Receptor Specific Mechanisms of Endothelin Control of the Renal Microcirculation

肾微血管功能是控制肾小球毛细血管压力的重要因素， 肾小球滤过率（GFR）和钠排泄。盐敏感性高血压患者表现出一种钝化的 血压-利钠反应和高血压肾损伤的易感性，可能由受损的 血流动力学控制。我们的实验室已经建立了控制机制的兴趣 肾血流量和GFR。项目2将检验一个新的假设，即膳食盐的慢性升高 改变肾微血管对内皮素-1（ET-1）的反应，通过受体特异性 途径。最近的研究表明，ETA受体有助于盐敏感性高血压， 而ETB受体刺激内皮依赖性血管舒张并抑制钠重吸收。 然而，ETB受体生理学是复杂的，因为它们可以产生相反的血管收缩， 肾小球前循环内的血管舒张。我们已经表明，大鼠的传入小动脉喂养高， 盐饮食显示ET-1介导的血管收缩和减弱的自身调节作用的显著性偏移， 反应性（初步数据），可能涉及ETB受体。这些新的观察表明， 盐诱导的ETB受体表达的增强降低了自身调节敏感性以促进ETB 受体介导的盐排泄。虽然这可能在短期内产生积极影响， 自动调节效率确实使肾脏易受其他血液动力学损害，如高血压， 可能会加速肾损伤的进程因此，重要的是要确立ETB的作用 受体在传入小动脉反应高盐。项目2的核心假设是， 盐饮食增强ETB受体特异性途径，促进传入小动脉扩张，钝性自身调节 效率和促进钠排泄。我们建议通过调查来解决这个中心假设 三个具体目标。目的1将检验高盐饮食增强传入小动脉内皮素依赖性的假说。 血管舒张导致GFR增加，ETB受体阻止了这种作用 缺陷目标2将检验高盐饮食通过以下方式减弱自动调节效率的假设： 与ETB受体激活相关的机制。目标3将检验高盐饮食会改变 ETB受体活性通过降低传入小动脉对P2或PI的反应性来钝化自身调节效率 分别通过ATP或腺苷激活受体。这些研究将提供独特的见解， 肾脏对盐有反应以促进NaCl排泄。

Renal microvascular function is an essential element in the control of glomerular capillary pressure, glomerular filtration rate (GFR) and sodium excretion. Salt-sensitive hypertensive patients exhibit a blunted pressure-natriuretic response, and susceptibility to hypertensive renal injury, possibly arising from impaired hemodynamic control. Our laboratory has an established interest in the mechanisms involved in controlling renal blood flow and GFR. Project 2 will examine a novel hypothesis that chronic elevation of dietary salt modifies the renal microvascular response to endothelin-1 (ET-1) to facilitate salt excretion through receptorspecific pathways. Recent studies establish that ETA receptors contribute to salt-sensitive hypertension, whereas ETB receptors stimulate endothelium-dependent vasorelaxation and inhibit sodium reabsorption. However, ETB receptor physiology is complex as they can produce opposing vasoconstriction and vasodilation within the pre-glomerular circulation. We have shown that afferent arterioles of rats fed a high salt diet exhibit a marked rightward shift in ET-1-mediated vasoconstriction and attenuated autoregulatory reactivity (preliminary data), which may involve ETB receptors. These novel observations suggest that the salt-induced enhancement of ETB receptor expression reduces autoregulatory sensitivity to facilitate ETB receptor mediated excretion of salt. While this may have a positive effect in the short-term, reduced autoregulatory efficiency does leave the kidney vulnerable to other hemodynamic insults, like hypertension, that may hasten the progression to renal injury. Therefore, it is important to establish the role of ETB receptors in the afferent arteriolar response to high salt. The central hypothesis for Project 2 is that a high salt diet enhances ETB receptor-specific pathways to promote afferent arteriolar dilation, blunt autoregulatory efficiency and facilitate sodium excretion. We propose to address this central hypothesis by investigating three specific aims. Aim 1 will test the hypotheses that a high salt diet enhances afferent arteriolar ETBdependent vasorelaxation resulting in increased GFR and that this effect is prevented by ETB receptor deficiency. Aim 2 will test the hypothesis that a high salt diet blunts autoregulatory efficiency through mechanisms linked to ETB receptor activation. Aim 3 will test the hypothesis that a high salt diet changes ETB receptor activity to blunt autoregulatory efficiency by reducing afferent arteriolar reactivity to P2 or PI receptor activation via ATP or adenosine, respectively. These studies will provide unique insights into how the kidney responds to salt to facilitate NaCI excretion.