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-）在血管中的积累增加了高血压的反应性和张力。然而，肾脏被认为在长期血压调节中起主要作用。高血压的肾机制集中于传入小动脉的增加的反应性或张力，这限制了压力传递到肾中，因此增加了BP调节的设定点，增加了激素如肾素的释放，以及增加了肾小管对NaCl的重吸收，这损害了作为盐敏感性基础的盐的快速和定量消除。由于目前对ROS在高血压肾脏机制中的作用知之甚少，这是本提案的重点。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将研究肾脏中NADPH氧化酶的O2-和特别是p22 phox激活在传入小动脉反应性、盐负荷和高血压期间的盐排泄中的作用。项目2将研究ROS诱导的改变的原因和后果，其中Na+被近端肾单位重吸收，导致O2在肾脏中的化学工作效率低下，表现为肾皮质缺氧。项目3将使用碱性成纤维细胞生长因子/FGF-2的可诱导激活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例。项目4将研究由多巴胺D5受体协调的近端小管抗氧化应激的分子机制。这些都是由一个行政，动物和分子生物学核心支持。这项工作的目标是为更好地理解ROS在高血压及其后果中的作用提供基础，从而为新形式的预防或治疗提供合理的基础。

DESCRIPTION (provided by applicant): Accumulation of reactive oxygen species (ROS), notably superoxide anion (O2-) in blood vessels increases their reactivity and tone in hypertension. However, the kidney is acknowledged to play 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, an increased release of hormones such as renin, and an increased reabsorption of NaCI by the tubules which impairs the rapid and quantitative elimination of salt that underlies salt sensitivity. Since presently less is known concerning the roles of ROS in renal mechanism of hypertension, this is the focus for this proposal. We have assembled an interactive group of integrative, microvascular and micropuncture physiologists and molecular and cellular biologist to tackle this problem. Project 1 will investigate the role of O2- and specifically p22phox activation of NADPH oxidase in the kidney, in afferent arteriolar reactivity, salt excretion during salt loading and hypertension. Project 2 will investigate the causes and consequences of ROS-induced alterations in the manner in which Na+ is reabsorbed by the proximal nephron that contribute to an inefficient use of O2 for chemical work in the kidney, manifest as renal cortical hypoxia. Project 3 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/FGF-2. Project 4 will investigate the molecular mechanisms of defense against oxidative stress in the proximal tubule that are coordinated by the dopamine D5 receptor. These are supported by an Administrative, Animal and Molecular Biology Core. The goal of this work is to provide a basis for better understanding of the role of ROS in hypertension and its consequences and thereby providing a rational basis for new forms of prevention or treatment.