βGemigliptin mitigates TGF-(3-induced renal fibrosis through FGF21-mediated inhibition of the TGF-β/Smad3 signaling pathway

Fibroblast growth factor 21 (FGF21), a well-known regulator of metabolic disorders, exhibits the potential to prevent renal fibrosis by negatively regulating the transforming growth factor (3 (TGF-(3)/Smad3 signaling pathway. Gemigliptin and other dipeptidyl peptidase-4 inhibitors are frequently used for the management of patients with type 2 diabetes. However, the protective effect of gemigliptin against renal fibrosis, particularly its potential to upregulate the expression of FGF21, remains incompletely understood. This study assessed the renoprotective effects of gemigliptin against TGF-(3-induced renal fibrosis by enhancing the expression of FGF21 in the cultured human proximal tubular epithelial cell line HK-2. Treatment with FGF21 effectively prevented TGF-(3-induced renal fibrosis by attenuating the TGF-(3/Smad3 signaling pathway. Similarly, gemigliptin exhibited protective effects against TGF-(3-induced renal fibrosis by mitigating TGF-(3/Smad3 signaling through the upregulation of FGF21 expression. However, the protective effects of gemigliptin were blocked when FGF21 expression was knocked down in TGF-(3-treated HK-2 cells. These results indicate that gemegliptin has the potential to exhibit protective effects against TGF-(3-induced renal fibrosis by elevating FGF21 expression levels in cultured human proximal tubular epithelial cells.