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Oxidative Stress And Sympathetic Nerve Activity

氧化应激和交感神经活动

基本信息

批准号：
6992744
负责人：
VITO M CAMPESE
金额：
$ 37.06万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-24 至 2008-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Hypertension is a common manifestation of renal disease and greatly contributes to its progression as well as to cardiovascular morbidity. Clearly, hypertension is an important etiology in the pathogenesis of renal failure. In the United States, hypertension is the primary cause of end-stage renal disease in approximately 29 percent of dialysis patients. In conjunction with other diseases such as diabetes and chronic glomerulonephritides, hypertension, when uncontrolled, hastens the progression of renal disease. Cardiovascular disease is the leading cause of death in patients receiving maintenance hemodialysis and hypertension is considered the most important factor responsible for cardiovascular events in these patients. Adequate BP control may reduce the progression of renal disease and cardiovascular morbidity in these patients, but often this is difficult to achieve with currently available drugs. The old paradigm is that hypertension in renal disease is the result of activation of the renin-angiotensin system and/or volume expansion. Our studies strongly support the notion that a renal injury may result in activation of renal afferent pathways that integrate with the central nervous system, and lead to stimulation of efferent SNS activity and hypertension. Locally produced angiotensin II in the brain in response to these afferent stimuli seems to be responsible for SNS activation through inhibition of nitric oxide. Our hypothesis is that angiotensin-II activation of ROS may reduce NO availability in key brain region and result in increased SNS activity in a model of neurogenic hypertension caused by renal injury developed in our laboratory. To test this hypothesis we will pursue 3 specific Aims: 1. Test the hypothesis that locally produced Ang II mediates the activation of central SNS activity caused by phenol-renal injury. To this end, we will measure Ang II concentration in the dialysate collected from the PH using the microdialysis technique, and the expression of renin mRNA in the posterior hypothalamus. 2. Test the hypothesis that radical oxygen species (ROS) activated by Angiotensin II down-regulate nitric oxide production in the brain resulting in increased SNS activity. To this end, we will measure the concentration of reactive oxygen species (ROS) in the hypothalamus or rats with the phenol-renal injury or rats infused with Ang II in the lateral ventricle. In addition, we will evaluate the effects of anti-oxidants, or scavengers of ROS, and Ang II AT1 receptor antagonists on BP, sympathetic activation and ROS concentrations in the hypothalamic region. 3. Test the hypothesis that increased ROS production may result in NO inhibition and SNS activation in other forms of experimental hypertension, such as the DOCA-sait model, and the renovascular hypertension model. If our hypothesis were to be correct, administration of inhibitors of the renin-angiotensin system particularly if combined with antioxidants should result in better control of BP in these models.

描述(申请人提供)：高血压是肾脏疾病的一种常见表现，极大地促进了肾脏疾病的进展和心血管疾病的发病率。显然，高血压是肾功能衰竭发病机制中的一个重要病因。在美国，在大约29%的透析患者中，高血压是终末期肾病的主要原因。与糖尿病和慢性肾小球肾炎等其他疾病一起，高血压如果得不到控制，会加速肾脏疾病的发展。心血管疾病是维持性血液透析患者的主要死亡原因，高血压被认为是导致这些患者心血管事件的最重要因素。在这些患者中，适当的血压控制可能会减少肾脏疾病的进展和心血管疾病的发病率，但目前可用的药物往往难以实现这一点。旧的模式是肾脏疾病中的高血压是肾素-血管紧张素系统激活和/或容量扩张的结果。我们的研究有力地支持了这样的观点，即肾脏损伤可能导致与中枢神经系统整合的肾脏传入通路的激活，并导致刺激传出的SNS活动和高血压。脑内局部产生的血管紧张素II对这些传入刺激的反应似乎是通过抑制一氧化氮来激活SNS的。我们的假设是，在本实验室建立的肾损伤神经原性高血压模型中，血管紧张素-II激活ROS可能减少关键脑区NO的可获得性，导致SNS活性增加。为了验证这一假说，我们将追求三个特定的目标：1.检验局部产生的Ang II介导酚肾损伤引起的中枢SNS活性激活的假说。为此，我们将使用微透析技术检测PH患者透析液中Ang II的浓度，并检测下丘脑后叶肾素mRNA的表达。2.验证由血管紧张素II激活的自由基氧物种(ROS)下调大脑中一氧化氮的产生，从而增加SNS活性的假设。为此，我们将测定下丘脑、苯酚肾损伤大鼠和侧脑室注射血管紧张素转换酶II大鼠脑组织中的ROS浓度。此外，我们还将评估抗氧化剂或ROS清除剂以及Ang II AT1受体拮抗剂对下丘脑区BP、交感神经兴奋和ROS浓度的影响。3.在其他形式的实验性高血压中，如DOCA-SAIT模型和肾性高血压模型，验证ROS产生增加可能导致NO抑制和SNS激活的假说。如果我们的假设是正确的，在这些模型中，给予肾素-血管紧张素系统的抑制剂，特别是如果与抗氧化剂结合使用，应该会导致更好的血压控制。