Therapeutic Potential of Ertugliflozin in Renal Ischemia/Reperfusion Injury by Modulating Nrf2 and Necroptosis Pathways: A Preclinical Study in Rats

Introduction Renal ischemia/reperfusion injury is a sequence of complicated events that involve a reduction in blood supply followed by a recovery of perfusion and oxygenation to the kidneys. Ertugliflozin is a selective inhibitor of SGLT2. To our best knowledge, there is limited published data about the nephroprotective effects of ertugliflozin via the Nrf2 and RIPK1/MLKL molecular pathways. The aim of this study is to investigate the nephroprotective effects of ertugliflozin through Nrf2 and RIPK1/MLKL molecular pathways. Materials and Methods 24 Sprague Dawley rats were assigned to four groups: Sham, I/R, I/R + Veh, and I/R + EGZ. The sham group underwent laparotomy without induction of the I/R model. The other three groups were subjected to 30 minutes of bilateral renal ischemia and 24 hours of reperfusion. The I/R + Veh and I/R + EGZ groups received DMSO and 20 mg/kg ertugliflozin intraperitoneally one hour before ischemia induction, respectively. Results KIM-1, TNF-α, IL-1β, NF-κB, and caspase-3 levels were quantified using ELISA. Nrf2 and MLKL were assessed through IHC, while RIPK1 expression was determined via RT-qPCR, in addition to histopathological examination. In I/R and I/R + Veh groups, KIM-1, TNF-α, IL-1β, NF-κB, caspase-3, RIPK1, MLKL, and histopathological findings were remarkably elevated. On the contrary, the administration of ertugliflozin substantially reduced renal damage, inflammation, cell death, and histological features. Nuclear translocation of Nrf2 was greatly increased in the ertugliflozin-treated group, and molecular docking revealed that ertugliflozin was bound to Keap1. Discussion The administration of ertugliflozin notably increased the Nrf2 expression. These findings, along with the reduction in renal damage, Necroptosis, and apoptosis, indicate the nephroprotective effect of ertugliflozin. Conclusion Ertugliflozin showed marked nephroprotective effects evidenced by reduced oxidation, inflammation, Necroptosis, apoptosis, and necrosis through translocation of Nrf2 and inhibition of RIPK1/MLKL pathways.