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.
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.
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.
Zhiying
Z
Yang
Laboratory Animal Center, Sun Yat-sen University, Guangzhou 510080, China.
Jie
J
Li
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.
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.
Peiqing
P
Liu
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Laboratory Animal Center, Sun Yat-sen University, Guangzhou 510080, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou 510006, China. Electronic address: huangheq@mail.sysu.edu.cn.
Heqing
H
Huang
D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000633:toxicity*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D005353:Fibronectins; C518268:Gpbar1 protein, rat; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D001599:Berberine; D018799:Intercellular Adhesion Molecule-1; D005947:Glucose
Berberine; Fibronectin; Mapk; S1p2; Tgr5