Mechanisms of Salt-Sensitive Hypertension

盐敏感性高血压的机制

• 批准号: 7163816
• 负责人: R DAVIS MANNING
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7163816
• 关键词: NAD(P)H dehydrogenase; angiotensin /renin /aldosterone hypertension; blood pressure; clinical research; diet; dietary sodium; endothelin; enzyme activity; free radical oxygen; glutathione; hemodynamics; kidney function; laboratory rat; nutrition related tag; oxidative stress; pathologic process; renal failure; salt intake; saluresis; superoxide dismutase; xanthine oxidase

Although the arterial pressure of a large percentage of hypertensive patients is sensitive to a high sodium diet, the mechanisms underlying the progression of hypertension and end-stage renal disease in salt-sensitive hypertension are unknown. Recent studies in humans and in animal models of salt- sensitive hypertension indicate that an increase in oxidative stress is associated with the progressive elevation in arterial pressure and reduction in renal function. One of the mediators in causing increased superoxide (O2.-) release in salt-sensitive hypertension is increased endothelin levels which may stimulate NADPH oxidase formation. Studies derived from our previous Program project grant have shown that the Dahl salt-sensitive rat has elevated oxidative stress and endothelin, decreased renal superoxide dismutase (SOD) levels and progressive renal damage. After a 3 week-high Na diet, Dahl S rats experience increased urinary excretion of isoprostanes, increased O2.- release from the kidneys, increased arterial pressure and urinary protein excretion, mild increases in the percentage of glomeruli with glomerulosclerosis and no change in GFR or renal plasma flow. In contrast, after a 5 week-high Na diet, O2.- release from the kidneys is elevated, arterial pressure and urinary protein excretion are much higher than in the S rats on 3 weeks of high Na, glomerular damage is significant, and GFR and renal plasma flow are markedly decreased. Preliminary studies from our laboratory also indicate that vitamin E+C administration decreases renal O2.- release and arterial pressure, prevents the decreases in GFR and renal plasma flow, decreases urinary protein excretion and markedly decreases renal damage. In the 5-week S rats, renal SOD activity is decreased, and the antioxidants, allopurinol which inhibits XO, and Tempol, a SOD mimetic, both decreased the renal O2.- release in the 5-week S high Na rats. In addition, in S high Na rats, a 5-week administration of N-acetylcysteine, which increases glutathione levels, decreased arterial pressure, increased GFR and renal plasma flow and decreased urinary protein excretion. Based on these preliminary findings we propose the central hypothesis that excessive production of reactive oxygen species by specific oxidases in the kidney and or deficiencies in renal antioxidant mechanisms play an important role in the progression of hypertension and renal damage in Dahl salt-sensitive rats. The following specific aims will test this central hypothesis: 1) To test the hypothesis that increases in reactive oxygen species mediate the progressive increases in arterial pressure, the decreases in GFR and renal plasma flow, and the increase in renal damage that occur in Dahl salt-sensitive hypertension. 2) To test the hypothesis that increases in xanthine oxidase activity in the kidney play an important role in the increases in renal O2.- release and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension. 3) To test the hypothesis that increases in NADPH oxidase activity in the kidney play an important role in the increases in renal O2.- release and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension. 4) To test the hypothesis that endothelin plays an important role in the increases in renal O2.- and the reduction in renal function via stimulation of NADPH oxidase in Dahl salt-sensitive hypertension. 5) To test the hypothesis that decreases in SOD activity in the kidney play an important role in the increases in renal O2.- release and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension. 6) To test the hypothesis that decreases in renal glutathione levels play an important role in the increases in renal release of reactive oxygen species and the abnormalities in cardiovascular and renal function in Dahl salt-sensitive hypertension.

虽然大部分高血压患者的动脉压对高钠饮食敏感，但盐敏感性高血压患者高血压和终末期肾病进展的机制尚不清楚。最近在人类和盐敏感性高血压动物模型中的研究表明，氧化应激的增加与动脉压的进行性升高和肾功能的降低有关。引起超氧化物（O2.-）盐敏释放 高血压是内皮素水平增加，其可刺激NADPH氧化酶形成。 来自我们以前的计划项目资助的研究表明，达尔盐敏感大鼠的氧化应激和内皮素升高，肾脏超氧化物歧化酶（SOD）水平下降，肾损伤进行性。在3周的高钠饮食后，Dahl S大鼠经历了异前列腺素的尿排泄增加，O2.从肾脏释放，动脉压和尿蛋白排泄增加，肾小球硬化的肾小球百分比轻度增加，GFR或肾血浆流量无变化。相比之下，在5周高钠饮食后，O2.从肾脏释放升高，动脉压和尿蛋白 高钠3周时，肾小球滤过率和肾血流量明显降低，肾小球损害明显。我们实验室的初步研究还表明，维生素E+C的使用会降低肾脏O2。通过降低肾组织中蛋白质的释放和动脉压，防止GFR和肾血浆流量的降低，减少尿蛋白排泄，并显著降低肾损伤。在5周的S大鼠中，肾脏SOD活性降低，抗氧化剂，抑制XO的别嘌呤醇和Tempol， 一种SOD模拟物，两者都降低了肾脏的O2。5周S高Na大鼠中的释放。此外，在S高Na大鼠中，给予N-乙酰半胱氨酸5周，可增加谷胱甘肽水平，降低动脉压，增加GFR和肾血浆流量，减少尿蛋白排泄。基于这些初步的研究结果，我们提出了一个中心假设，即过量生产的活性氧物种的特定氧化酶在肾脏和/或肾脏抗氧化机制的不足发挥了重要作用，在达尔盐敏感大鼠的高血压和肾损伤的进展。以下具体目的将检验这一中心假设：1）检验活性氧增加介导动脉压进行性升高、GFR和肾血浆流量降低以及Dahl盐敏感性高血压中发生的肾损伤增加的假设。2)为了检验肾脏中黄嘌呤氧化酶活性增加在肾脏O2增加中起重要作用的假设。释放和心血管和肾脏的异常 在达尔盐敏感性高血压中的作用。3)为了检验肾脏中NADPH氧化酶活性增加在肾脏O2增加中起重要作用的假设。Dahl盐敏感性高血压的心血管和肾功能异常。4)为了检验内皮素在肾O2增加中起重要作用的假设。以及Dahl盐敏感性高血压中通过NADPH氧化酶的刺激而导致的肾功能降低。5)为了检验肾脏中SOD活性降低在肾脏O2增加中起重要作用的假设。Dahl盐敏感性高血压的心血管和肾功能异常。6)为了检验肾谷胱甘肽水平降低在肾活性氧释放增加中起重要作用的假设， Dahl盐敏感性高血压患者的心血管和肾功能异常。