Forebrain electroneutral transporters in salt-sensitive hypertension

盐敏感性高血压中的前脑电中性转运蛋白

基本信息

批准号：
10736529
负责人：
SEAN D STOCKER
金额：
$ 72.04万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-08 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736529
关键词：
Acute Adult Age Animal Model Animals Attenuated Blood Blood - brain barrier anatomy Blood Pressure Blood Vessels Brain Brain region Cardiovascular Diseases Cells Cerebrospinal Fluid Chronic Collaborations Dahl Salt-Resistant Rats Data Development Elements Excess Dietary Salt Functional Magnetic Resonance Imaging Furosemide Goals Homeostasis Human Hypernatremia Hypertension Hypothalamic structure Impairment In Vitro Infusion procedures Ingestion Interruption Intravenous infusion procedures Kidney Laboratories Lesion Mediating Modeling Molecular Nerve Neural Pathways Neurons Organ Pathogenesis Pathway interactions Peripheral Resistance Plasma Population Prosencephalon Protein Isoforms Public Health Rattus Regulation Resistance Rest Rodent Rodent Model Sodium Sodium Chloride Subfornical Organ System Techniques Testing Thirst Vasopressins Water antagonist blood pressure regulation cost experimental study extracellular high salt diet human model human subject in vivo neural neurotransmission novel novel therapeutic intervention novel therapeutics optogenetics organum vasculosum of the lamina terminalis patch clamp pharmacologic prevent response salt intake salt sensitive salt sensitive hypertension sensor sex symporter transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Excess dietary salt intake is associated with cardiovascular disease and is a major contributing factor to the pathogenesis of hypertension. Salt-sensitive hypertension in both humans and rodent models is associated with elevations in plasma or cerebrospinal fluid [NaCl]. The resultant relative hypernatremia activates central circuits to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP). There are brain NaCl-sensors in the circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO); activation of OVLT/SFO neurons stimulates thirst, vasopressin (AVP) secretion, and SNA, whereas interruption of neurotransmission in OVLT/SFO lowers ABP in salt-sensitive models. However, the mechanisms by which OVLT/SFO neurons sense extracellular [NaCl] are not known. Recent data suggest the Na+-K+-2Cl- co-transporter (NKCC2) is not kidney specific but is also expressed in brain regions that regulate whole body NaCl and water homeostasis. The central hypothesis of this proposal is that the ingestion of excess dietary salt elevates extracellular [NaCl] to activate NaCl-sensitive neurons in the OVLT/SFO through NKCC2. In turn, this activates descending pathways to elevate SNA and ABP. Furthermore, we hypothesize that these NaCl-sensing mechanisms are sensitized in salt-sensitive humans, since our preliminary data show hypernatremia evokes a greater increase in OVLT discharge of Dahl-salt sensitive versus Dahl-salt resistant rats fed a high salt diet. We propose 2 specific aims. Specific Aim 1 will determine the extent by which NKCC2 mediates NaCl-sensing in OVLT/SFO neurons and elevate SNA and ABP to acute NaCl loading or chronic salt- sensitive hypertension in rodents. Specific Aim 2 will test the hypothesis that an NKCC2 antagonist will blunt hypernatremia-induced central neural activation and SNA in salt resistant and salt sensitive adults with high BP, and that central neural activation will be greater in salt sensitive adults, suggesting heightened sodium sensing. Successful completion of these aims will provide needed information on the cellular elements that mediate intrinsic NaCl-sensing of hypothalamic neurons and provide novel data on central sodium sensing in salt sensitive humans. This is a translational R01, bringing two laboratories together that have a track record of successful collaboration, and these studies will provide a framework for the development of novel therapeutic treatments of salt-sensitive hypertension.

项目概要/摘要膳食盐摄入过多与心血管疾病有关，是导致心血管疾病的一个主要因素高血压的发病机制。人类和啮齿动物模型中的盐敏感性高血压与血浆或脑脊液[NaCl]升高。由此产生的相对高钠血症激活中枢回路增加交感神经活动（SNA）和动脉血压（ABP）。大脑中有 NaCl 传感器在室周器官中，例如终板血管器 (OVLT) 和穹窿下器官（SFO）； OVLT/SFO 神经元的激活会刺激口渴、加压素 (AVP) 分泌，以及 SNA，而 OVLT/SFO 中神经传递的中断会降低盐敏感模型中的 ABP。然而， OVLT/SFO 神经元感知细胞外 [NaCl] 的机制尚不清楚。最新数据表明 Na+-K+-2Cl- 协同转运蛋白 (NKCC2) 不是肾脏特异性的，但也在调节大脑的区域中表达全身氯化钠和水的稳态。该提案的中心假设是摄入过量膳食盐会升高细胞外 [NaCl]，通过 NKCC2 激活 OVLT/SFO 中的 NaCl 敏感神经元。反过来，这会激活下行通路以提高 SNA 和 ABP。此外，我们假设这些氯化钠感应机制对盐敏感的人类来说是敏感的，因为我们的初步数据显示高钠血症引起 Dahl 盐敏感大鼠与 Dahl 盐抗性大鼠的 OVLT 放电增加更大喂养高盐饮食。我们提出 2 个具体目标。具体目标 1 将确定 NKCC2 的程度介导 OVLT/SFO 神经元中的 NaCl 感应，并将 SNA 和 ABP 提升至急性 NaCl 负荷或慢性盐负荷啮齿类动物的敏感性高血压。具体目标 2 将检验 NKCC2 拮抗剂会钝化的假设高钠血症诱导的中枢神经激活和 SNA 在耐盐和盐敏感的高血压成人中，盐敏感成年人的中枢神经激活程度更高，这表明钠感应能力增强。成功完成这些目标将提供有关介导细胞元素的所需信息下丘脑神经元的内在 NaCl 感应，并提供盐中中枢钠感应的新数据敏感的人类。这是一个转化型 R01，将两个拥有以下记录的实验室结合在一起：成功的合作，这些研究将为开发新型治疗方法提供框架盐敏感性高血压的治疗。