Emerging roles of PCSK9 in kidney disease: lipid metabolism, megalin regulation and proteinuria.

Chronic kidney disease (CKD) is a significant risk factor for cardiovascular disease (CVD). Key features of CKD include proteinuria and reduced glomerular filtration rate, both of which are linked to disease progression and adverse outcomes. Dyslipidemia, a major CVD risk factor, often correlates with CKD severity and is inadequately addressed by conventional therapies. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in lipid metabolism by modulating low-density lipoprotein receptor (LDLR) levels and has emerged as a therapeutic target for managing dyslipidemia. PCSK9 inhibitors, including monoclonal antibodies and siRNA, effectively lower LDL cholesterol levels and have demonstrated safety in patients with mild to moderate CKD. Recent findings indicate that PCSK9 aggravates proteinuria by interacting with and downregulating megalin, a proximal tubule receptor essential for protein reabsorption in the kidney. Inhibition of PCSK9 has been shown to preserve megalin levels, reduce proteinuria, and improve the disease phenotype in experimental models. However, conflicting data from preclinical studies underscore the need for further research to clarify the mechanisms underlying PCSK9's role in kidney disease. This review highlights the potential of PCSK9 inhibition in addressing proteinuria and dyslipidemia in CKD, emphasizing its promise as a therapeutic strategy, while addressing current challenges and future directions for research.