Salt-sensitive hypertension: Role of renal superoxide

盐敏感性高血压：肾超氧化物的作用

• 批准号: 7145734
• 负责人: Jeffrey L. Garvin
• 金额: $ 25.38万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145734
• 关键词: angiotensin /renin /aldosterone hypertension; dietary sodium; hypertension; laboratory rat; membrane transport proteins; nitric oxide; nutrition related tag; oxidative stress; protein kinase C; renal tubular transport; saluresis; second messengers; superoxides

DESCRIPTION (provided by applicant): There is a balance between factors promoting renal salt and water retention and those favoring excretion. Inappropriate salt retention may lead to hypertension. This project focuses on superoxide (O2-), which favors salt and water retention. Renal O2- is an important regulator of kidney function and has been implicated in salt-sensitive hypertension. The thick ascending limb of the loop of Henle is one of the nephron segments responsible for inappropriate NaCI retention in salt-sensitive hypertension and is the site of action of loop diuretics. In the last funding period we showed that O2- increased thick ascending limb transport by enhancing the activity of the luminal Na/K/2CI cotransporter. This effect was due to both activation of protein kinase C (PKC) and scavenging of nitric oxide (NO). However, few studies have directly addressed how O2- production is regulated along the nephron. Urine flow through thick ascending limbs is not static, but acutely varies from more than 25 nl/min to as little as 0 nl/min (actually stopping) due to peristalsis of the papilla. Our preliminary data show that increasing luminal flow through the thick ascending limb (THAL-flow) stimulates O2- generation. Our general hypothesis is that factors that increase urine flow and therefore augment stretch, pressure or shear stress in the thick ascending limb enhance O2- production, which in turn promotes NaCI absorption and therefore Na retention. The increase in Na retention caused by enhanced O2- in the thick ascending limb may be important in the pathogenesis of hypertension and other diseases associated with Na retention. Aim 1 will test whether acutely increasing THAL-flow causes the assembly and activation of NADPH oxidase, thereby enhancing O2- generation and NaCI absorption. Aims 2 and 3 will study the signaling cascades responsible for flow-stimulated O2- production focusing on protein kinase C and the small G-protein Rac1. Aim 4 will investigate how flow-induced NO regulates NADPH oxidase activity and its impact on NaCI absorption. We will employ state of the art techniques to address these aims, including fluorescence energy transfer and in vivo viral transduction in addition to standard physiological, biochemical and pharmacological techniques. Successful completion of this project will give us new insights into how O2- is generated in the kidney as well as its role in salt retention, and predict new targets for treatment of hypertension.

描述（由申请人提供）：促进肾盐和水潴留的因素与有利于排泄的因素之间存在平衡。不适当的盐潴留可能导致高血压。该项目的重点是超氧化物（O2-），它有利于盐和水的保留。肾 O2- 是肾功能的重要调节因子，与盐敏感性高血压有关。亨利袢的粗升肢是负责盐敏感性高血压中不适当的氯化钠潴留的肾单位段之一，并且是袢利尿剂的作用部位。在上一个资助期间，我们表明 O2- 通过增强管腔 Na/K/2CI 协同转运蛋白的活性来增加厚升肢转运。这种效应是由于蛋白激酶 C (PKC) 的激活和一氧化氮 (NO) 的清除所致。然而，很少有研究直接探讨肾单位如何调节 O2- 的产生。流经粗上升肢的尿流不是静态的，而是由于乳头的蠕动而急剧变化，从超过 25 nl/min 到低至 0 nl/min（实际上停止）。我们的初步数据表明，增加通过粗升肢的管腔流量（THAL 流量）会刺激 O2 的产生。我们的一般假设是，增加尿流量并因此增加厚升肢中的拉伸、压力或剪切应力的因素增强O 2 的产生，这反过来促进NaCl吸收并因此促进Na潴留。在粗壮的升肢中，O2- 增强引起的 Na 潴留增加可能在高血压和其他与 Na 潴留相关的疾病的发病机制中很重要。目标 1 将测试急剧增加 THAL 流量是否会导致 NADPH 氧化酶的组装和激活，从而增强 O2 生成和 NaCl 吸收。目标 2 和 3 将研究负责流量刺激 O2 产生的信号级联，重点关注蛋白激酶 C 和小 G 蛋白 Rac1。目标 4 将研究流量诱导的 NO 如何调节 NADPH 氧化酶活性及其对 NaCl 吸收的影响。我们将采用最先进的技术来实现这些目标，除了标准的生理、生化和药理学技术之外，还包括荧光能量转移和体内病毒转导。该项目的成功完成将使我们对肾脏中如何产生 O2- 及其在盐潴留中的作用有新的认识，并预测治疗高血压的新目标。