OXIDATIVE STRESS AND KIDNEY OXYGEN USAGE

氧化应激和肾氧利用

• 批准号: 7821402
• 负责人: William J Welch
• 金额: $ 38.38万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7821402
• 关键词: ATP Hydrolysis; Acute; Acute Kidney Failure; Adenosine; Adult; Angiotensin II; Antioxidants; Bicarbonates; Blood Pressure; Cell physiology; Cells; Chemicals; Chronic; Coupled; Cuprozinc Superoxide Dismutase; Cytokine Signaling; Data; Development; Disabled Persons; Distal; Dose; Duct (organ) structure; Electrolytes; End stage renal failure; Energy Metabolism; Environment; Enzymes; Equilibrium; Evaluation; Event; Failure; Family; Feedback; Fibrosis; Free Energy; Functional disorder; Gene Bank; Generations; Genes; Genetic; Genetic Transcription; Homeostasis; Hypertension; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inflammation; Intake; Interruption; Ischemia; Juxtaglomerular Apparatus; Kidney; Kidney Diseases; Knowledge; Lead; Liquid substance; Macula densa; Manganese Superoxide Dismutase; Measurement; Measures; Messenger RNA; Metabolism; Micropuncture; Mitochondria; Modeling; Mus; NADPH Oxidase; Nephrons; Outcome; Output; Oxidants; Oxidases; Oxidative Stress; Oxygen; Pathway interactions; Plasma; Principal Investigator; Protein Isoforms; Proteins; RNA Interference; Rat-1; Rattus; Renal Artery Stenosis; Renal Blood Flow; Renal Tissue; Renal function; Renin; Renin-Angiotensin System; Resistance; Role; Sclerosis; Secondary Hypertension; Series; Signal Transduction; Site; Sodium; Source; Structure of ascending limb of Henle' s loop; Superoxide Dismutase; Superoxides; Susceptibility Gene; System; Testing; Thick; Time; Tubular formation; Vascular resistance; Wild Type Mouse; absorption; arteriole; design; empowered; extracellular; human CYBA protein; in vivo; insight; kidney cortex; kidney vascular structure; monolayer; pressure; receptor; renal ischemia; research study; response; solute; tempol; transmission process; uptake; vasoconstriction

DESCRIPTION (provided by applicant): Renal oxidative stress is determined by the balance between the primary source of superoxide, NADPH oxidase (NOX) and intrarenal enzymes that scavenge superoxide, superoxide dismutases (SOD). Renal oxidative stress contributes to the development of systemic hypertension by alterations in renal function, including vasoconstriction, increased solute and electrolyte retention and tubular dysfunction. The reabsorption of sodium is the major energy requirement for the kidney and the efficient use of oxygen for Na+ transport is reduced during oxidative stress. We propose to test the effects of oxidative stress on oxygen usage in the kidney and to determine the mechanism(s) by which Na+ reabsorption requires greater oxygen. In a series of experiments measuring in vivo single nephron function in gene deleted mice and in vitro measurements of PT cell function we will identify specific sites of oxygen utilization dysfunction. In aim 1, we will test the hypothesis that the inefficient use of oxygen is dependent on the balance between NOX and SOD, by using single gene deleted mice. In aim 2 we will examine the mechanism of the inefficient use of oxygen, focusing on Na+ reabsorption in the proximal tubule (PT). In a series of both in vivo and in vitro experiments, we will evaluate the cellular integrity and function of the PT during acute and chronic oxidative stress. We will examine paracellular and transcellular function in PT cells. In aim 3 we will test the hypothesis that the increased blood pressure associated with angiotensin II-induced oxidative stress is dependent on increased generation of adenosine and enhancement of tubuloglomerular feedback, leading to decreased renal blood flow and increased renal vascular resistance. These studies should provide new and valuable information on the relationship between oxygen usage in the kidney and the pro-vasoconstriction events associated with oxidative stress and hypertension. Project Narrative: Ischemia, the lack of efficient oxygen delivery is the most common cause of acute renal failure and renal artery stenosis causing renal ischemia is the second most common cause of secondary hypertension. These conditions are accompanied by severe oxidative stress within the kidneys. Therefore, knowledge of the interaction of oxidants and oxygen within the kidney will provide insight into the causes of these renal diseases.

描述（由申请人提供）：肾氧化应激由超氧化物的主要来源、NADPH氧化酶（NOX）和清除超氧化物、超氧化物歧化酶（SOD）的肾内酶之间的平衡决定。肾脏氧化应激通过改变肾功能，包括血管收缩、溶质和电解质潴留增加以及肾小管功能障碍，导致全身性高血压的发生。钠的重吸收是肾脏的主要能量需求，在氧化应激过程中，钠离子转运中氧气的有效利用会降低。我们建议测试氧化应激对肾脏耗氧量的影响，并确定 Na+ 重吸收需要更多氧气的机制。在一系列测量基因缺失小鼠的体内单个肾单位功能和体外测量 PT 细胞功能的实验中，我们将确定氧利用功能障碍的特定位点。在目标 1 中，我们将通过使用单基因缺失小鼠来测试氧气的低效利用取决于 NOX 和 SOD 之间的平衡的假设。在目标 2 中，我们将研究氧气利用效率低下的机制，重点关注近端小管 (PT) 中的 Na+ 重吸收。在一系列体内和体外实验中，我们将评估急性和慢性氧化应激期间 PT 的细胞完整性和功能。我们将检查 PT 细胞的旁细胞和跨细胞功能。在目标 3 中，我们将检验以下假设：与血管紧张素 II 诱导的氧化应激相关的血压升高取决于腺苷生成的增加和肾小球反馈的增强，从而导致肾血流量减少和肾血管阻力增加。这些研究应该为肾脏的耗氧量与氧化应激和高血压相关的促血管收缩事件之间的关系提供新的有价值的信息。 项目叙述：缺血、缺乏有效的氧气输送是急性肾功能衰竭的最常见原因，而导致肾缺血的肾动脉狭窄是继发性高血压的第二个最常见原因。这些情况伴随着肾脏内严重的氧化应激。因此，了解肾脏内氧化剂和氧气的相互作用将有助于深入了解这些肾脏疾病的原因。