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

• 批准号: 10394215
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-19 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394215
• 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; blood pressure elevation; 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

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%的患者患有糖尿病 最终将发展为糖尿病肾病，这是美国终末期肾病的主要原因 国家。糖尿病患者的高血压发病率是非糖尿病人群的两倍多。糖尿病患者 高血压患者心血管风险增加，糖尿病肾病恶化， 然而，糖尿病患者高血压的机制仍不清楚。 本提案将检验中心假设，即黄斑处葡萄糖浓度的增加 糖尿病中的 densa 激活 SGLT1，从而增强 NOS1 活性，促进肾小球发育 超滤。致密黄斑生成的一氧化氮不足会诱发糖尿病和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。 该假设将通过以下具体目标进行检验： 目标 1. 假设：致密斑处的葡萄糖激活 SGLT1 并增强 SGLT1 的表达和活性 Ser1412 磷酸化导致的致密斑 NOS1 剪接变体。 TGF 反应性减弱 致密斑 NOS1 促进 1 型和 2 型糖尿病过度滤过的发生。 目标 2. 假设：致密黄斑生成的 NO 不足会诱发高血压并加剧 1 型和 2 型糖尿病的糖尿病肾损伤。所涉及的机制是增强 TGF 反应 限制肾小球过度滤过的发展，从而损害肾钠排泄和压力 糖尿病中的尿钠排泄。

项目成果

Tacrolimus Causes Hypertension by Increasing Vascular Contractility via RhoA (Ras Homolog Family Member A)/ROCK (Rho-Associated Protein Kinase) Pathway in Mice.

他克莫司通过 RhoA（Ras 同源家族成员 A）/ROCK（Rho 相关蛋白激酶）通路增加小鼠血管收缩力，从而导致高血压。

• 发表时间: 2022-10
• 作者: Wang, Xiaohua;Jiang, Shan;Fei, Lingyan;Dong, Fang;Xie, Lanyu;Qiu, Xingyu;Lei, Yan;Guo, Jie;Zhong, Ming;Ren, Xiaoqiu;Yang, Yi;Zhao, Liang;Zhang, Gensheng;Wang, Honghong;Tang, Chun;Yu, Luyang;Liu, Ruisheng;Patzak, Andreas;Persson, Pontus B
• 通讯作者: Persson, Pontus B