Role of tubuloglomerular feedback in the development of hypertension in diabetes

肾小球反馈在糖尿病高血压发生中的作用

基本信息

批准号：
9917816
负责人：
RUISHENG LIU
金额：
$ 59.11万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-19 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917816
关键词：
Address Adenosine American Blood Pressure Blood Volume Cardiovascular Diseases Complications of Diabetes Mellitus Conscious Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse End stage renal failure Excretory function Exhibits Feedback Functional disorder Generations Genetic Glomerular Filtration Rate Glucose Hyperglycemia Hypertension Impairment In Vitro Injury to Kidney Insulin-Dependent Diabetes Mellitus Juxtaglomerular Apparatus Kidney Link Macula densa Measurement Measures Mediating Micropuncture Molecular Mus Natriuresis Nephrons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Non-Insulin-Dependent Diabetes Mellitus Oxides Patients Pharmacology Phosphorylation Population Protein Isoforms RNA Splicing Role Sodium Techniques Testing Tissues United States Variant Water arteriole base cardiovascular disorder risk cardiovascular risk factor diabetic diabetic patient fluorescence imaging in vivo knockout animal laser capture microdissection new therapeutic target non-diabetic novel pressure response solute

项目摘要

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.

有超过2900万美国人患有糖尿病。约30-40％的糖尿病患者最终将出现糖尿病性肾病，这是联合终端肾脏疾病的主要原因国家。糖尿病患者的高血压率是非糖尿病患者的两倍以上。糖尿病高血压患者的心血管风险增加和糖尿病性肾病的加剧，但是，糖尿病患者高血压的机制尚不清楚。目前的提案将检验中心假设，即黄斑处的葡萄糖浓度升高糖尿病中的densa激活了SGLT1，从而增强了NOS1活性并促进肾小球的发展过滤。黄斑丹萨（Macula densa 通过限制GFR升高并损害钠排泄的机制加剧了糖尿病肾脏损伤。该假设将以以下特定目的进行检验： AIM 1。假设：黄斑densa的葡萄糖激活SGLT1并增强的表达和活性 Macula densa nos1剪接变体通过Ser1412的磷酸化。钝的TGF响应能力由黄斑densa NOS1促进了1型和2型糖尿病中的过滤过滤的发展。目标2。假设：黄斑densa没有任何产生会诱发高血压和恶化 1型和2型糖尿病中的糖尿病肾损伤。涉及的机制是增强的TGF响应限制肾小球过滤的发展，这会损害肾脏钠排泄和压力糖尿病中的纳特里雷SIS。