Receptor Specific Mechanisms of Endothelin Control of the Renal Microcirculation

内皮素控制肾微循环的受体特异性机制

• 批准号: 8002583
• 负责人: Edward W Inscho
• 金额: $ 35.74万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8002583
• 关键词: Address; Adenosine; Attenuated; Behavior; Blood Circulation; Blood Vessels; Chronic; Clinical Sciences; Complex; Data; Dialysis patients; Diet; Endothelin; Endothelin-1; Endothelium; Excretory function; Exhibits; Glomerular Capillary; Glomerular Filtration Rate; Health; Hemodialysis; Hypertension; In Vitro; Indium; Information Systems; Injury; Juxtamedullary Nephron; Kidney; Kidney Diseases; Laboratories; Left kidney; Link; Mediating; Microcirculation; Pathway interactions; Patients; Peritoneal Dialysis; Physiology; Play; Predisposition; Rattus; Receptor Activation; Renal Blood Flow; Role; Signal Transduction; Signaling Molecule; Smooth Muscle; Sodium; Sodium Chloride; Testing; Vasodilation; arteriole; extracellular; feeding; hemodynamics; in vivo; insight; interest; novel; pressure; prevent; programs; receptor; receptor expression; research study; response; salt sensitive; saluretic; vasoconstriction

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.

肾脏微血管功能是控制肾小球毛细管压力的重要元素， 肾小球滤过率（GFR）和钠排泄。盐敏感高血压患者表现出钝的 压力 - 催生反应，以及对高血压肾脏损伤的敏感性，可能因受损而引起 血流动力控制。我们的实验室对控制机制具有既定的兴趣 肾血流和GFR。项目2将研究一个新的假设，即饮食盐的慢性升高 修改对内皮素-1（ET-1）的肾脏微血管反应，以促进通过受体特异的盐分排泄 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的血管延缓并抑制钠的重吸收。 但是，ETB受体生理学很复杂，因为它们可以产生相反的血管收缩和 胶质前循环中的血管舒张。我们已经表明，大鼠的传入小动脉 盐饮食在ET-1介导的血管收缩并减弱自动调节中表现出明显的向右转移 反应性（初步数据），可能涉及ETB受体。这些新颖的观察表明 盐诱导的ETB受体表达增强可降低自动调节敏感性以促进ETB 受体介导的盐排泄。虽然这可能在短期内产生积极影响，但减少了 自动调节效率确实使肾脏容易受到其他血液动力学侮辱，例如高血压， 这可能会加速肾脏受伤的进展。因此，建立ETB的作用很重要 传入小动脉对高盐的反应中的受体。项目2的中心假设是 盐饮食增强了ETB受体特异性途径，以促进传入小动脉扩张，钝性调节 效率并促进钠排泄。我们建议通过研究这一中心假设 三个具体目标。 AIM 1将测试高盐饮食可增强传入小动脉ETB依赖性的假设 血管延缓导致GFR增加，并且ETB受体阻止了这种作用 不足。 AIM 2将检验以下假设：高盐饮食通过 与ETB受体激活相关的机制。 AIM 3将检验高盐饮食变化的假设 ETB受体活性通过降低传入的小动脉反应性对P2或PI来钝化自动调节效率 通过ATP或腺苷的受体激活。这些研究将提供有关如何 肾脏对盐的反应以促进NACI排泄。