Pilot--Mechanism of End-organ Damage in eNOS Deficiency

Pilot--eNOS缺陷的终末器官损伤机制

• 批准号: 7491038
• 负责人: M AUDREY RUDD
• 金额: $ 7.4万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7491038
• 关键词: Adrenergic Agents; African American; Animals; Biological Availability; Blood Pressure; Blood Vessels; Clinical; Data; End stage renal failure; Event; Exercise; Face; Generations; Goals; Heart Diseases; Histologic; Hypertension; Implant; Incidence; Inflammatory; Injury; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Laboratories; Lead; Measurement; Measures; Methods; Mus; Nitric Oxide; Nitric Oxide Synthase; Organ; Physiological; Plasma; Population; Production; Rate; Reactive Oxygen Species; Renal Blood Flow; Renal Tissue; Research; Rest; Risk; Running; Specific qualifier value; Staging; Stress; Stroke; Structure; Telemetry; Time; Tissues; Urine; Vascular resistance; Vasoconstrictor Agents; Wild Type Mouse; Work; adrenergic; cytokine; design; exhaustion; experience; hemodynamics; human NOS3 protein; kidney vascular structure; programs; renal ischemia; response; tool; vasoconstriction

The overall goal of the research program is to understand the mechanism(s) of end-organ damage, particularly end-stage renal disease (ESRD). This research problem is relevant to the clinical problem of the increased incidence of target organ damage associated with hypertension. Although the rate of stroke and heart disease has gradually declined over the last several decades, the rate of ESRD has been steadily increasing. The African American population particularly experiences a disproportionately greater risk for ESRD. We hypothesize that one possible mechanism of ESRD associated with hypertension may be stressed-induced renal ischemia in the presence of impaired NO bioavailability. In support of this goal, preliminary data generated in the applicant's laboratory demonstrate that the physiologic stress of infrequent bouts of exhaustive exercise cause progressive gross histologic renal damage in the moderately hypertensive endothelial NO synthase (eNOS) knockout mouse, but not in the wild type control. It is proposed that physiologic stress such as infrequent exhaustive exercise results in increased renal vasoconstrictor activity and ischemia which in turn lead to increased production of reactive oxygen species and cytokine production in the face of an NO deficiency. Therefore, in an effort to generate preliminary data to support this hypothesis we propose the following Specific Aims. Specific Aim 1 is designed to generate renal vasoconstriction data. Mice will be chronically implanted with both renal blood flow (RBF) and blood pressure probes to measure RBF and blood pressure at rest and during physiologic stress of infrequent running to exhaustion in control and eNOS knockout mice. Renal vascular resistance will be calculated from these values. It is expected that eNOS knockout mice will have a greater and more sustained renal vasoconstriction with subsequent ischemia as compared to normal wild type mice. Specific Aim 2 is designed to generate data showing that ischemia develops in the kidney during the stress of infrequent running to exhaustion. Plasma, urine as well as tissue will be collected for measurement of markers of vascular ischemia. Since it is not certain which markers are best to specifically detect renal ischemia we will measure various vascular ischemia markers in plasma, urine and renal tissue.

该研究计划的总体目标是了解终末器官损伤的机制， 特别是终末期肾病（ESRD）。该研究问题与临床问题相关 与高血压相关的靶器官损伤发生率增加。虽然率 中风和心脏病在过去几十年中逐渐下降，ESRD 的发病率也有所下降 一直在稳步增加。非裔美国人尤其经历了 ESRD 的风险不成比例地增加。我们假设 ESRD 的一种可能机制 与高血压相关的可能是在 NO 受损的情况下应激引起的肾缺血 生物利用度。为了支持这一目标，申请人实验室生成的初步数据 证明不频繁的力竭运动带来的生理压力会导致进行性 中度高血压内皮一氧化氮合酶 (eNOS) 的总体组织学肾损伤 敲除小鼠，但不在野生型对照中。建议生理应激，例如 不频繁的力竭运动会导致肾血管收缩活性增加和缺血，从而导致 导致活性氧和细胞因子的产生增加 无缺乏。因此，为了生成初步数据来支持这一假设，我们 提出以下具体目标。具体目标 1 旨在产生肾血管收缩 数据。小鼠将被长期植入肾血流（RBF）和血压探针，以 测量休息时和不经常跑步的生理应激期间的 RBF 和血压 对照组和 eNOS 敲除小鼠的疲劳。肾血管阻力将根据这些计算 价值观。预计 eNOS 敲除小鼠将具有更大、更持久的肾功能 与正常野生型小鼠相比，血管收缩并随后出现缺血。具体目标 2 是 旨在生成数据，显示在不频繁的压力下肾脏会发生缺血 跑到筋疲力尽。将收集血浆、尿液和组织用于测量标记物 血管缺血。由于尚不确定哪些标记物最适合特异性检测肾缺血 我们将测量血浆、尿液和肾组织中的各种血管缺血标志物。