Role of tubuloglomerular feedback in the development of hypertension in diabetes

美国有超过2900万人患有糖尿病。约30-40%的糖尿病患者 糖尿病肾病是糖尿病肾病的主要病因之一。 States.糖尿病患者的高血压发病率是非糖尿病人群的两倍多。糖尿病 高血压患者表现出心血管风险增加和糖尿病肾病恶化， 然而，糖尿病患者高血压的机制仍不清楚。 本提案将测试中心假设，即黄斑处葡萄糖浓度的增加 糖尿病中的densa激活SGLT 1，从而增强NOS 1活性并促进肾小球的发育。 超滤致密斑产生的NO不足诱导糖尿病患者的高血压， 通过限制GFR升高和损害钠排泄的机制加剧糖尿病肾损伤。 将以下列具体目标检验这一假设： 目标1.假设：致密斑的葡萄糖激活SGLT 1并增强SGLT 1的表达和活性。 致密斑NOS 1剪接变体通过丝氨酸1412磷酸化。通过以下途径介导的减弱的TGF反应性 致密斑NOS 1促进1型和2型糖尿病中超滤的发展。 目标二。假设：致密斑产生的NO不足诱导高血压并加重 2型糖尿病患者的肾脏损害所涉及的机制是，增强的TGF-β反应 限制肾小球超滤的发展，肾小球超滤损害肾钠排泄和血压 糖尿病的尿钠排泄

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.