Renal Vascular Oxidative Stress in Hypertension

高血压中的肾血管氧化应激

基本信息

  • 批准号:
    6951570
  • 负责人:
  • 金额:
    $ 214.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-09-30 至 2007-03-31
  • 项目状态:
    已结题

项目摘要

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)对肾皮质(传入小动脉)和髓质(外髓质直降血管,OMDVR)的主要阻力血管的作用被认为是临界高血压的作用。长期暴露于Ang II导致缓慢的升压反应,以增强肾血管阻力。这项建议将审查的概念,血管紧张素II诱导的氧化应激的基础上,这些肾性高血压的机制。这项建议将审查的概念,血管紧张素II诱导的氧化应激的基础上,这些肾性高血压的机制。Ang II诱导的氧化应激意味着活性氧(ROS)的产生增加或代谢减少,特别是超氧阴离子(P2)、过氧化氢(H2 O2)和羟基自由基(OH)。将在选定的敲除模型中研究这一概念,以评估通过p47/phox NAD(P)H氧化酶产生的ROS或通过eNOS产生的NO的缺失的影响,以及细胞外超氧化物歧化酶(EC-SOD)或多巴胺5受体(D5-R)缺失的影响的氧化防御的影响。子项目1将利用新的方法结合体内微穿刺和微灌注测量肾小管内和小动脉的pO 2。研究Ang II刺激NAD(P)H氧化酶依赖性ROS的假说。这会导致功能性NO缺乏,肾脏O2输送下降和O2利用效率低下。由此导致的肾pO 2下降抑制了持续的ROS生成。子项目2将在Ang II变化期间对比分离的肾传入血管和肠系膜阻力血管的反应,并结合子项目#3和#4中开发的收缩性测量结果与[NO]和[ROS]。它将测试这样的概念,即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舒张肠系膜血管。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的NO释放的直接测量,研究分离灌注OMDVR中Ang II和pO 2(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。它将研究组成性活性D5-R与Ang II在肾脏调节NAD(P)H氧化酶和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中探索。这是一个建议,一个集成的功能基因组学方法来研究高血压的机制介导的血管紧张素II刺激的活性氧在肾脏内。

项目成果

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CHRISTOPHER S WILCOX其他文献

CHRISTOPHER S WILCOX的其他文献

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{{ truncateString('CHRISTOPHER S WILCOX', 18)}}的其他基金

Regulation of Renal Function and BP by Thromboxane
血栓素对肾功能和血压的调节
  • 批准号:
    9265467
  • 财政年份:
    2016
  • 资助金额:
    $ 214.4万
  • 项目类别:
Regulation of microvascular function by ROS
ROS对微血管功能的调节
  • 批准号:
    8148026
  • 财政年份:
    2010
  • 资助金额:
    $ 214.4万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8148032
  • 财政年份:
    2010
  • 资助金额:
    $ 214.4万
  • 项目类别:
REGULATION OF RENAL FUNCTION AND BP BY THROMBOXANE
血栓烷对肾功能和血压的调节
  • 批准号:
    7990209
  • 财政年份:
    2009
  • 资助金额:
    $ 214.4万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7218287
  • 财政年份:
    2006
  • 资助金额:
    $ 214.4万
  • 项目类别:
Regulation of Microvascular Function by ROS
ROS对微血管功能的调节
  • 批准号:
    7218283
  • 财政年份:
    2006
  • 资助金额:
    $ 214.4万
  • 项目类别:
Regulation of renal afferent arteriolar function by ROS
ROS对肾传入小动脉功能的调节
  • 批准号:
    6656538
  • 财政年份:
    2002
  • 资助金额:
    $ 214.4万
  • 项目类别:
NEPHROLOGY AND HYPERTENSION TRAINING GRANT
肾脏病学和高血压培训补助金
  • 批准号:
    7501384
  • 财政年份:
    2001
  • 资助金额:
    $ 214.4万
  • 项目类别:
OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
高血压患者肾脏的氧化应激
  • 批准号:
    7177424
  • 财政年份:
    2001
  • 资助金额:
    $ 214.4万
  • 项目类别:
OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
高血压患者肾脏的氧化应激
  • 批准号:
    8611952
  • 财政年份:
    2001
  • 资助金额:
    $ 214.4万
  • 项目类别:

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心力衰竭患者肾功能急性变化与临床结局的关系
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