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）的关键高血压作用已因其对肾皮质（传入小动脉）和髓质（外髓外降含量DASA RECTA，OMDVR）的主要抗性血管的影响而被假设。长时间暴露于ANG II会导致升压速度缓慢，从而增强肾血管耐药性。该建议将研究ANG II诱导的氧化应激的概念是这些肾高血压机制的基础。该建议将研究ANG II诱导的氧化应激的概念是这些肾高血压机制的基础。 ANG II诱导的氧化应激意味着活性氧（ROS）的代谢增强或降低，尤其是超氧化物阴离子（P2），过氧化氢（H2O2）和羟基自由基（OH）。该概念将在选定的敲除模型中进行研究，以评估通过p47/phox NAD（P）H氧化酶产生的ROS的影响，或通过eNOS和氧化剂防御产生的氧化剂防御因细胞外超氧化物歧化酶（EC-SOD）（EC-SOD）（EC-SOD）或多巴胺5受体（D5-R）的影响。 subproject 1将利用新的方法用于po2的管内和小动脉测量，并在体内结合微孔和微灌注。它将研究ANG II刺激NAD（P）H氧化酶依赖性ROS的假设。这会导致功能不足，肾脏O2递送下降和效率低下的O2利用率。肾脏PO2导致的下降限制了正在进行的ROS产生。在ANG II的变化中，隔离的肾脏传统和肠系膜抗性容器将对比2对比，将收缩力与[NO]和[no]和[ROS]相结合，并在子标题3和4中开发[NO]和[ROS]。它将测试以下概念：ANG II的选择性肾皮质血管收缩作用是由于[NO]的ROS依赖性减少，从而促进了传入动脉的血管收缩，而ROS实际上通过依赖性超极化来放松肠系膜血管。亚参数3将使用血管[ROS]和[NO]的新型荧光显微镜研究，并在隔离的灌注OMDVR中直接测量了单个OMDVR的无释放的直接测量来研究Ang II和PO2的ROS和NO的调节。 subproject 4将使用新型模型用于多巴胺5受体（D5-R）基因敲除小鼠中的高血压和氧化应激。它将研究组成型活性D5-R与ANG II在NAD（P）H氧化酶的肾脏调节中的相互作用，以及其他细胞氧化剂或防御途径。 D5-R基因敲除的功能效应将在＃1，＃2和＃3中探索。这是针对肾脏内Ang II刺激的ROS介导的高血压机制研究的综合功能基因组学方法的建议。