MECHANISM OF PRESSURE NATRIURESIS

尽管几十年来人们一直认识到对盐分运输的监管是 对维持正常血压至关重要，几乎没有 了解钠离子转运体在排钠或排钠时的调节 高血压的产生。血压的快速升高抑制了 近端小管(PT)的盐分和液体重吸收。这一反应 对肾小管小球反馈的功能起关键作用 向黄斑提供错误信号(增加氯化钠的输送) Densa维持传入小动脉的血管收缩。他们的回应 也会导致压力性钠尿，这种情况会在 高血压。Hen1e(Talh)环的粗大上行支是 参与反馈响应的程度，而不是 完全重新吸收离开PT的增加的负荷。的目标是 这项提议是为了定义负责 由于动脉血流量急剧增加而发生的一种钠尿症 压力，并确定机制是否改变在前 高血压大鼠。我们已经证实，血压的升高 迅速降低PT Na，K-ATPase活性和α、β亚基 基底膜的丰度和顶端钠氢的减少 与两个钠转运体重新分配相关的交换器 到推测的内膜。这些结果证明了该方法的可行性。 剖析了压力性钠尿的细胞机制。我们会 应用亚细胞分离、免疫细胞化学、液体分离等技术 相吞噬作用，并回答了以下分子生物学问题：目的1. 急性心肌梗死后PT钠转运的迅速减少 心尖部和心尖部动脉再分布引起的动脉压升高 基底侧钠转运蛋白到内体池，是对 钠转运体特异性或全面性的表面内化 膜？目标2.TALH是否对压力挑战和/或 通过调节钠的表面表达来增加体积流量 运输机？目的3.PT和TALH对急性压力的反应 挑战在高血压前期大鼠中变钝了？我们将研究果糖饲料 大鼠，和米兰高血压品系大鼠(内收蛋白突变) 测试改变钠转运体丰度的假设，他们 分布或与细胞骨架的相互作用可能会削弱对 一项严峻的压力挑战。实现这些目标将填补我们在 对改变的离子传输如何参与生成的理解 和维持高血压(盐敏感性)，并将识别 响应中涉及的可被测试为“候选”的组件 可能参与疾病过程的“基因”。

Although recognized for decades that regulation of salt transport is crucial for maintenance of normal blood pressure, very little is understood about sodium transporter regulation during natriuresis or generation of hypertension. A rapid increase in blood pressure inhibits salt and fluid reabsorption in the proximal tubule (PT). This response is critical to the operation of tubuloglomerular feedback (TGF) by providing an error signal (increased delivery of NaCl) to the macula densa to sustain vasoconstriction in the afferent arteriole. The response also contributes to pressure natriuresis, which is altered in hypertension. The thick ascending limb of the loop of Hen1e (TALH) is involved in the feedback response to the extent that it does not completely reabsorb the increased load leaving the PT. The objective of this proposal is to define the cellular mechanisms responsible for the natriuresis that occurs in response to an acute increase in arterial pressure, and to determine whether the mechanisms are altered in pre- hypertensive rats. We have established that an increase in blood pressure rapidly decreases PT Na,K-ATPase activity and alpha and beta subunits' abundance in basolateral membranes and decreases apical sodium hydrogen exchangers associated with a redistribution of both sodium transporters to putative internal membranes. These results demonstrate the feasibility of dissecting the cellular mechanisms of pressure natriuresis. We will apply techniques of subcellular fractionation, immunocytochemistry, fluid phase endocytosis, and molecular biology to answer the following: Aim 1. Is the rapid decrease in PT sodium transport that accompanies an acute increase in arterial pressure due to a redistribution of apical and basolateral sodium transporters to endosomal pools, and is the response sodium transporter specific or a generalized internalization of surface membranes? Aim 2. Does the TALH respond to a pressure challenge and/or increased volume flow by regulating surface expression of sodium transporters? Aim 3. Is the response of PT and TALH to acute pressure challenge blunted in prehypertensive rats? We will study the fructose fed rats, and the Milan Hypertensive Strain rats (mutation in adducin) to test the hypothesis that altered abundance of sodium transporters, their distribution or interaction with cytoskeleton may blunt the response to an acute pressure challenge. Accomplishing the aims will fill gaps in our understanding of how altered ion transport is involved in the generation and maintenance of hypertension (salt sensitivity) and will identify components involved in the response that can be tested as "candidate genes" that may be involved in the disease process.