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)和钠排泄率。盐敏感型高血压患者表现出迟钝 血压-利钠反应和高血压肾损伤的易感性，可能由受损引起 血流动力学控制。我们的实验室对参与控制的机制有既定的兴趣 肾血流量和肾小球滤过率。项目2将检验一种新的假设，即慢性增加饮食中的盐分 改变肾微血管对内皮素-1(ET-1)的反应，通过受体特异性促进盐的排泄 小路。最近的研究表明，ETA受体与盐敏感型高血压有关， 而ETB受体则刺激内皮依赖性血管松弛，抑制钠重吸收。 然而，ETB受体的生理学是复杂的，因为它们可以产生相反的血管收缩和 肾小球前循环内的血管扩张。我们已经证明，高剂量喂养的大鼠的传入小动脉 盐饮食明显右移ET-1介导的血管收缩和减弱的自身调节 反应性(初步数据)，可能涉及ETB受体。这些新奇的观察表明， 盐诱导ETB受体表达增强降低自身调节敏感性以促进ETB 受体介导的盐分排泄。虽然这可能在短期内产生积极影响，但减少了 自我调节的效率确实会让肾脏容易受到其他血液动力学方面的侮辱，比如高血压， 这可能会加速肾脏损伤的进展。因此，确立ETB的作用非常重要 传入小动脉对高盐反应的受体。项目2的中心假设是高 盐饮食增强ETB受体特异性通路促进传入小动脉扩张，钝化自我调节 提高效率，促进钠的排泄。我们建议通过研究来解决这一中心假设 三个具体目标。目标1将验证高盐饮食增强传入小动脉ETB依赖性的假设 血管松弛导致肾小球滤过率增加，这种作用可被ETB受体阻止 缺乏症。目标2将验证高盐饮食通过以下途径钝化自我调节效率的假设 与ETB受体激活相关的机制。目标3将检验高盐饮食会改变这一假设 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 受体分别通过三磷酸腺苷或腺苷激活。这些研究将提供独特的见解，了解如何 肾脏对盐有反应，以促进NaCI的排泄。

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.