Mechanisms of Salt-Sensitive Hypertension

虽然很大比例的高血压患者的动脉压对高钠饮食敏感，但盐敏感型高血压的高血压进展和终末期肾脏疾病的机制尚不清楚。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下降有关。盐敏症中引起超氧化物(O2.-)释放增加的介体之一 高血压是内皮素水平升高，可能会刺激NADPH氧化酶的形成。 从我们之前的项目拨款中获得的研究表明，Dahl盐敏感大鼠的氧化应激和内皮素水平升高，肾脏超氧化物歧化酶(SOD)水平降低，肾脏进行性损害。高钠饮食3周后，Dahl S大鼠尿异前列腺素排泄量增加，肾脏O2-释放量增加，动脉压和尿蛋白排泄量增加，肾小球硬化的肾小球百分率轻度增加，肾小球滤过率和肾血浆流量无明显变化。相比之下，在高钠饮食5周后，肾脏释放的O2增加，动脉压和尿蛋白增加 3周高钠组大鼠肾小球排泄量明显高于S组，肾小球损伤明显，肾小球滤过率和肾血浆流量明显减少。本实验室的初步研究还表明，维生素E+C可降低肾脏O2.-释放和动脉压，阻止GFR和肾脏血浆流量的减少，减少尿蛋白排泄，显著减轻肾脏损害。在5周龄的S大鼠，肾组织超氧化物歧化酶活性降低，抗氧化剂、抑制XO的别嘌醇和坦普尔， 超氧化物歧化酶模拟物均能降低5周龄S高钠大鼠肾脏O2.-释放量。此外，在S高钠大鼠中，给予N-乙酰半胱氨酸5周，可提高谷胱甘肽水平，降低动脉压，增加肾小球滤过率和肾脏血浆流量，并减少尿蛋白排泄。基于这些初步发现，我们提出了一个中心假设，即肾脏中特定氧化酶过度产生的活性氧物种和/或肾脏抗氧化机制的缺陷在Dahl盐敏感大鼠的高血压和肾脏损害的进展中起着重要作用。以下特定目标将检验这一中心假说：1)检验这一假说，即在Dahl盐敏感型高血压中，活性氧的增加介导了动脉压进行性升高、GFR和肾脏血浆流量的减少以及肾脏损害的增加。2)验证肾脏黄嘌呤氧化酶活性升高在肾脏O2.-释放增加及心血管和肾脏异常中起重要作用的假说。 在Dahl盐敏性高血压中的作用。3)验证肾脏NADPH氧化酶活性升高在Dahl盐敏感型高血压肾脏O2.-释放增加及心血管和肾功能异常中的重要作用。4)验证内皮素在Dahl盐敏感型高血压肾氧分压升高和NADPH氧化酶刺激肾功能下降中的重要作用。5)验证肾脏超氧化物歧化酶活性降低在Dahl盐敏感型高血压肾脏O2.-释放增加及心血管和肾功能异常中的重要作用。6)检验以下假设：肾脏谷胱甘肽水平降低在肾脏活性氧释放增加和 Dahl盐敏感型高血压患者的心血管和肾功能异常。

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.