TGR5 activation suppressed S1P/S1P2 signaling and resisted high glucose-induced fibrosis in glomerular mesangial cells.
Glucose and lipid metabolism disorders and chronic inflammation in the kidney tissues are largely responsible for causative pathological mechanism of renal fibrosis in diabetic nephropathy (DN). As our previous findings confirmed that, sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling activation promoted renal fibrosis in diabetes. Numerous studies have demonstrated that the G protein-coupled bile acid receptor TGR5 exhibits effective regulation of glucose and lipid metabolism and anti-inflammatory effects. TGR5 is highly expressed in kidney tissues, whether it attenuates the inflammation and renal fibrosis by inhibiting the S1P/S1P2 signaling pathway would be a new insight into the molecular mechanism of DN. Here we investigated the effects of TGR5 on diabetic renal fibrosis, and the underlying mechanism would be also discussed. We found that TGR5 activation significantly decreased the expression of intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta 1 (TGF-β1), as well as fibronectin (FN) induced by high glucose in glomerular mesangial cells (GMCs), which were pathological features of DN. S1P2 overexpression induced by high glucose was diminished after activation of TGR5, and AP-1 activity, including the phosphorylation of c-Jun/c-Fos and AP-1 transcription activity, was attenuated. As a G protein-coupled receptor, S1P2 interacted with TGR5 in GMCs. Furthermore, INT-777 lowered S1P2 expression and promoted S1P2 internalization. Taken together, TGR5 activation reduced ICAM-1, TGF-β1 and FN expressions induced by high glucose in GMCs, the mechanism might be through suppressing S1P/S1P2 signaling, thus ameliorating diabetic nephropathy.
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China.
Zhiying
Z
Yang
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Fengxiao
F
Xiong
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Yu
Y
Wang
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Wenyan
W
Gong
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Junying
J
Huang
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Cheng
C
Chen
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China.
Peiqing
P
Liu
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, China. Electronic address: huangheq@mail.sysu.edu.cn.
Heqing
H
Huang
D000818:Animals; D002478:Cells, Cultured; D002793:Cholic Acids / Q000494:pharmacology*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005947:Glucose / Q000633:toxicity*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C545501:6alpha-ethyl-23(S)-methylcholic acid; D002793:Cholic Acids; D005353:Fibronectins; C513561:Gpbar1 protein, mouse; C518268:Gpbar1 protein, rat; C000609942:ICAM1 protein, rat; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C508962:Tgfb1 protein, rat; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; C570053:sphingosine-1-phosphate receptor-2, rat; D018799:Intercellular Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D005947:Glucose; D013110:Sphingosine
AP-1; Fibronectin; INT-777 (PubChem CID: 45483949); JTE-013 (PubChem CID: 10223146); Renal fibrosis; S1P2; TGR5