Depletion of renal cortical collecting duct-secreted PCSK9 in early proteinuria prevents sustained nephrotic syndrome-related hypercholesterolemia.

The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndrome is related to PCSK9 secreted by the cortical collecting duct (CCD), whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated whether early neutralization of circulating CCD-secreted PCSK9 could prevent sustained hypercholesterolemia. We showed that PAN rats, a widely used animal model that mimics nephrotic syndrome phenotype of human minimal change disease (MCD), developed increased levels of PCSK9 of CCD origin before peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, whereas both SREBP2 and PCSK9 were unmodified and reduced, respectively, in the liver. Treatment of PAN rats with anti-PCSK9 antibodies administrated at or shortly after the onset of proteinuria prevented the development of significant and sustained hypercholesterolemia through the course of PAN. These data confirm that PCSK9 secreted from the kidney initiates the development of hypercholesterolemia in MCD and suggest that early depletion of PCSK9 during the initial stages of MCD prevents sustained hypercholesterolemia.NEW & NOTEWORTHY The goal of this study was to investigate the biology of CCD-secreted PCSK9 and its role in MCD-associated hypercholesterolemia. PCSK9 expression was increased in the kidney, but reduced in the liver, suggesting that elevated circulating PCSK9 levels may originate from the kidney. Administration of anti-PCSK9 antibodies targeting circulating kidney-derived PCSK9 prevented the development of significant and sustained hypercholesterolemia in the PAN rat model of human MCD-associated nephrotic syndrome.