Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: a novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade

Abstract

Cyclophosphamide (CP) is widely used as a chemotherapy against various types of cancers. However, CP is accompanied with multiple organ toxicity due to production of reactive oxygen species (ROS), induction of inflammation and consequently apoptosis. Alogliptin (Alo) is a dipeptidyl peptidase 4 (DPP-IV) inhibitor, which is booming as an antidiabetic agent. Interestingly, gliptins are currently studied for their counter-regulatory effects against oxidative stress and inflammation via multiple pathways, among which is the mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway. This cascade can reduce inflammation via mitigating the activity of mothers against decapentaplegic homolog 3 (SMAD3) and c-Jun. However, Alo effect against CP-induced kidney injury has not been previously elucidated. This tempted us to investigate the possible beneficial effect of Alo against CP-induced kidney injury via modulating the MAP3K/JNK/SMAD3 signaling cascade. Thirty-two male Wistar rats were randomly allocated into four groups. CP-treated group received a single dose of CP (200 mg/kg; i.p.). Alo-treated group received Alo (20 mg/kg/day; p.o.) for 7 days with single CP injection on day 2. Marked decrease in renal injury was observed upon Alo treatment, as evidenced through declined serum kidney function markers, oxidative stress and apoptosis markers, MAP3K expression, phospho (p)-SMAD3, p-JNK, and p-c-Jun levels. These cellular effects were reflected in reduced transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α) fibrotic and inflammatory mediators, coinciding with improved histopathological portrait. In conclusion, the current study provides novel application of Alo as a therapeutic modality against CP-induced nephrotoxicity.