Renal endothelin receptor-specific function in angiotensin ll-dependent hypertens

血管紧张素II依赖性高血压中肾内皮素受体的特异性功能

• 批准号: 8002577
• 负责人: DAVID M POLLOCK
• 金额: $ 32.02万
• 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/8002577
• 关键词: Address; Angiotensins; Animal Model; Animals; Attenuated; Blood Pressure; Blood Vessels; Chronic; Chronic Kidney Failure; Development; Disease; Endothelin Receptor; Endothelin-1; Excretory function; Female; Functional disorder; Genetic; Goals; Health; Human; Hypertension; Inflammation; Inflammatory; Infusion procedures; Kidney; Kidney Diseases; Mediating; Modeling; Natriuresis; Nerve; Organ; Oxidative Stress; Pathway interactions; Permeability; Process; Rattus; Receptor Activation; Relaxation; Reporting; Role; Sodium; Sodium Chloride; Testing; Vascular Smooth Muscle; Vasodilation; Water; base; biological adaptation to stress; blood pressure regulation; hemodynamics; human subject; improved; inhibitor/antagonist; male; pressure; receptor; receptor function; response; salt intake; salt sensitive; saluretic; vasoconstriction

Renal control of sodium excretion is of obvious importance in determining salt-sensitivity and blood pressure. High blood pressure related to impaired pressure natriuresis is evident in a nnajority of human subjects and a primary consequence of this disorder is vascular dysfunction and end-organ damage. Animal studies have established that ETA receptors cause hypertension in saltdependent models. In contrast, ETB receptors function in the opposite manner by promoting salt and water excretion as well as stimulating vascular relaxation. However, ETB receptor function is complicated due to their presence on nerves and vascular smooth muscle, which can produce vasoconstriction under some circumstances. Furthermore, we have recently reported that female, but not male, rats have an ETA-dependent natriuretic pathway similar to that of the ETB receptor. Therefore, the discernment of receptor-specific mechanisms for the control of renal hemodynamic and excretory function by ET-1 requires clarification. The current project is based on our recent observations that ETA receptor blockade reduces renal Inflammation, and considerable evidence that a lack of ETB receptor function results in salt-sensitive hypertension. Our proposal will first address the hypothesis that the ETA receptor is an important pro-inflammatory mechanism in the kidney and that the ETB receptor normally functions to protect against these changes. We further propose that the ETB receptor is unable to fully compensate for increased ET-1 activity in salt-dependent hypertension due to an impaired ability of renal medullary ETB receptors to promote sodium excretion. The proposed studies will determine the role of Inflammation and oxidative stress in rat models that are associated with increased ET-1 activation. Aim 1. Test the hypothesis that ET-1, via the ETA receptor, directly stimulates inflammation, oxidative stress, and increases in glomerular permeability in the kidney - actions that are opposed by ETB receptor activation. Aim 2. Test the hypothesis that ETB dependent control of blood pressure, microcirculatory function, and natriuresis is attenuated in Ang ll-dependent hypertension. Aim 3. Test the hypothesis that female rats are protected against salt- sensitive hypertension by the existence of an ETA-dependent natriuretic mechanism.

肾脏对钠排泄的控制对于确定盐敏感性和盐敏感性具有明显的重要性。 血压。与压力性尿钠排泄受损相关的高血压在以下人群中很明显： 大多数人类受试者和这种疾病的主要后果是血管功能障碍和 终末器官损伤。动物研究证实，ETA 受体会导致盐依赖型高血压 模型。相反，ETB 受体以相反的方式发挥作用，通过促进盐 和水的排泄以及刺激血管松弛。然而，ETB 受体功能是 由于它们存在于神经和血管平滑肌上，因此变得复杂，这可以产生 在某些情况下会出现血管收缩。此外，我们最近报道称，女性， 但雄性大鼠除外，其具有与 ETB 受体相似的 ETA 依赖性尿钠排泄途径。 因此，识别控制肾血流动力学的受体特异性机制 ET-1 的排泄功能需要澄清。当前的项目是基于我们最近的 ETA 受体阻断可减少肾脏炎症的观察结果，以及大量证据 ETB 受体功能缺乏会导致盐敏感性高血压。我们的建议首先 解决了 ETA 受体是重要促炎机制的假设 肾脏中的 ETB 受体正常功能可以防止这些变化。 我们进一步提出 ETB 受体无法完全补偿 ET-1 的增加 由于肾髓质 ETB 能力受损而导致盐依赖性高血压的活性 促进钠排泄的受体。拟议的研究将确定的作用 大鼠模型中与 ET-1 激活增加相关的炎症和氧化应激。 目标 1. 检验 ET-1 通过 ETA 受体直接刺激炎症的假设， 氧化应激和肾脏肾小球通透性增加 - 相反的作用 通过ETB受体激活。 目标 2. 检验 ETB 依赖性控制血压、微循环的假设 功能，并且尿钠排泄在 Ang II 依赖性高血压中减弱。 目标 3. 检验雌性大鼠免受盐敏感的假设 高血压是由 ETA 依赖性尿钠排泄机制的存在引起的。