Renal Vascular Oxidative Stress in Hypertension

高血压中的肾血管氧化应激

• 批准号: 6798843
• 负责人: CHRISTOPHER S WILCOX
• 金额: $ 209.02万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798843
• 关键词: hypertension; kidney function; oxidative stress; vasomotion

Critical hypertensive roles for angiotensin II (Ang II) have been postulate for its effects on the major resistance vessels of the renal cortex (afferent arteriole) and medulla (outer medullary descending vasa recta, OMDVR). Prolonged exposure to Ang II leads to slow pressor response to enhancement of renal vascular resistance. This proposal will examine the concept that Ang II-induced oxidative stress underlies these renal hypertensive mechanisms. This proposal will examine the concept that Ang II-induced oxidative stress underlies these renal hypertensive mechanisms. Ang II-induced oxidative stress implies either an enhanced generation, or decreased metabolism of reactive oxygen species (ROS), notably superoxide anion (P2), hydrogen peroxide (H2O2)and hydroxyl radical (OH). This concept will be studied in selected knockout models to assess the effects of deletion of ROS generated via p47/phox NAD(P)H oxidase, or NO generated via eNOS and of oxidant defense from the effects of deletions of extracellular superoxide dismutase, (EC-SOD) or dopamine 5 receptor (D5-R). Subproject 1 will utilize novel methods for intra-tubular and arteriolar measurements of pO2 combined with micropuncture and microperfusion in vivo. It will study the hypothesis that Ang II stimulates NAD(P)H oxidase-dependent ROS. This causes functional NO deficiency, a fall in renal O2 delivery and inefficient O2 utilization. The resulting fall in renal pO2 restrains ongoing ROS generation. Subproject 2 will contrast responses in isolated renal afferent and mesenteric resistance vessels during changes in Ang II combining measurements of contractility with [NO] and [ROS] developed in subprojects #3 and #4. It will test the concept that selective renal cortical vasoconstrictor actions of Ang II are due to ROS-dependent reduction in [NO], thereby promoting vasoconstriction of the afferent arteriole, whereas ROS actually relax mesenteric vessels via endothelium- dependent hyperpolarization. Subproject 3 will use novel fluorescence microscopy studies of vascular [ROS] and [NO], combined with direct measures of NO releases from single OMDVR to study the regulation of ROS and NO by Ang II and pO2 (defined in subproject #1) in isolated perfused OMDVR. Subproject 4 will use the novel model for hypertension and oxidative stress in the dopamine 5 receptor (D5-R) knockout mouse. It will investigate the interaction of the constitutively active D5-R with Ang II in the renal regulation of NAD(P)H oxidase, and other cellular oxidant or defense pathways. The functional effects of D5- R knockout will be explored in subprojects #1, #2, and #3. This is a proposal for an integrated functional genomics approach to the study of hypertensive mechanisms mediated by Ang II-stimulated ROS within the kidneys.

血管紧张素 II (Ang II) 的临界高血压作用因其对肾皮质（传入小动脉）和髓质（外髓质降支直肠，OMDVR）主要阻力血管的影响而被假定。长时间暴露于 Ang II 会导致肾血管阻力增强的升压反应缓慢。该提案将研究血管紧张素 II 诱导的氧化应激是这些肾高血压机制的基础这一概念。该提案将研究血管紧张素 II 诱导的氧化应激是这些肾高血压机制的基础这一概念。 Ang II 诱导的氧化应激意味着活性氧 (ROS)，特别是超氧阴离子 (P2)、过氧化氢 (H2O2) 和羟自由基 (OH) 的生成增强或代谢减少。这一概念将在选定的敲除模型中进行研究，以评估删除 p47/phox NAD(P)H 氧化酶产生的 ROS 或通过 eNOS 产生的 NO 的影响，以及氧化防御免受细胞外超氧化物歧化酶 (EC-SOD) 或多巴胺 5 受体 (D5-R) 删除影响的影响。子项目 1 将利用新方法结合体内微穿刺​​和微灌注进行肾小管内和小动脉内 pO2 测量。它将研究 Ang II 刺激 NAD(P)H 氧化酶依赖性 ROS 的假设。这会导致功能性一氧化氮缺乏、肾氧输送量下降和氧利用效率低下。由此导致的肾 pO2 下降抑制了正在进行的 ROS 生成。子项目 2 将结合子项目 #3 和 #4 中开发的 [NO] 和 [ROS] 收缩力测量，对比 Ang II 变化过程中离体肾传入血管和肠系膜阻力血管的反应。它将检验Ang II的选择性肾皮质血管收缩作用是由于ROS依赖性[NO]减少所致，从而促进传入小动脉的血管收缩，而ROS实际上通过内皮依赖性超极化来松弛肠系膜血管。子项目 3 将使用血管 [ROS] 和 [NO] 的新型荧光显微镜研究，结合单个 OMDVR 释放 NO 的直接测量，以研究分离灌注 OMDVR 中 Ang II 和 pO2（在子项目 #1 中定义）对 ROS 和 NO 的调节。子项目 4 将在多巴胺 5 受体 (D5-R) 敲除小鼠中使用高血压和氧化应激的新模型。它将研究组成型活性 D5-R 与 Ang II 在 NAD(P)H 氧化酶的肾脏调节以及其他细胞氧化或防御途径中的相互作用。 D5-R 敲除的功能效应将在子项目#1、#2 和#3 中进行探讨。这是一项综合功能基因组学方法的提案，用于研究肾脏内 Ang II 刺激的 ROS 介导的高血压机制。