Proprotein convertase subtilisin/kexin type 9 contributes to cisplatin-induced acute kidney injury by interacting with cyclase-associated protein 1 to promote megalin lysosomal degradation

Cisplatin-induced acute kidney injury (AKI) is associated with a considerable risk of mortality, highlighting the critical need for effective preventive and therapeutic strategies to mitigate its impact on patients' outcomes. Mounting evidence suggests that administration of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab significantly reduces the risk of AKI, however, the underlying mechanisms remain poorly understood. Megalin is an endocytic receptor that plays a crucial role in tubular cells. In this study, elevated PCSK9 expression, accompanied by decreased megalin expression, was observed in cellular and murine models of cisplatin-induced AKI. Further experiments revealed that PCSK9 overexpression downregulated megalin expression and promoted tubular injury. Additionally, the PCSK9 inhibitor evolocumab inhibited megalin loss and protected against increases in urinary protein levels, blood urea nitrogen, serum creatinine, and the kidney injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule 1. Mechanistically, PCSK9 binds to megalin and facilitates its lysosomal degradation through the coordinated actions of cyclase-associated protein 1 (CAP1) and human leukocyte antigen C (HLA-C). Similar to evolocumab, CAP1 deletion significantly protected against megalin loss and mitigated tubular injury both in vitro and in vivo. Collectively, these findings suggest that PCSK9 and CAP1 are potential therapeutic targets for patients with cisplatin-induced AKI.