Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Podocytes in Mouse Nephrotic Syndrome

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to play a crucial role in dyslipidemia, and an increase in serum PCSK9 levels has also been reported in patients with nephrotic syndrome (NS). However, the specific effects of PCSK9 in kidney disease and the therapeutic potential of targeting PCSK9 in NS remain elusive. We thus investigated the effects of evolocumab (EVO) in mice with adriamycin (ADR)-induced NS. Male BALB/c mice were divided into the following 4 groups: Control, N = 11; EVO (monoclonal antibody for PCSK9), N = 11; ADR, N = 11; and ADR+EVO, N = 11. We also performed in vitro experiments using immortalized murine podocyte cells to validate the direct effects of PCSK9 on podocytes. EVO decreased urinary albumin levels and ameliorated podocytopathy in mice with ADR nephropathy. Further, EVO suppressed the Nod-like receptor protein 3 (NLRP3) inflammasome pathway in podocytes. PCSK9 expression upregulated CD36, a scavenger receptor of oxidized low-density lipoprotein (Ox-LDL), which in turn stimulated the absorption of Ox-LDL in vitro. EVO downregulated CD36 expression in podocytes both in vitro and in vivo. Immunofluorescence staining analysis reveals that CD36 and PCSK9 colocalized in the glomerular tufts of mice with ADR nephropathy. In the patients with focal segmental glomerulosclerosis, the CD36⁺ area in glomerular tufts increased compared with those diagnosed with minor glomerular abnormalities. This study revealed that EVO ameliorated mouse ADR nephropathy through the regulation of CD36 and NLRP3 inflammasome signaling. EVO treatment represents a potential therapeutic strategy for human NS.