Pathophysiology of insulin-regulated renal blood flow and sodium excretion

项目摘要/摘要 肾血流调节受损(Rbf)被认为是糖尿病发病的关键因素。 通过对肾小球压力、肾小球滤过率和尿钠排泄(UNaV)的影响而导致代谢综合征。 在这些情况下，RBF调节受损的机制尚不清楚。我们有一本小说的证据 胰岛素对RBF的生理作用可能是影响RBF的病理生理机制。 我们的数据表明，防止餐后过量钠流失是胰岛素的生理功能-- 受监管的UNAV。这并不完全像文献预测的那样，完全是由于管状钠的重吸收。我们 研究表明，胰岛素可能通过血栓素A2(TXA2)在餐后对肾脏血管产生收缩作用。 限制进餐引起的肾血管扩张程度。生理功能损害应引起 餐后肾血管过度扩张，导致肾盐浪费，并可能对 慢性肾脏病的进展。这种生理功能的夸大应该会导致明显的肾脏血管收缩， 钠滞留，和高血压，如果持续。更多数据显示，阻断病毒的保护作用 一氧化氮(NO)使高糖饮食导致高血压，我们可以通过阻断高血压来预防 高胰岛素血症。我们将检验中心假设：生理上的，保存钠的作用 胰岛素部分是通过餐后肾血管收缩的影响来调节的，这种影响限制了餐后诱导的程度 肾血管扩张。需要平衡来自一氧化氮的输入以防止明显的肾血管收缩 还有高血压。具体目标将检验是否： 目的1：胰岛素的生理保钠作用部分是通过餐后肾脏来实现的。 对血管收缩的影响。这些实验将检验这样的假设：a.防止饮食诱导 血浆胰岛素的增加将导致RBF和UNaV的更大和更持续的增加 发生在正常对照大鼠身上。B.胰岛素依赖的肾血管收缩作用需要血栓素A2。C.在 背景条件下一氧化氮合酶抑制，葡萄糖团注会引起全肾血管收缩并放大 钠滞留。D.ENAC介导急性保存钠的肾小管重吸收成分 胰岛素的作用。目的2：NO合成受损导致胰岛素依赖性肾血管收缩和 高蔗糖摄入期间的高血压。实验验证了假设：a.抑制一氧化氮合酶将使 慢性高蔗糖摄入导致高血压(DSI遥测，24小时/天)。B.阻断高胰岛素血症将 预防高蔗糖摄入引起的高血压反应。仅恢复肾内高胰岛素血症 恢复高血压反应。C.抑制TXA2合成酶将阻止慢性高血压的影响 高蔗糖摄入量。

Project Summary/Abstract Impaired regulation of renal blood flow (RBF) is recognized as a critical element in the pathologies of diabetes and metabolic syndrome through effects on glomerular pressure, GFR, and urinary sodium excretion (UNaV). The mechanism for impaired RBF regulation in these conditions is not known. We have evidence for a novel physiological effect of insulin on RBF that may translate to mechanisms for pathophysiological RBF impact. Our data suggest that preventing excess sodium loss after meals is the physiological function of insulin- regulated UNaV. This is not due solely to tubular sodium reabsorption, as the literature would predict. We show that insulin also exerts renal vasoconstrictor tone after meals, possibly via thromboxane (TXA2), that limits the degree of meal-induced renal vasodilation. Impairment, of that physiological function should cause excessive renal vasodilation after meals, causing renal salt wasting and potential long-term implications on the progression of CKD. Exaggeration of this physiological function should cause overt renal vasoconstriction, sodium retention, and hypertension if sustained. Additional data show that blocking the protective role of nitric oxide (NO) enables high-sucrose diet to cause hypertension, which we can prevent by blocking hyperinsulinemia. We will test the central hypothesis that: The physiological, sodium-conserving effect of insulin is mediated in part by a post-meal renal vasoconstrictor influence that limits the degree of meal-induced renal vasodilation. Counterbalancing input from nitric oxide is required to prevent overt renal vasoconstriction and hypertension. The specific aims will test whether: Aim 1: The physiological, sodium-conserving effect of insulin is mediated in part by a post-meal renal vasoconstrictor influence. The experiments will test the hypotheses that: a. Preventing the meal-induced increase in plasma insulin will cause greater and more sustained increases in RBF and greater UNaV than occurs in normal control rats. b. The insulin-dependent renal vasoconstrictor influence requires TXA2. c. Under conditions of background NOS inhibition, glucose bolus will cause overall renal vasoconstriction and amplified sodium retention. d. ENaC mediates the tubular reabsorption component of the acute sodium-conserving effect of insulin. Aim 2: Impaired NO synthesis causes insulin-dependent renal vasoconstriction and hypertension during high-sucrose intake. Experiments test the hypotheses that: a. NOS inhibition will enable chronic high-sucrose intake to cause hypertension (DSI telemetry, 24 hr/day). b. Blocking hyperinsulinemia will prevent the hypertensive response to high-sucrose intake. Restoring only intra-renal hyperinsulinemia restores the hypertension response. c. TXA2 synthase inhibition will prevent the hypertensive effect of chronic high-sucrose intake.