Involvement of the Brain Orexin System in Hypertension

摘要 高血压(HTN)是心血管疾病的主要危险因素，盐敏感型高血压(SSH) 占所有案件的51%。作为增强的交感神经活动(SNA)和升高的血浆 加压素(AVP)在SSH的发生发展中起关键作用，我们提议进行一项研究来探讨 中枢食欲素系统影响SNA失调和AVP兴奋的机制 生产，以期阐明SSH发展的一个主要组成部分。 脑室旁核(PVN)在控制SNA流出和AVP释放中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神经肽 具有许多功能，但越来越多的证据表明，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(OX1R)结合而发挥作用 和/或食欲素2受体(OX2R)，与前者有更高的亲和力。脑内增食欲素受体的上调 在几种HTN动物模型中观察到了包括室旁核在内的心血管相关区域，以及 食欲素受体拮抗剂可降低这些大鼠的血压，提示脑部食欲素受体过度活跃参与了 血压偏高。然而，食欲素受体在SSH发生发展中的作用尚未得到研究。 下定决心。我们在本申请中的初步数据显示，OX1R和AVP的表达显著 SSH动物模型--脱氧皮质酮-盐性高血压大鼠室旁核的升高 模仿人类的醛固酮增多症，这种症状在盐敏感患者中观察到，在耐药患者中更是如此 高血压患者。在正常SD大鼠，中枢给予增食欲素A增加 PVN AVP表达增加，PVN内微量注射增食欲素A可增加SNA流出。这一增长 SNA外流可被预先给予OX1R拮抗剂阻断。此外，我们的初步数据显示， 用遗传方法降低PVN OX1R的表达显著降低PVN AVP的表达，并 预防DOCA-SALT大鼠HTN的发生。这些观察结果使我们假设DOCA- 盐处理上调PVN增食欲素信号，进而增加SNA流出并刺激 AVP的产生和释放，最终导致HTN。我们将使用普通SD和DOCA-SALT模型 进行各种最先进的分子和生理研究，以回答以下问题：(1) OX1R在正常大鼠PVN中的长期过度表达是否导致HTN？(2)是否 PVN OX1R的慢性敲除阻止SSH的发展？(3)增食欲素信号通路 调节中枢盐皮质激素受体(MR)或大脑肾素-血管紧张素系统(RAS)的活动， SSH开发中的两个老牌参与者？这项研究的结果可能会提供一个 SSH和耐药HTN治疗的新靶点。最重要的是，我们将为毕业生提供一个机会 和本科生一起参与这项研究项目。

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.