Back to Search
Start Over
TGR5 activation suppressed S1P/S1P2 signaling and resisted high glucose-induced fibrosis in glomerular mesangial cells.
- Source :
-
Pharmacological research [Pharmacol Res] 2016 Sep; Vol. 111, pp. 226-236. Date of Electronic Publication: 2016 Jun 16. - Publication Year :
- 2016
-
Abstract
- 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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cells, Cultured
Diabetic Nephropathies genetics
Diabetic Nephropathies metabolism
Diabetic Nephropathies pathology
Disease Models, Animal
Fibronectins metabolism
Fibrosis
Intercellular Adhesion Molecule-1 metabolism
Mesangial Cells metabolism
Mesangial Cells pathology
Mice, Inbred C57BL
Phosphorylation
RNA Interference
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled genetics
Receptors, G-Protein-Coupled metabolism
Sphingosine metabolism
Sphingosine-1-Phosphate Receptors
Transcription Factor AP-1 metabolism
Transfection
Transforming Growth Factor beta1 metabolism
Cholic Acids pharmacology
Diabetic Nephropathies prevention & control
Glucose toxicity
Lysophospholipids metabolism
Mesangial Cells drug effects
Receptors, G-Protein-Coupled agonists
Receptors, Lysosphingolipid metabolism
Signal Transduction drug effects
Sphingosine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1096-1186
- Volume :
- 111
- Database :
- MEDLINE
- Journal :
- Pharmacological research
- Publication Type :
- Academic Journal
- Accession number :
- 27317945
- Full Text :
- https://doi.org/10.1016/j.phrs.2016.05.035