Pathophysiology of insulin-regulated renal blood flow and sodium excretion

项目总结/摘要 肾血流量调节受损（RBF）被认为是糖尿病病理学的关键因素 通过对肾小球压力、GFR和尿钠排泄（UNaV）的影响而影响代谢综合征。 在这些条件下受损的RBF调节机制尚不清楚。我们有一本小说的证据 胰岛素对RBF的生理作用可能转化为病理生理RBF影响的机制。 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- 规范的UNAV。这并不像文献预测的那样仅仅是由于肾小管钠重吸收。我们 显示胰岛素在餐后也可能通过血栓素（TXA2）产生肾血管收缩张力， 限制了进餐引起的肾血管舒张的程度。生理功能的损伤会导致 餐后肾血管过度扩张，导致肾性盐浪费，并对肾功能产生潜在的长期影响。 CKD的进展。这种生理功能的放大应引起明显的肾血管收缩， 钠潴留和高血压。额外的数据显示，阻断 一氧化氮（NO）使高糖饮食引起高血压，我们可以通过阻断 高胰岛素血症我们将检验中心假设： 胰岛素部分地由餐后肾血管收缩剂影响介导， 肾血管舒张需要平衡一氧化氮的输入以防止明显的肾血管收缩 和高血压。具体目标将检验： 目的1：胰岛素的生理、钠保存作用部分由餐后肾脏介导 血管收缩剂的影响。实验将检验以下假设：a.防止饮食引起的 血浆胰岛素的增加将导致RBF和UNaV的更大和更持续的增加， 发生在正常对照组大鼠中。B.胰岛素依赖性肾血管收缩剂的影响需要TXA2。C.下 在背景NOS抑制的条件下，葡萄糖推注将引起整体肾血管收缩并放大 钠潴留D. ENaC介导急性钠保存性肾小管重吸收组分 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， 高蔗糖摄入时的高血压。实验验证了以下假设：a。NOS抑制将使 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. TXA2合酶抑制剂可预防慢性高血压效应 高糖摄入。

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.