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 prior to peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, while 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.