Nitric Oxide Deficiency in Hypertensive Nephropathies

高血压肾病中的一氧化氮缺乏

• 批准号: 8263684
• 负责人: Aaron James Polichnowski
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263684
• 关键词: Ablation; Acute; African American; Angiotensin II; Animals; Area; Biological Models; Blood Pressure; Blood Vessels; Chronic; Chronic Kidney Failure; Clinical; Collaborations; Development; Dietary Intervention; Dysbarism; End stage renal failure; Endothelium; Environmental Risk Factor; Etiology; Evolution; Exhibits; Experimental Models; Exposure to; Functional disorder; Funding; Genetic Risk; Glomerular Capillary; Glomerular Filtration Rate; Goals; Human; Hypertension; Hypoxia; Inbred Mouse; Individual; Injury; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Lead; Measures; Mediating; Mediator of activation protein; Medicine; Mentors; Mesenteric Arteries; Mesentery; Micropuncture; Modeling; Mus; Nitrates; Nitric Oxide; Nitrites; Other Genetics; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Population; Predisposition; Prevalence; Prevention; Rattus; Regulation; Relative (related person); Relative Risks; Renal Hypertension; Renal function; Reporting; Research; Risk; Risk Factors; Rivers; Role; Severities; Sprague-Dawley Rats; Techniques; Time; Training Activity; United States; Universities; Variant; Vasodilation; Veterans; arteriole; career; career development; clinically relevant; clinically significant; dietary nitrate; hemodynamics; improved; indexing; insight; kidney vascular structure; novel; osteopontin; pressure; public health relevance; renal hypoxia; research study; response; tempol; tetrahydrobiopterin; vasoconstriction

DESCRIPTION (provided by applicant): Hypertension is the second leading primary cause of end-stage renal disease; however, considerable variation exists with respect to the relative risk of hypertensive-induced renal damage in the veteran population. The factors that alter the susceptibility to hypertensive renal injury as well as the underlying mechanisms remain poorly understood. One of the difficulties in investigating the mechanisms that contribute to hypertensive renal injury is the wide spectrum of pathology observed in hypertensive patients with kidney damage. The two major pathophysiologic mechanisms thought to contribute to the pathogenesis and progression of hypertensive renal injury include local exposure to excessive pressures with resulting barotrauma and chronic ischemia with resulting hypoxia. While both mechanisms will contribute to the progression of renal injury, the relative contribution of barotrauma and ischemia to the observed injury likely differs among hypertensive individuals depending on the underlying pathophysiologic context and the presence of additional genetic or environmental risk factors. One such risk factor that is thought to alter the susceptibility to hypertensive renal injury is endothelial dysfunction with reduced levels of nitric oxide (NO). Reduced NO levels have been reported in human populations susceptible to an accelerated progression of hypertensive renal injury, such as African- Americans and individuals with chronic kidney disease. Yet, the role of NO availability on the relative contribution of BP dependent and independent pathways of renal injury, its effects on pathways of barotrauma vs. ischemia induced injury, and the underlying mechanisms remain poorly understood. In the studies proposed in this career development application, we will utilize groups of rats and mice with differences in NO availability as a broad model system to investigate the mechanisms by which reduced NO levels alter the susceptibility to hypertensive injury. We will perform these studies in two models of hypertension in which the pathogenesis of renal injury is thought to be predominantly mediated via barotrauma vs. ischemia pathways. These studies are of clinical significance and should lead to very novel insights regarding the mechanisms by which NO availability alters the susceptibility barotrauma and ischemia mediated pathways of renal injury during the pathogenesis and progression of hypertension. Studies in Aim 1 will focus on the temporal evolution of renal injury, several indices of NO availability, oxidative stress, and purported cellular mediators of injury (i.e., hypoxia, osteopontin, etc.). Dietary interventions will be used to alter the level of NO availability to determine the importance of NO in ameliorating renal injury in various hypertensive states. Studies in Aim 2 are focused on the potential BP dependent and independent mechanisms by which reduced NO availability may enhance the susceptibility to hypertensive renal injury. These studies will focus on the pressor and nonpressor effects of NO availability on the regulation of renal hemodynamics, renal function, and renal oxygenation levels during the pathogenesis and progression of hypertensive renal injury. The studies in Aim 3 will investigate the relative contribution of endothelial dependent and independent pathways in isolated mesenteric arteries to improve our understanding of the mechanisms contributing to the differences in NO availability between the experimental animals. In addition to the novel and clinically relevant set of research experiments, there are numerous informal and formal training activities that should prepare the applicant for an independent career in academic medicine. Furthermore, the proposed studies should also lead to several novel and relevant areas of research, which are independent of his mentoring group, which the applicant can pursue for independent funding. PUBLIC HEALTH RELEVANCE: Hypertension is the second leading cause of kidney failure. Some hypertensive populations, such as individuals of African-American heritage or those with underlying chronic kidney disease, have a much greater risk of progressing to kidney failure. This pattern is also observed in the veteran population. The goal of this project is to determine the potential mechanisms by which some risk factors, commonly found in individuals who are prone to develop chronic kidney disease, increase the susceptibility to hypertensive injury. These studies may lead to new treatments for the prevention of chronic kidney disease in the veteran population.

描述（由申请人提供）： 高血压是终末期肾病的第二大主要原因；然而，退伍军人群体中高血压引起的肾损伤的相对风险存在相当大的差异。改变高血压肾损伤易感性的因素及其潜在机制仍知之甚少。研究导致高血压肾损伤的机制的困难之一是在患有肾损伤的高血压患者中观察到的广泛病理学。被认为有助于高血压肾损伤的发病机制和进展的两种主要病理生理机制包括局部暴露于过度压力导致气压伤和慢性缺血导致缺氧。虽然这两种机制都会导致肾损伤的进展，但气压伤和缺血对观察到的损伤的相对贡献在高血压个体之间可能有所不同，具体取决于潜在的病理生理背景以及其他遗传或环境危险因素的存在。人们认为改变高血压肾损伤易感性的一个危险因素是内皮功能障碍和一氧化氮（NO）水平降低。据报道，易受高血压肾损伤加速进展的人群（例如非裔美国人和患有慢性肾病的人）中一氧化氮水平降低。然而，NO 可用性对血压依赖性和独立性肾损伤途径的相对贡献的作用、其对气压伤与缺血引起的损伤途径的影响以及潜在的机制仍然知之甚少。在此职业发展申请中提出的研究中，我们将利用 NO 可用性存在差异的大鼠和小鼠组作为广泛的模型系统，以研究 NO 水平降低改变高血压损伤易感性的机制。我们将在两种高血压模型中进行这些研究，其中肾损伤的发病机制被认为主要是通过气压伤与缺血途径介导的。这些研究具有临床意义，并且应该对高血压发病和进展过程中NO可用性改变气压伤和缺血介导的肾损伤途径的易感性机制产生非常新颖的见解。目标 1 的研究将重点关注肾损伤的时间演变、NO 可用性的几个指标、氧化应激和所谓的损伤细胞介质（即缺氧、骨桥蛋白等）。饮食干预将用于改变 NO 的可用性水平，以确定 NO 在改善各种高血压状态下肾损伤中的重要性。目标 2 的研究重点是潜在的血压依赖性和独立机制，通过这些机制，NO 可用性的降低可能会增加对高血压肾损伤的易感性。这些研究将重点关注在高血压肾损伤的发病机制和进展过程中，NO 可用性对肾血流动力学、肾功能和肾氧合水平调节的升压和非升压作用。目标 3 中的研究将调查离体肠系膜动脉中内皮依赖性和独立通路的相对贡献，以提高我们对导致实验动物之间 NO 可用性差异的机制的理解。除了新颖且与临床相关的研究实验之外，还有许多非正式和正式的培训活动，可以帮助申请人为学术医学的独立职业做好准备。此外，拟议的研究还应导致几个新颖且相关的研究领域，这些领域独立于其指导小组，申请人可以寻求独立资助。 公共卫生相关性： 高血压是肾衰竭的第二大原因。一些高血压人群，例如非裔美国人或患有潜在慢性肾病的人，进展为肾衰竭的风险要大得多。在退伍军人群体中也观察到这种模式。该项目的目标是确定一些危险因素（常见于易患慢性肾脏病的个体）增加高血压损伤易感性的潜在机制。这些研究可能会带来预防退伍军人慢性肾病的新疗法。