OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION

描述（由申请人提供）： 活性氧（ROS），特别是超氧阴离子（O2-）在血管中增加其反应性和高血压的张力。肾脏在长期血压调节中起着主要作用。高血压的肾脏机制集中在传入小动脉的反应性或张力增加，这限制了压力传递到肾脏中，因此增加了BP调节的设定点，同时增加了肾素的释放和肾小管对NaCl的重吸收，这是盐敏感性的基础。本研究的重点是ROS在高血压肾脏机制中的作用。我们已经组建了一个由综合微血管和微穿刺生理学家以及分子和细胞生物学家组成的互动小组来解决这个问题。项目1将集中于ROS在调节小鼠传入小动脉肌源性反应（MR）中的作用。它比较了正常小鼠中的反应，其中ROS产生增强了MR和慢性肾脏疾病的肾质量减少模型以及ROS损害MR的高血压的血管紧张素输注模型。它将分离灌注的传入小动脉中MR的直接测量与基因阵列和这些微血管上的RNA seq分析以及ROS的荧光定量相结合，和Ca 2+使用敲除和转基因小鼠或具有单肾基因转染或缺失的小鼠。项目2将使用碱性成纤维细胞生长因子的诱导活化及其与特定FGF分子和受体的相互作用的小鼠模型，研究生长因子相关的氧化应激和高血压的新范式。研究将联合收割机BP和传入小动脉对血管紧张素的反应性与信号传导机制及其与ROS相互作用的细胞和分子研究相结合。项目3将研究由多巴胺D2受体协调的近端小管抗氧化应激的分子机制。新的假说是D2-R信号增强了对加氧酶-2，从而激活了由DJ 2启动的转录氧化还原调节途径，抑制NADPH氧化酶诱导的ROS。这些由管理、动物和生物分析核心支持。

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.