes, which were inhibited by VPC23019. These results suggest that S1P bound to ApoM possesses properties protective against the phenotypes of IgA nephropathy through S1P1 and S1P3, whereas S1P bound to albumin exerts deteriorating effects through S1P2. ApoM may be useful as a therapeutic target to treat or retard the progression of IgA nephropathy.—Kurano, M., Tsuneyama, K., Morimoto, Y., Nishikawa, M., Yatomi, Y. Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice. FASEB J. 33, 5181–5195 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 60%

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

et al. 2019

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“…A recent study reported that activation of TGR5 attenuated inflammation and renal fibrosis in diabetic nephropathy by inhibiting S1PR2 expression and promoting S1PR2 internalization in glomerular mesangial cells. (38) It would be of interest to determine whether S1PR2 expression in cholangiocytes is altered in TGR5 -/mice. Previous studies have reported that bile acids activated the epidermal growth factor receptor/ERK1/2 signaling pathway in hepatocytes in the absence of TGR5.…”

Section: Discussionmentioning

confidence: 99%

The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

et al. 2017

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Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the AKT and ERK1/2 signaling pathways via the sphingosine 1-phosphate receptor 2 (S1PR2) in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)-induced apoptosis. However, the role of S1PR2 in bile acid-mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA- and S1P-induced activation of ERK1/2 and AKT were inhibited by JTE-013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA- and S1P-induced cell proliferation and migration were inhibited by JTE-013 and a specific shRNA of S1PR2 as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, the expression of S1PR2 was upregulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL-induced cholangiocyte proliferation and cholestatic injury as indicated by significant reduction of inflammation and liver fibrosis in S1PR2−/− mice. Treatment of BDL mice with JTE-013 significantly reduced total bile acid levels in the serum and cholestatic liver injury. This study suggests that the CBA-induced activation of S1PR2-mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases.

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“…TGR5 is also implicated in the mitochondrial response to inflammation and the development of fibrosis in the kidney [ 8 , 9 ]. TGR5 expression is present in a variety of tissues including kidney [ 9 – 11 ]. Some studies have reported strong TGR5 expression in renal tubular cells [ 10 , 11 ] as well as the mesangial cells of rat kidney [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

TGR5 expression in normal kidney and renal neoplasms

et al. 2018

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BackgroundThe G protein-coupled bile acid receptor (TGR5) is a cell surface receptor which induces the production of intracellular cAMP and promotes epithelial-mesenchymal transition in gastric cancer cell lines. TGR5 is found in a wide variety of tissues including the kidney. However, the patterns of TGR5 expression have not been well characterized in physiologic kidney or renal neoplasms. We explore the expression of TGR5 in benign renal tissue and renal neoplasms and assess its utility as a diagnostic marker.MethodsSixty-one renal cortical neoplasms from 2000 to 2014 were retrieved. TGR5 protein expression was examined by immunohistochemistry. TGR5 mRNA was also measured by real-time PCR.ResultsIn normal renal tissue, TGR5 was strongly positive in collecting ducts, distal convoluted tubules and thin loop of Henle. Proximal convoluted tubules showed absent or focal weak staining. In clear cell renal cell carcinomas (RCCs), 25 of 27 cases (92%) were negative for TGR5 (p < 0.001). TGR5 mRNA was also significantly decreased in clear cell RCCs, suggesting that decreased TGR5 protein expression may be attributable to the downregulation of TGR5 mRNA in these tumors. All 11 papillary RCCs expressed TGR5 with 45% (5/11) exhibiting moderate to strong staining. All chromophobe RCCs and oncocytomas were positive for TGR5 with weak to moderate staining. TGR5 mRNA expression in these tumors was similar to normal kidney. All urothelial carcinomas of the renal pelvis strongly expressed TGR5 including a poorly differentiated urothelial carcinoma with sarcomatoid features.ConclusionTGR5 is strongly expressed in collecting ducts, distal convoluted tubules and thin loop of Henle. TGR5 protein and mRNA expression were notably decreased in clear cell RCCs and may be helpful in differentiating these tumors from other RCCs.

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TGR5 activation suppressed S1P/S1P2 signaling and resisted high glucose-induced fibrosis in glomerular mesangial cells

Cited by 36 publications

References 36 publications

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

TGR5 expression in normal kidney and renal neoplasms

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