Endothelial Receptor Action in Na-Dependent Hypertension

钠依赖性高血压中内皮受体的作用

• 批准号: 7228246
• 负责人: DAVID M POLLOCK
• 金额: $ 18.72万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228246
• 关键词: NAD(P)H dehydrogenase; angiotensin /renin /aldosterone hypertension; angiotensin II; drug delivery systems; endothelin; enzyme induction /repression; genetically modified animals; hemodynamics; hormone biosynthesis; hormone receptor; interleukin 1; ion transport; kidney function; laboratory mouse; laboratory rat; northern blottings; oxidative stress; receptor expression; renal medulla; statistics /biometry; superoxides; transforming growth factors; ultrasound blood flow measurement; urinalysis; vascular endothelium

The objective of Project 4 is to elucidate mechanisms responsible for changes in endothelin (ET)-dependent vascular and renal function in salt-dependent hypertension produced by chronic administration of angiotensin II (Ang II). ETA and ETB receptors have opposing effects on renal hemodynamics and tubular function so as to decrease or increase the kidney's ability to eliminate salt, respectively. We have shown that ET production in renal medullary epithelial cells is stimulated by transforming growth factor-Beta (TGFbeta) and interleukin-1Beta (IL-1beta), two factors that are increased in the kidneys during salt loading. We hypothesize that in salt-dependent hypertension, TGFbeta and/or IL-1beta stimulate renal ET production, that in turn, contributes to hypertension via ETA-dependent superoxide production. Overproduction of superoxide can negate the beneficial actions of NO and other factors important in fluid-volume regulation. We further hypothesize that salt-dependent hypertension is due, in part, to the lack of appropriate ETB receptor mediated responses due to oxidative stress. The first aim in Project 4 is to test the specific hypothesis that TGFbeta and/or IL-1beta stimulate ET production in the kidney of hypertensive rats given a high salt diet. We will utilize a rat model of chronic Ang II hypertension to determine the relationship between changes in intrarenal TGFbeta, IL-1beta, and ET production. In addition, we expect less ET production and functional activity following Ang II infusion in TGFbeta and/or IL-1beta knock-out mice. Aim 2 will test the hypothesis that ETA receptor activation stimulates superoxide production in the kidney of rats with salt-dependent hypertension. Our hypothesis predicts that ETA receptor blockade will inhibit oxidative stress in Ang II hypertensive rats on high salt, and that the effects of ET are mediated by activation of NADPH oxidase in vivo. Aim 3 will test the hypothesis that ETB-mediated inhibition of sodium transport is inactivated by superoxide in salt-dependent hypertension. Our hypothesis predicts that superoxide will limit the ability of ET to decrease transport in primary cultures of renal inner medullary collecting duct cells. In vivo, we expect that the diuretic effects of ETB receptor agonists will be reduced in salt-dependent hypertension when superoxide levels are increased.

项目 4 的目标是阐明长期服用血管紧张素 II (Ang II) 引起的盐依赖性高血压中内皮素 (ET) 依赖性血管和肾功能变化的机制。 ETA和ETB受体对肾血流动力学和肾小管功能具有相反的作用，从而分别降低或增加肾脏消除盐的能力。我们已经证明，转化生长因子-β (TGFbeta) 和白细胞介素-1β (IL-1beta) 会刺激肾髓质上皮细胞中 ET 的产生，这两种因子在盐负荷期间会在肾脏中增加。我们假设在盐依赖性高血压中，TGFbeta 和/或 IL-1beta 刺激肾脏 ET 的产生，进而， 通过 ETA 依赖性超氧化物的产生导致高血压。超氧化物的过量产生会抵消一氧化氮和其他在液体容量调节中重要的因素的有益作用。我们进一步假设盐依赖性高血压部分是由于氧化应激导致缺乏适当的 ETB 受体介导的反应。项目 4 的第一个目标是测试以下具体假设：TGFbeta 和/或 IL-1beta 刺激高盐饮食的高血压大鼠肾脏中 ET 的产生。我们将利用慢性 Ang II 高血压大鼠模型来确定肾内 TGFβ、IL-1β 和 ET 产生变化之间的关系。此外，我们预计在 TGFbeta 和/或 IL-1beta 敲除小鼠中输注 Ang II 后，ET 的产生和功能活性会减少。目标 2 将检验这样的假设：ETA 受体激活会刺激盐依赖性高血压大鼠肾脏中超氧化物的产生。我们的假设预测，ETA 受体阻断将抑制 Ang II 高血压大鼠对高盐的氧化应激，并且 ET 的作用是通过体内 NADPH 氧化酶的激活介导的。目标 3 将检验以下假设：在盐依赖性高血压中，ETB 介导的钠转运抑制作用会被超氧化物失活。我们的假设 预测超氧化物将限制 ET 减少肾内髓质集合管细胞原代培养物转运的能力。在体内，我们预计当超氧化物水平增加时，ETB 受体激动剂的利尿作用将在盐依赖性高血压中降低。