Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension

调节大脑 RAS 活性的新机制：在神经源性高血压中的作用

• 批准号: 10213809
• 负责人: Curt Daniel Sigmund
• 金额: $ 47.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213809
• 关键词: Address; Alleles; Angiotensin II; Angiotensinogen; Blood; Blood Pressure; Brain; Budgets; CRISPR/Cas technology; Cardiovascular system; Cell Line; Cell Nucleus; Cells; DOCA; Data; Disinhibition; Energy Metabolism; Exhibits; Exons; Experimental Water Deprivation; Exposure to; Future; Generations; Genes; Genetic; Genetic Transcription; High Fat Diet; Homeostasis; Hypertension; Hypothalamic structure; Impairment; In Vitro; Inactive Renin; Intake; Kidney; Light; Liquid substance; Mediating; Messenger RNA; Metabolic; Methods; Modeling; Molecular; Mus; Nerve; Neuroglia; Neurons; Pathologic; Peptide Signal Sequences; Physiological; Play; Prevention; Production; Prosencephalon; Protein Isoforms; Regulation; Renin; Renin-Angiotensin System; Reporter; Role; Seminal; Signal Transduction; Site; Sodium Chloride; Stimulus; Structure of nucleus infundibularis hypothalami; Subfornical Organ; Sympathetic Nervous System; System; Testing; Upstream Enhancer; dietary; extracellular; genetic manipulation; genome editing; inhibitor/antagonist; innovation; mouse model; neuroblastoma cell; neurogenic hypertension; novel; paraventricular nucleus; preservation; promoter; receptor; response; stressor; synergism

Summary/Abstract The brain renin-angiotensin system (RAS) plays a crucial role in regulating cardiovascular and metabolic function. Nuclei-specific synthesis and action of angiotensin-II (ANG) in the brain affords mechanisms for the independent regulation of fluid intake and sympathetic nerve activity (SNA) controlling blood pressure (BP) and metabolic responses. That angiotensinogen (AGT), the substrate for renin and precursor to ANG is constitutively released from glial cells throughout the brain, and from neurons in nuclei controlling cardiovascular and metabolic function, implores the central question of how ANG production in the brain is regulated? We identified an unexpected and novel mechanism regulating expression of renin in the brain which may address this. However, the initiating signals and mechanisms involved remains unknown. This project will examine the innovative concepts and hypotheses that: 1) there is coordinate regulation of renin mRNA isoforms which controls RAS activity in the brain, and 2) impairment of this novel control mechanism causes neurogenic hypertension and increases sensitivity of exposure to hypertension-causing stimuli. We will examine this original concept in the following two specific aims: 1) test the hypothesis that coordinated expression of Ren-b and Ren-a in the subfornical organ (SFO), paraventricular nucleus (PVN), and arcuate nucleus (ARC) mediates local ANG production and action which alters SNA controlling cardiovascular and metabolic function, and 2) test the hypothesis that disinhibition of Ren-a expression with concomitant inhibition of renin-b expression in the SFO, PVN and ARC is required to mediate sensitization of the hypertensive response (HTR) to mild humoral (e.g. ANG) and dietary (e.g. high fat diet) stressors. The studies will advance the concepts that a) Ren-b expression is an endogenous inhibitor of Ren-a expression limiting ANG production in the presence of excess extracellular AGT, and b) under conditions which threaten homeostasis (e.g. water deprivation) or in response to pathological stimuli (e.g. DOCA-salt or high fat diet), previously dormant Ren-a expression is disinhibited leading to site-specific prorenin activation, ANG generation and ANG action. Importantly, we hypothesize that impairment of this regulatory circuit causes neurogenic hypertension. The project has natural synergy as other projects that will similarly examine blood pressure and metabolic signaling in forebrain and hypothalamic nuclei. Moreover, this project will be informed by the data collected by the other projects and will synergize by exploring RAS-dependent and renin-dependent mechanisms in those systems.

总结/摘要 脑组织中的肾素-血管紧张素系统（RAS）在调节心血管和代谢中起着至关重要的作用 功能血管紧张素-II（ANG）在脑中的核特异性合成和作用为血管紧张素-II（ANG）在脑中的表达提供了机制。 独立调节液体摄入和控制血压（BP）的交感神经活动（SNA）， 代谢反应血管紧张素原（AGT），肾素的底物和血管紧张素的前体， 组成性地从整个大脑的神经胶质细胞释放，并且从控制神经元的核中的神经元释放。 心血管和代谢功能，恳求的核心问题是如何在大脑中的ANG生产是 监管？我们发现了一种意想不到的新机制，调节脑中的肾素表达， 这可以解决这个问题。然而，涉及的启动信号和机制仍然未知。这 本计画将探讨创新的概念与假设：1）肾素有协调的调控 控制脑中RAS活性的mRNA亚型，以及2）这种新的控制机制的损害 引起神经源性高血压并增加暴露于引起高血压的刺激的敏感性。我们将 在以下两个具体目标中检查这个原始概念：1）测试协调的假设 Ren-b和Ren-a在穹窿下器（SFO）、室旁核（PVN）和弓状核（ARG）中的表达 ARC调节局部ANG的产生和作用，改变SNA控制心血管和 2）检验Ren-a表达的去抑制伴随抑制的假设， SFO、PVN和ARC中肾素-b表达的增加是介导高血压致敏的必要条件。 对轻度体液（如ANG）和饮食（如高脂饮食）应激的反应（HTR）。研究将继续进行 a）Ren-b表达是限制ANG产生的Ren-a表达的内源性抑制剂 在过量的细胞外AGT存在下，和B）在威胁体内平衡的条件下（例如水 剥夺）或响应于病理刺激（例如DOCA-盐或高脂肪饮食），先前休眠的Ren-a 表达被解除抑制，导致位点特异性前肾素活化、ANG产生和ANG作用。 重要的是，我们假设这一调节回路的受损导致神经源性高血压。的 该项目具有自然的协同效应，因为其他项目将类似地检查血压和代谢信号 在前脑和下丘脑核团中。此外，该项目将由其他机构收集的数据提供信息。 项目，并将协同探索RAS依赖和肾素依赖机制，在这些系统。