Aprepitant ameliorates vancomycin-induced kidney injury: Role of GPX4/system Xc^- and oxidative damage

Vancomycin, a glycopeptide antibiotic, is used in cases of drug-resistant bacterial infections, but unfortunately is associated with acute kidney injury (AKI). We here explore the protective potential of aprepitant against vancomycin-induced AKI. Vancomycin (500 mg/kg/i.p) was given to rats for seven days and aprepitant (20 mg/kg/p.o) was administered one day before and for seven days concomitant with vancomycin. At the end of the experiment, kidney function, oxidative stress, autophagy and ferroptosis markers were assessed. We show that aprepitant reduced kidney/body weight ratio, serum creatinine and blood urea nitrogen levels. It improved renal structure and enhanced the antioxidant machinery as indicated by elevated catalase activity and GSH levels and reduced renal MDA. Aprepitant managed to inhibit ferroptosis by decreasing system Xc^- and GPX4 renal levels. As a result, levels of autophagic markers ATG3, LC3A and LC3B were attenuated. These results were confirmed by electron microscopy examination of cellular structures. In addition, aprepitant increased p62 protein expression. Moreover, aprepitant decreased the apoptotic marker cleaved caspase-3 levels. Our results suggest a new repurposed role for aprepitant in protecting against AKI. This protective effect relies on its antioxidant effect and the influence of inhibiting ferroptosis which resulted in downregulation of autophagy and apoptosis.