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: 10445017
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445017
• 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; blood pressure elevation; dietary; extracellular; genetic manipulation; genome editing; hypertensive; inhibitor; 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方面起着至关重要的作用 功能。脑内血管紧张素-II(Ang)的核特异性合成和作用为 独立调节液体摄入和交感神经活动(SNA)控制血压(BP)和 代谢反应。血管紧张素原(AGT)是肾素的底物和血管紧张素的前体 从整个大脑的神经胶质细胞和控制神经核的神经元中结构性释放 心血管和代谢功能，提出了一个中心问题，即大脑中血管紧张素的产生是如何 受监管？我们发现了一种意想不到的新机制，调节大脑中肾素的表达。 这可能会解决这个问题。然而，涉及的启动信号和机制仍不清楚。这 该项目将检验创新的概念和假设：1)存在肾素的协调调节 控制大脑中RAS活性的mRNA亚型，以及2)这一新的控制机制的损害 会导致神经性高血压，并增加对引起高血压的刺激的敏感性。我们会 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在穹隆下器、室旁核和弓状核中的表达 核团(ARC)介导局部血管紧张素的产生和作用，从而改变SNA控制心血管和 代谢功能，以及2)检验Ren-a表达解除抑制伴随抑制的假设 肾素-b在SFO、PVN和ARC中的表达是介导高血压增敏所必需的 对轻度体液(如血管紧张素转换酶)和饮食(如高脂肪饮食)应激源的反应(HTR)。这些研究将会取得进展 A)Ren-b表达是限制Ang产生的Ren-a表达的内源性抑制因子的概念 在细胞外AGT过多的情况下，以及b)在威胁动态平衡的条件下(例如水 剥夺)或对病理刺激(如DOCA-盐或高脂肪饮食)的反应，以前休眠的REN-A 表达被抑制，导致位点特异性的前肾素激活、Ang的产生和Ang的作用。 重要的是，我们假设这一调节回路的损伤会导致神经源性高血压。这个 与其他类似检查血压和代谢信号的项目一样，该项目具有自然的协同作用 在前脑和下丘脑核团中。此外，这个项目将由另一个项目收集的数据提供信息 项目和将通过探索这些系统中依赖RAS和肾素依赖的机制来实现协同作用。