OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION

高血压患者肾脏的氧化应激

• 批准号: 8611952
• 负责人: CHRISTOPHER S WILCOX
• 金额: $ 181.49万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611952
• 关键词: Address; Angiotensin II; Angiotensins; Animals; Blood Vessels; Chronic Kidney Failure; DRD2 gene; Defense Mechanisms; Dopamine; Dopamine D2 Receptor; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Figs - dietary; Fluorescence; Generations; Genes; Goals; Growth Factor; Homeostasis; Hydrogen Peroxide; Hypertension; Infusion procedures; Kidney; Knockout Mice; Link; Liquid substance; Measures; Micropuncture; Modeling; Molecular; Mus; NADPH Oxidase; Natriuresis; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peripheral; Play; Prevention; Reactive Oxygen Species; Regulation; Renal Mass; Renal tubule structure; Renin; Role; Signal Transduction; Sodium Chloride; Superoxides; System; Time; Transfection; Transgenic Mice; Tubular formation; Vascular resistance; Work; absorption; abstracting; arteriole; base; cardiovascular risk factor; mouse model; pressure; receptor; response; transcriptome sequencing; transmission process

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS), notably superoxide anion (O2-) in blood vessels increases their reactivity and tone in hypertension. The kidney plays the predominant role in long-term BP regulation. Renal mechanisms of hypertension center on an increased reactivity or tone of the afferent arteriole which limits the transmission of pressure into the kidney and hence increases the set point of BP regulation together with increased release of renin and an increased re-absorption of NaCl by the tubules which underlies salt sensitivity. The focus of this proposal is on the roles of ROS in renal mechanism of hypertension. We have assembled an interactive group of integrative, microvascular and micropuncture physiologists and molecular and cellular biologist to tackle this problem. Project 1 will center on the role of ROS in modulating myogenic responses (MRs) of the mouse afferent arteriole. It compares responses in normal mice, where ROS generation enhanced MRs and the reduced renal mass model of chronic kidney disease and the angiotensin infusion model of hypertension where ROS impaired MRs. It combines direct measures of MR in isolated perfused afferent arterioles with gene arrays and RNA seq analyses on these microvessels and fluorescence quantitation of ROS, and Ca2+ using knockout and transgenic mice or mice with single kidney gene transfection or deletion. Project 2 will investigate a new paradigm of growth-factor related oxidative stress and hypertension using a mouse model of inducible activation of basic fibroblast growth factor and its interaction with specific FGF molecules and receptors. Studies combine BP and afferent arteriolar reactivity to angiotensin with cellular and molecular studies of the signaling mechanism and their interaction with ROS. Project 3 will investigate the molecular mechanisms of defense against oxidative stress in the proximal tubule that are coordinated by the dopamine D2 receptors. The new hypothesis is that D2-R signaling enhances paraoxygenase-2 which activates a transcriptional redox-regulating pathways initiated by DJ2 to inhibit NADPH oxidase-induced ROS. These are supported by the Administrative, Animal and Bioanalytical Cores.

描述（由申请人提供）： 活血管中的活性氧（ROS），尤其是超氧化物阴离子（O2-）会增加其高血压的反应性和张力。肾脏在长期BP调节中起主要作用。高血压的肾机制以增加的反应性或传入小动脉的张力为中心，从而限制了压力向肾脏的传播，因此增加了BP调节的固定点，以及增加肾素的释放以及肾小管的重新吸收NaCl的释放，而小管的NACL吸收了，这是盐敏感性的基础。该提议的重点是ROS在高血压肾脏机理中的作用。我们组装了一个综合，微血管和微气管生理学家以及分子和细胞生物学家的互动群，以解决此问题。项目1将以ROS在调节小鼠传入小动脉的肌源反应（MRS）中的作用为中心。它比较了正常小鼠的反应，其中ROS的产生增强了MRS和慢性肾脏疾病的肾脏质量模型减少，以及在ROS损害MRS的高血压的血管紧张素输注模型。它结合了分离的灌注传入动脉中MR的直接度量与基因阵列和对这些微型固定的RNA SEQ分析以及ROS的荧光定量，以及使用单肾基因转染或缺失的基因和转基因小鼠或小鼠对ROS的荧光定量。项目2将利用基本成纤维细胞生长因子的诱导型激活的小鼠模型及其与特定的FGF分子和受体的相互作用来研究生长因素相关的氧化应激和高血压的新范式。研究结合了BP和传入的动脉对血管紧张素的反应性与信号机制的细胞和分子研究及其与ROS的相互作用。项目3将研究由多巴胺D2受体协调的近端小管中氧化应激的分子机制。新的假设是D2-R信号传导增强了偏氧酶-2，该酶-2激活DJ2引发的转录氧化还原调节途径以抑制NADPH氧化酶诱导的ROS。这些由行政，动物和生物分析核心支持。