Berberine attenuates high glucose-induced fibrosis by activating the G protein-coupled bile acid receptor TGR5 and repressing the S1P2/MAPK signaling pathway in glomerular mesangial cells.

Abstract

Berberine (BBR) exerts powerful renoprotective effects on diabetic nephropathy (DN), but the underlying mechanisms remain unclear. We previously demonstrated that activation of the G protein-coupled bile acid receptor TGR5 ameliorates diabetic nephropathy by inhibiting the activation of the sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling pathway. In this study, we explored the role of TGR5 in the BBR-induced downregulation of sphingosine 1-phosphate receptor 2 (S1P2)/mitogen-activated protein kinase (MAPK)-mediated fibrosis in glomerular mesangial cells (GMCs). Results showed that, BBR suppressed the expression of FN, ICAM-1, and TGF-β1 in high-glucose cultures of GMCs, and the phosphorylation level of c-Jun/c-Fos was downregulated. The high glucose lowered TGR5 expression in a time-dependent manner; this effect was reversed by BBR in a dose-dependent manner. The TGR5 agonist INT-777 decreased the high glucose-induced FN, ICAM-1, and TGF-β1 protein contents. In addition, TGR5 siRNA blocked S1P2 degradation by BBR. And MAPK signaling, which plays important regulatory roles in the pathological progression of DN, was activated by TGR5 siRNA. Apart from this, MAPK signaling as well as FN, ICAM-1, and TGF-β1 suppressed by BBR under high glucose conditions were limited by TGR5 depletion. Thus, BBR decreases FN, ICAM-1, and TGF-β1 levels under high glucose conditions in GMCs possibly by activating TGR5 and inhibiting S1P2/MAPK signaling.

• Authors: Zhiying Yang, Jie Li, Fengxiao Xiong, Junying Huang, Cheng Chen, Peiqing Liu, Heqing Huang
• Journal: Experimental cell research (Exp Cell Res) Vol. 346 Issue 2 Pg. 241-7 (08 15 2016) ISSN: 1090-2422 [Electronic] United States
• PMID: 27292312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Fibronectins
• Gpbar1 protein, rat
• Receptors, G-Protein-Coupled
• Receptors, Lysosphingolipid
• Transcription Factor AP-1
• Transforming Growth Factor beta1
• Berberine
• Intercellular Adhesion Molecule-1
• Glucose

Topics

• Animals
• Berberine (pharmacology)
• Cells, Cultured
• Down-Regulation (drug effects)
• Fibronectins (metabolism)
• Fibrosis
• Gene Knockdown Techniques
• Glucose (toxicity)
• Intercellular Adhesion Molecule-1 (metabolism)
• Kidney Glomerulus (pathology)
• MAP Kinase Signaling System (drug effects)
• Mesangial Cells (drug effects, metabolism, pathology)
• Phosphorylation (drug effects)
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (metabolism)
• Receptors, Lysosphingolipid (metabolism)
• Transcription Factor AP-1 (metabolism)
• Transforming Growth Factor beta1 (metabolism)