Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity.

Abstract

This study aimed to investigate the potential protective effect of sitagliptin on gentamicin-induced nephrotoxicity and to elucidate the underlying mechanism. Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase-3 and bax were evaluated. Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase-3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment. These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney.