Ertugliflozin mitigates renal ischemia-reperfusion injury through the downregulation of HIF-1α expression

Renal ischemia reperfusion (I/R) injury can lead to acute kidney injury. SGLT2 inhibitors, commonly used as hypoglycemic agents, have demonstrated the ability to mitigate cardiac I/R injury. Nevertheless, research on their efficacy in treating renal I/R injury is limited. Some studies have indicated that SGLT-2 inhibitors may safeguard renal tubular epithelial cells from damage caused by high glucose levels via mitochondrial mechanisms. SGLT2 inhibitors alleviate renal hypoxia and cellular stress, and enhance nutrient deprivation signaling. These combined effects may account for their inhibition of HIF-1α and activation of HIF-2α, which in turn leads to increased erythropoiesis, while also preventing organelle dysfunction, inflammation, and fibrosis. We assessed whether Ertugliflozin, a novel SGLT2 inhibitor, exhibits a renoprotective effect in an in vitro hypoxia model and confirmed that Ertugliflozin can attenuate renal injury in an I/R mouse model. Furthermore, we treated hypoxic HK-2 cells with or without Ertugliflozin and an HIF-1α inhibitor to explore the molecular pathways involved in Ertugliflozin's protective effect against HK-2 cells hypoxia/re-oxygenation (H/R) injury. Our findings indicate that Ertugliflozin significantly improves renal hypoxia, apoptosis, and oxidative stress, and reduces the further deterioration of renal function caused by H/R injury. These protective changes are achieved by targeting the HIF-1α protein. Both in vivo and in vitro experiments revealed that Ertugliflozin alleviates renal I/R-induced stress through the HIF-1α pathway. Transcriptome sequencing analysis further showed that the HIF-1 signaling pathway is also a crucial pathway for Ertugliflozin in treating renal I/R injury.