Role of tubuloglomerular feedback in the development of hypertension in diabetes

美国有2900多万人患有糖尿病。约30%-40%的糖尿病患者 最终会发展成糖尿病肾病，这是美国终末期肾病的主要原因。 各州。糖尿病患者的高血压患病率是非糖尿病人群的两倍多。糖尿病患者 高血压患者心血管风险增加，糖尿病肾病加重， 然而，糖尿病患者高血压的机制仍不清楚。 目前的提议将检验中心假设，即黄斑部葡萄糖浓度的增加 糖尿病患者Densa激活SGLT1，增强NOS1活性，促进肾小球发育 超滤。致密黄斑产生的NO不足会导致糖尿病和高血压 通过限制GFR升高和减少钠排泄的机制加重糖尿病肾脏损伤。 这一假设将以以下具体目标进行检验： 目的1.假设：致密黄斑葡萄糖激活SGLT1，增强SGLT1的表达和活性 致密黄斑Ser1412的磷酸化剪接变异体。钝化的转化生长因子反应性由 致密黄斑NOS1促进1型和2型糖尿病患者发生高滤过。 目的2.假设：致密黄斑产生的NO不足会导致高血压并加重 1型糖尿病和2型糖尿病合并糖尿病肾损害。其中涉及的机制是增强的转化生长因子反应 限制肾小球高滤过的发展，这会损害肾脏的钠排泄和压力 糖尿病患者的钠尿症。

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.