Inhibition of the expression of TGF-β1 and CTGF in human mesangial cells by exendin-4, a glucagon-like peptide-1receptor agonist

摘要

Background: Despite the presence of glucagon-like peptide-1 receptor (GLP-1R) in kidney tissues, its direct effect on diabetic nephropathy remains unclear. The transforming growth factor-β _1(TGF- β _1) and the connective tissue growth factor (CTGF) both induce extracellular matrix accumulation and persistent fibrosis in the glomerular mesangium of patients with diabetic nephropathy. Objective: Herein, we demonstrate that a GLP-1R agonist, exendin-4, exerts renoprotective effects through its influence on TGF-β _1and CTGF in human mesangial cells (HMCs), cultured in a high glucose medium. Method: HMCs, cultured in a high glucose medium, were used for the current study. The direct effect of exendin-4 on TGF-β _1and CTGF expression was confirmed in HMCs. MDL-12330A (a specific adenylate cyclase inhibitor) and PKI14-22 (a protein kinase A inhibitor) were used to examine the role of the cAMP signaling pathway in exendin's anti-fibrosis action. Results: The findings showed that exendin-4 inhibited the proliferation of HMCs, and upregulated the expression of TGF-β _1and CTGF, induced by high glucose. The effect of exendin-4 is largely dependent on the activation of adenylate cyclase. Conclusion: This study provides new evidence that GLP-1 acts as an antifibrotic agent in HMCs.