Omarigliptin/shikonin combination alleviates cyclosporine-induced nephrotoxicity: The role of sirtuin 1, glucagon-like peptide-1, HMGB1/RAGE/TLR4 signaling, and p38/ERK/JNK MAPKs.

Abstract

IntroductionCyclosporine is a calcineurin inhibitor that is widely used to decrease the incidence of organ transplant rejection and in the management of immunological diseases. However, these effects may be associated with increased incidence of nephrotoxicity. This work aimed to the exploration of the impact of omarigliptin with or without shikonin on a rodent model of cyclosporine nephrotoxicity and the precise determination of the mechanisms that may represent the basis of these effects.MethodsIn a Wistar rat model of cyclosporine-elicited nephrotoxicity, the effect of omarigliptin and shikonin, each alone and in combination, was determined at the level of the biochemical parameters and the histomorphological changes.ResultsOmarigliptin and/or shikonin administered to cyclosporine-injected animals induced a significant restoration of renal functions and glucagon-like peptide-1 (GLP-1) and augmentation of the antioxidant defenses, associated with increased sirtuin 1 expression and its related signaling changes in comparison to animals that received cyclosporine alone. Additionally, omarigliptin and/or shikonin elicited a significant amelioration of the inflammatory response and cellular differentiation and a significant improvement of the renal tissue disruptive changes elicited by cyclosporine. These effects were evident with omarigliptin/shikonin combination when compared to the groups treated with each agent alone.ConclusionOmarigliptin/shikonin combination suggests potential therapeutic benefit for the mitigation of cyclosporine nephrotoxicity, possibly via their effects on dipeptidyl peptidase 4 activity and GLP-1 levels with subsequent modulation of the redox status, cellular proliferation, and the inflammatory pathways.