Omarigliptin ameliorates cisplatin-induced renal damage: Cross-talk between glucagon-like peptide-1, HMGB1/RAGE/TLR4 signaling, and TXNIP/NLRP3 inflammasome/gasdermin D axis

Background and objectives: Cisplatin is a platinum compound that is effective in the management of neoplastic conditions including testicular, ovarian, and lung malignancies. However, the possible incidence of kidney damage may significantly affect its therapeutic value. Omarigliptin is a dipeptidyl peptidase-4 inhibitor that is effective in treatment of type 2 diabetes mellitus. Interestingly, omarigliptin exhibited significant antioxidant, anti-inflammatory, and pro-autophagic properties in various body tissues. The focus of this research was to evaluate the possible effects of omarigliptin on the renal insult induced by cisplatin and to determine the pathological mechanisms that may precipitate these effects. Materials and methods: This study employed forty Wistar rats which were randomized into 4 equal groups as follows: control group; cisplatin group (injected intraperitoneally with cisplatin at increasing weekly doses at 0.8, 1.6, 3.2, 4.8 mg/kg starting from the end of the first week of the experiments); and 2 other groups treated with cisplatin as described above concomitantly with omarigliptin at 2.5 mg/kg/day and 5 mg/kg/day respectively orally starting 1 week before cisplatin administration and continuing for 6 days after the last cisplatin injection. Key findings: Omarigliptin dose-dependently combatted the renal damaging effects of cisplatin via regulation of glucagon-like peptide-1 levels which subsequently modulates autophagy, the oxidant/antioxidant balance, pyroptosis, and the inflammatory microenvironment of the renal tissues. These favorable responses were associated with dose-dependent significant improvement of the renal morphological changes elicited by cisplatin. Significance: Omarigliptin may be introduced, for the first time, as a promising agent to mitigate the nephrotoxic effects of cisplatin.