Exendin-4 Ameliorates High-Glucose-Induced Fibrosis by Inhibiting the Secretion of miR-192 from Injured Renal Tubular Epithelial Cells

Extracellular vesicles (EVs), which contain microRNA (miRNA), constitute a novel means of cell communication that may contribute to the inevitable expansion of renal fibrosis during diabetic kidney disease (DKD). Exendin-4 is effective for treating DKD through its action on GLP-1R. However, the effect of exendin-4 on EVs miRNA expression and renal cell communication during the development of DKD remains unknown. In this study, we found that EVs derived from exendin-4 and high-glucose (Ex-HG)-pretreated HK-2 cells, which was taken up by normal HK-2 cells, resulted in decreased levels of FN and Col-I compared with those treated with HG pretreated HK-2 cells derived EVs. Furthermore, we found this may contribute to a decrease in miR-192 in both HK-2 cells and EVs after exendin-4 treatment in a p53-dependent manner. Besides, we found that the amelioration of renal fibrosis by exendin-4 occurs through a miR-192-GLP-1R pathway, indicating a new pathway by which exendin-4 regulates GLP-1R. The results of this study suggest that exendin-4 can inhibit the transfer of EVs miR-192 from HG-induced renal tubular epithelial cells to normal cells, thus inhibiting GLP-1R down-regulation and protecting renal cells. This study reports a new mechanism by which exendin-4 exerts a protective effect against DKD.