Renal Control of Blood Pressure in Early Diabetes

描述（由申请人提供）：我们已经证明，如果在慢性一氧化氮（NO）合成抑制的情况下发生，糖尿病首次发作的高血糖会导致显著的肾血管收缩和高血压。这些高血糖的有害后果可以通过超氧化物（SO）歧化酶模拟物tempol的抗氧化处理来预防。潜在的假设是，早期糖尿病的高血糖发作诱导了血管紧张素ii依赖性、超氧介导的肾压-尿钠关系的右移，而一氧化氮是预防高血压的重要对抗力。该项目的实验将通过验证一氧化氮抵消血管紧张素ii依赖性、超氧化物介导的肾血管收缩以预防糖尿病早期高血糖期间高血压的中心假设，来确定这些重要相互作用的机制。实验将通过测试3个子假设来验证这一点：在糖尿病发病时，一氧化氮是预防肾血管收缩和高血压所必需的。我们的L-NAME、乙酰胆碱和肾小球滤过率（GFR）数据支持这一点，但为了更好地了解NO并确定其在早期糖尿病中控制肾功能的部位，我们将：

DESCRIPTION (provided by applicant): We have shown that the first onset of hyperglycemia in diabetes causes significant renal vasoconstriction and hypertension if it occurs under conditions of chronic nitric oxide (NO) synthesis inhibition. Those deleterious consequences of hyperglycemia are prevented by antioxidant treatment with the superoxide (SO) dismutase mimetic, tempol. The underlying hypothesis is that onset of hyperglycemia in early diabetes induces an angiotensin II-dependent, superoxide-mediated right-shift in the renal pressure-natriuresis relationship, and that nitric oxide is an important counteracting force that prevents hypertension. The experiments in this project will determine the mechanisms for these important interactions by testing the central hypothesis that nitric oxide counteracts angiotensin II-dependent, superoxide-mediated renal vasoconstriction to prevent hypertension during hyperglycemia early in diabetes. Experiments will test this by testing the 3 subhypotheses that: 1. Nitric oxide is required to prevent renal vasoconstriction and hypertension at the onset of diabetes. Our L-NAME, ACh, and glomerular filtration rate (GFR) data support this, but to better implicate NO and define the site(s) for its control of renal function in early diabetes, we will: a. measure renal blood flow 24 hr/d to quantify the changes in resistance and filtration fraction; b. determine the time-, glucose-, and insulin-dependent changes in eNOS and nNOS; c. determine when, and if, vasodilatory prostaglandins assume the vasoprotective role of NO; d. determine the roles of eNOS vs. nNOS using knockout mice and infusion of antagonists. 2. Angiotensin II increases sensitivity to renal vasoconstriction and hypertension during hyperglycemia and is required for those responses to occur. Our evidence supports this role, but to determine Angll's importance independent of L-NAME-induced increases we will determine: a. whether low-sodium intake exacerbates the sensitivity of diabetic rats to NOS inhibition; b. the link between GFR and blood pressure by using decreased kidney mass to control GFR; c. whether onset of diabetes causes hypertension in rats with Angll hypertension; d. the superoxide-independent component of Angll's influence on MAP and renal resistance. 3. Superoxide induces a renal vasoconstrictor and hypertensive influence at the onset of hyperglycemia. We have shown that tempol prevents hypertension in L-NAME-treated diabetic rats, but to more specifically implicate SO, with or w/o NOS blockade, we will determine: a. whether antioxidant treatment can prevent hypertension without decreasing renin secretion; b. whether knockout of SO dismutase-1 (SOD1) exacerbates the hypertensive response; c. whether increased SOD1 in transgenic mice protects against hypertension similar to tempol; d. the role of NADPH oxidase, by measuring p22 phox expression and the effect of apocynin.