Inhibition of the expression of TGF-β1 and CTGF in human mesangial cells by exendin-4, a glucagon-like peptide-1 receptor agonist.
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(1) and CTGF in human mesangial cells (HMCs), cultured in a high glucose medium.


METHODS
HMCs, cultured in a high glucose medium, were used for the current study. The direct effect of exendin-4 on TGF-β(1) and 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(1) and CTGF, induced by high glucose. The effect of exendin-4 is largely dependent on the activation of adenylate cyclase.


CONCLUSIONS
This study provides new evidence that GLP-1 acts as an antifibrotic agent in HMCs.
Renal Division, Department of Medicine, Shandong Provincial Qianfoshan Hospital, Jinan City.
Wenbin
W
Li
Meiyu
M
Cui
Yong
Y
Wei
Xianglei
X
Kong
Lijun
L
Tang
Dongmei
D
Xu
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077270:Exenatide; D005109:Extracellular Matrix / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007097:Imines / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D002352:Carrier Proteins; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007097:Imines; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D053773:Transforming Growth Factor beta1; D014688:Venoms; C477818:myristoylated protein kinase A inhibitor amide 14-22; D055513:Connective Tissue Growth Factor; C014925:RMI 12330A; D000077270:Exenatide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D005947:Glucose