Role of tubuloglomerular feedback in the development of hypertension in diabetes

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There are more than 29 million Americans suffering from diabetes. About 30-40% of patients with diabetes will eventually develop diabetic nephropathy, which is the leading cause of end stage renal disease in the United States. The rate of hypertension is more than twice in diabetic patients than the non-diabetic population. Diabetic patients with hypertension exhibit increased cardiovascular risk and exacerbation of diabetic nephropathy, however, the mechanisms for hypertension in diabetic patients remains unclear. The present proposal will test the central hypothesis that the increase of glucose concentration at the macula densa in diabetes activates SGLT1, which enhances NOS1 activity and promotes the development of glomerular hyperfiltration. Inadequate NO generation by the macula densa induces hypertension in diabetes and exacerbates diabetic kidney injury by mechanisms of limiting elevations in GFR and impairing sodium excretion. This hypothesis will be tested with the following specific aims: Aim 1. Hypothesis: Glucose at the macula densa activates SGLT1 and enhances expression and activity of macula densa NOS1 splice variants by phosphorylation of Ser1412. Blunted TGF responsiveness mediated by the macula densa NOS1 promotes the development of hyperfiltration in type 1 and type 2 diabetes. Aim 2. Hypothesis: Inadequate NO generation by the macula densa induces hypertension and exacerbates diabetic kidney injury in type 1 and type 2 diabetes. The mechanism involved is that enhanced TGF response limits the development of glomerular hyperfiltration, which impairs renal sodium excretion and pressure natriuresis in diabetes.