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

BACKGROUND: 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. METHODS: RM-induced AKI models were established by FeG treatment and glycerol injection. Cell viability was analyzed by cell counting kit-8 assay. Reactive oxygen species (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 chromatin immunoprecipitation assays. The kidney pathological alterations were examined by hematoxylin-eosin staining. The levels of serum creatinine, uric acid, and blood urea nitrogen were examined using ELISA. Ferroptosis-related proteins (SLC7A11, GPX4, and ACSL4) were analyzed by Western blot. RESULTS: 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. CONCLUSION: PHC improved RM-mediated AKI by inhibiting ferroptosis through the HIF-1α/MT1G/SLC7A11/GPX4 axis.