Penehyclidine Hydrochloride Improves Rhabdomyolysis-Mediated Acute Kidney Injury by Inhibiting Ferroptosis through the HIF-1α/MT1G Axis

Penehyclidine hydrochloride (PHC) has been shown to be effective in the treatment of rhabdomyolysis (RM)-induced acute kidney injury (AKI). Our research sought to investigate the pharmacological effects and mechanisms of PHC on RM-induced AKI.RM-induced AKI models were established by FeG treatment and glycerol injection. Cell viability was analyzed by CCK-8 assay. ROS levels were examined by Flow cytometry. The LDH, Fe2+, MPO, MDA and GSH levels were measured using the corresponding kits. The interaction between HIF-1α and MT1G was analyzed by dual luciferase reporter gene and ChIP assays. The kidney pathological alterations were examined by HE staining. The levels of Scr, UA and BUN were examined using ELISA. Ferroptosis-related proteins (SLC7A11, GPX4 and ACSL4) were analyzed by western blot.PHC administration increased FeG-treated HK-2 cell viability, reduced ROS, LDH, Fe2+, MPO, MDA and ACSL4 levels, and raised GSH, SLC7A11 and GPX4 levels in cells, suggesting that PHC improved FeG-induced HK-2 cell ferroptosis and injury. PHC protected against AKI primarily by suppressing ferroptosis. HIF-1α blocked the SLC7A11/GPX4 pathway by transcriptionally activating MT1G. PHC alleviated glycerol-induced kidney injury in rats by inhibiting ferroptosis.PHC improved RM-mediated AKI by inhibiting ferroptosis through the HIF-1α/MT1G/ SLC7A11/GPX4 axis.