Involvement of the Brain Orexin System in Hypertension

总结 高血压（HTN）是心血管疾病的主要危险因素，其中盐敏感性高血压（SSH） 占所有病例的51%。随着交感神经活动（SNA）增强和血浆 血管加压素（AVP）在SSH的发展中起着关键作用，我们提出了一项研究，以调查 中枢食欲素系统影响SNA失调和AVP兴奋机制 生产，希望阐明一个主要组成部分的SSH的发展。 脑室旁核（PVN）在控制SNA流出和AVP释放方面起着至关重要的作用， 以及血浆钠浓度传感。食欲素A是由下丘脑神经元产生的一种神经肽 有许多功能，但新出现的证据表明，食欲素系统也参与了 调节血压（BP）和SNA。食欲素A通过与食欲素1受体（OX 1 R）结合发挥作用 和/或食欲素2受体（OX 2 R），对前者具有更高的亲和力。脑中食欲素受体的上调 在HTN的几种动物模型中已经观察到包括PVN在内的心血管相关区域， 食欲素受体拮抗剂降低了这些大鼠的血压，这表明过度活跃的大脑食欲素受体有助于 高血压然而，食欲素受体在SSH发生和发展中的作用还没有被证实。 测定我们在本申请中的初步数据显示，OX 1 R和AVP的表达显著增加。 增加醋酸脱氧皮质酮（DOCA）-盐高血压大鼠（SSH动物模型）的PVN 模仿人类醛固酮增多症，这是在盐敏感患者中观察到的症状，在耐盐患者中更是如此。 高血压患者。在正常的Sprague道利（SD）大鼠中，食欲素A的中枢给药增加 PVN AVP表达，并向PVN中微量注射食欲素A增加SNA流出。的这种增加 SNA流出通过预先给予OX 1 R拮抗剂阻断。此外，我们的初步数据显示， 使用遗传方法降低PVN OX 1 R表达显著降低PVN AVP表达， 防止DOCA-盐大鼠中HTN的发展。这些观察使我们假设DOCA- 盐处理上调PVN食欲素信号传导，这反过来又增加SNA流出并刺激 AVP的产生和释放，最终导致HTN。我们将使用正常SD和DOCA盐模型 进行各种最先进的分子和生理学研究，以回答以下问题：（1） 正常大鼠PVN中OX 1 R的长期过度表达是否导致HTN？(2)并 慢性敲低PVN OX 1 R阻止SSH的发展？(3)食欲素信号 调节中枢盐皮质激素受体（MR）或脑肾素-血管紧张素系统（RAS）的作用， 两个老牌玩家在开发SSH开发？这项研究的结果可以提供一个 SSH和耐药HTN治疗的新目标。最重要的是，我们将为毕业生提供一个机会， 和本科生参与本研究项目。

SUMMARY Hypertension (HTN) is a major risk factor for cardiovascular disease, with salt sensitive hypertension (SSH) accounting for 51% of all cases. As augmented sympathetic nerve activity (SNA) and increased plasma vasopressin (AVP) are known to play key roles in the development of SSH, we propose a study to investigate the mechanism underlying central orexin system influence on both SNA dysregulation and stimulation of AVP production, in the hopes of elucidating a primary component to the development of SSH. The brain paraventricular nucleus (PVN) plays a crucial role in controlling SNA outflow and AVP release, as well as plasma sodium concentration sensing. Orexin A is a neuropeptide produced by hypothalamic neurons with numerous functions, but emerging evidence suggests that the orexin system is also involved in the regulation of blood pressure (BP) and SNA. Orexin A elicits its action by binding to orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R), with a higher affinity for the former. Upregulation of orexin receptors in brain cardiovascular relevant regions including the PVN have been observed in several animal models of HTN, and orexin receptor antagonism lowers BP in those rats, suggesting overactive brain orexin receptors contribute to high BP. However, the impact of orexin receptor in the development and progression of SSH has not been determined. Our preliminary data in this application shows that expression of OX1R and AVP is dramatically increased in the PVN of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, an animal model of SSH mimicking human aldosteronism, a symptom observed in salt sensitive patients and even more so in resistant hypertensive individuals. In normal Sprague Dawley (SD) rats, central administration of orexin A increases PVN AVP expression, and microinjection of orexin A into the PVN increases SNA outflow. This increase in SNA outflow is blocked by pre-administration of an OX1R antagonist. In addition, our preliminary data shows that decreasing PVN OX1R expression using a genetic method markedly decreases PVN AVP expression and prevents HTN development in DOCA-salt rats. These observations have led us to hypothesize that DOCA- salt treatment upregulates PVN orexin signaling, which, in turn, increases SNA outflow and stimulates AVP production and release, ultimately resulting in HTN. We will use normal SD and DOCA-salt models to perform various state-of-the-art molecular and physiological studies to answer the following questions: (1) Does long-term overexpression of OX1R in the PVN of normal rats result in HTN? (2) Does chronic knockdown of the PVN OX1R prevent the development of SSH? (3) Does orexin signaling modulate the actions of central mineralocorticoid receptors (MR) or the brain renin-angiotensin system (RAS), two established players in the development of SSH development? The outcome of this study may provide a new target for both SSH and resistant HTN treatment. Most importantly, we will offer an opportunity for graduate and undergraduate students to participate in this research project.