Podocyte stress hypertrophy and depletion

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DESCRIPTION (provided by applicant): Glomerulosclerosis is the common pathologic process responsible for 90% of End Stage Kidney Disease (ESKD) associated with diabetes, hypertension, IgA nephropathy, Focal Segmental Glomerulosclerosis (FSGS), lupus and other glomerular diseases. Together these diseases cost approximately $18 billion per year in the US, and carry high morbidity and mortality. They are increasing in prevalence and are commoner in minority populations. They affect both children and adults, although ESKD is particularly a disease of aging with average onset of ESKD treatment at 64 years. The central hypothesis underlying this work is that glomerulosclerosis is caused by depletion of one of the glomerular cell types, the podocyte. During the prior grant cycle we developed a new transgenic model system in the rat where we can deplete podocytes by an amount and at a time of prior choosing. We show that podocyte depletion does indeed cause all the features of FSGS in a dose-dependant manner. Second we have developed a new method for counting podocytes in glomeruli. Third, we have shown how glomerular enlargement during aging on a high calorie diet causes relative podocyte depletion that predisposes to glomerulosclerosis, and how this can be prevented by calorie restiction. Because we know that hypertension is commonly associated with glomerulosclerosis and progression of glomerulosclerosis to ESKD, these new tools and concepts will be used to test specific hypotheses relevant to human glomerulosclerosis: Aim 1: Podocyte depletion itself causes systemic hypertension and mesangial expansion, an important pathologic component of early glomerulosclerosis in man. Aim 2: Test the hypothesis that limitation of the ability of the podocyte to increase in size makes the glomerulus more susceptible to glomerulosclerosis, while enhancement of podocyte's ability to increase in size prevents glomerulosclerosis, by using transgenes of the mTOR pathway of cell size control to modulate podocyte size. Aim 3: Validate the novel concepts of podocyte alteration in phenotype in response to stress that we have termed "adaptation" and "decompensation" in two rat models of glomerulosclerosis, with the underlying concept that understanding the biology of this process will allow us to develop markers for human podocyte stress as well as new approaches to treat and prevent podocyte stress before it results in loss of podocytes and consequent glomerulosclerosis.