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.

摘要/摘要 脑肾素 - 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）在大脑中的核特异性合成和作用提供了机制 独立调节液体摄入液和交感神经活动（SNA）控制血压（BP）和 代谢反应。那个血管紧张素原（AGT），肾素和ANG前体的底物为 从整个大脑中的神经胶质细胞和核控制中的神经元的组成性释放 心血管和代谢功能，涉及大脑中ANG的产生方式的核心问题 受监管？我们确定了一种意外的新型机制，用于调节肾素在大脑中的表达 这可以解决这个问题。但是，涉及的启动信号和机制仍然未知。这 项目将研究以下创新概念和假设：1）肾素有协调调节 控制大脑中RAS活性的mRNA同工型，以及2）这种新型控制机制的损害 引起神经源性高血压并增加暴露于引起高血压刺激的敏感性。我们将 在以下两个具体目的中检查这个原始概念：1）检验协调的假设 Ren-B和Ren-A在副脱机器官（SFO），室室核（PVN）和弧形中的表达 核（ARC）介导了局部ANG的产生和作用，从而改变了控制心血管和 代谢功能，以及2）检验以下假设：抑制Ren-A表达与抑制作用 SFO，PVN和ARC中的肾素-B表达需要介导高血压的敏化 对轻度体液（例如ANG）和饮食（例如高脂饮食）压力的反应（HTR）。研究将进步 a）ren-b表达是ren-a表达限制ANG产生的内源性抑制剂的概念 在存在过多的细胞外AGT的情况下，b）在威胁稳态的条件下（例如水 剥夺）或应对病理刺激（例如Doca-盐或高脂饮食），以前是休眠的REN-A 表达被抑制导致特异性特异性prorenin激活，ANG的产生和ANG作用。 重要的是，我们假设该调节回路的损害会导致神经源性高血压。这 项目具有自然协同作用，因为其他项目将同样检查血压和代谢信号传导 在前脑和下丘脑核中。此外，该项目将由另一个项目收集的数据告知 项目并将通过探索这些系统中的RAS依赖性和肾素依赖性机制来协同作用。