(max 30 lines): Nephrotic syndrome is a major manifestation of human glomerular disease, and patients with this condition develop large amounts of protein in the urine (proteinuria) and elevated levels of plasma cholesterol (hypercholesterolemia). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is well studied in the liver where it is implicated in the development of hypercholesterolemia but little is known about the link between kidney PCSK9 and hypercholesterolemia. Statins and/or PCSK9 antibodies are now considered the standard care for patients with hypercholesterolemia but this therapeutic approach only treats hypercholesterolemia once it is established and does not prevent the development of hypercholesterolemia. Recent studies from the applicant?s lab suggest that PCSK9 is expressed in the kidney, mainly in the cortical collecting duct (CCD) and that PCSK9 secreted from the CCD initiates hypercholesterolemia in nephrotic syndrome. In fact, PCSK9 expression is increased in the CCD in human focal and segmental glomerulosclerosis (FSGS) kidney biopsies compared to controls. This phenomenon was also noted in two animal models of FSGS. In this proposal, the PI will study molecular mechanisms of the origin of hypercholesterolemia of nephrotic syndrome and will identify the specific glycomic profile of CCD-secreted PCSK9. It will allow its detection and depletion during the early phase of hypercholesterolemia to prevent or reduce progression to the established phase.
In Specific Aim 1, the applicant will study by confocal microscopy, the expression of CCD-PCSK9 in biopsies from nephrotic patients with other kidney diseases and corresponding animal models.
In Specific Aim 2, the applicant will use mass spectrometry to identify the specific post-translational modification profile of PCSK9 secreted from the kidney CCD. The affinity of LDL receptor for different forms of recombinant PCSK9, that mimic liver or kidney secreted proteins, will also be assed.
In Specific Aim 3, the applicant will study the effect of modulating CCD-PCSK9 expression and its depletion from plasma on sustained hypercholesterolemia in nephrotic syndrome.
