Targeting STEAP4 ameliorates pericytes loss and vascular dysfunction in cisplatin induced mouse acute kidney injury.

Abstract

Nephrotoxicity is the most common complication of cisplatin, and effective therapeutic strategies are still limited. Vascular dysfunction is thought to be early response after cisplatin administration and contributes to renal damage. However, the precise mechanisms underlying this process have yet to be fully elucidated. In this study, we observed a significant increase in renal vascular permeability following cisplatin administration in vivo, accompanied by a rapid loss of perivascular pericytes. Consistently, in vitro experiments revealed that cisplatin markedly accelerated cell death in primary human kidney microvascular pericytes (HKMPs). RNA-sequencing and proteomics analysis further identified a significant downregulation of six-transmembrane epithelial antigen of the prostate 4 (STEAP4) mRNA and protein expression in HKMPs after cisplatin exposure. Mechanistically, reduced STEAP4 expression facilitates iron accumulation and lipid peroxidation in HKMPs, leading to potentiated ferroptosis, whereas STEAP4 overexpression conferred protection against cisplatin-induced pericytes injury. Finally, targeted delivery of AAV9via renal artery injection efficiently increased renal STEAP4 expression, reduced pericyte loss, and attenuated renal vascular leakage. Furthermore, the AAV9group exhibited significantly decreased kidney injury compared to the AAV9group. Collectively, these findings demonstrate that STEAP4 mediates pericyte injury in renal vascular dysfunction and suggest that targeting STEAP4 could represent a novel therapeutic strategy for cisplatin-induced acute kidney injury (AKI).