Oxidative Stress And Sympathetic Nerve Activity

描述（由申请人提供）：高血压是肾脏疾病的常见表现，并极大地促进其进展以及心血管发病率。显然，高血压是肾衰竭发病机制中的重要病因。在美国，高血压是约29%透析患者终末期肾病的主要原因。与其他疾病如糖尿病和慢性肾小球肾炎一起，高血压在不受控制时会加速肾脏疾病的进展。心血管疾病是接受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。适当的血压控制可能会减少这些患者的肾脏疾病和心血管疾病的发病率的进展，但通常这是很难实现与目前可用的药物。旧的范式是肾脏疾病中的高血压是肾素-血管紧张素系统激活和/或体积扩张的结果。我们的研究强烈支持这样的观点，即肾损伤可能导致与中枢神经系统整合的肾传入通路的激活，并导致传出SNS活动的刺激和高血压。局部产生的血管紧张素II在大脑中响应这些传入刺激似乎是负责SNS激活通过抑制一氧化氮。我们的假设是，血管紧张素-II激活ROS可能会减少NO的可用性在关键的大脑区域，并导致增加SNS活动在我们的实验室开发的肾损伤引起的神经源性高血压模型。为了验证这个假设，我们将追求3个具体目标：1。检验局部产生的Ang II介导苯酚肾损伤引起的中枢SNS活性激活的假设。为此，我们将使用微透析技术测量从PH收集的透析液中的Ang II浓度，以及后下丘脑中的肾素mRNA表达。2.检验由血管紧张素II激活的自由基氧（ROS）下调大脑中一氧化氮的产生，导致SNS活性增加的假设。为此，我们将测量下丘脑、苯酚肾损伤大鼠和侧脑室灌注Ang II大鼠中活性氧（ROS）的浓度。此外，我们将评估抗氧化剂，或清除剂的活性氧，和血管紧张素Ⅱ AT 1受体拮抗剂对血压，交感神经激活和活性氧浓度在下丘脑区域的影响。3.在其他形式的实验性高血压（如DOCA-sait模型和肾血管性高血压模型）中检验ROS产生增加可能导致NO抑制和SNS激活的假设。如果我们的假设是正确的，在这些模型中，给予肾素-血管紧张素系统抑制剂，特别是与抗氧化剂联合使用，应该能更好地控制血压。

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.