Neural control of the kidney and long-term blood pressure regulation

摘要 预计到2020年，高血压将成为全球死亡和残疾的主要原因。的 抗高血压药物的开发比预期的要少得多， 对血压调节的机械见解至关重要。本应用程序将测试假设， 机械感受器依赖性交感神经抑制性传入肾神经肾-肾反射抑制交感神经 流出到肾脏，以减少α1-肾上腺素受体刺激的NCC介导的钠重吸收， 高血压这些研究将采用我们的新技术，选择性传入肾神经消融，直接 机械和化学敏感性刺激，以及高血压大鼠模型中的药理学工具（目的1，2 & 3），一个独特的小鼠远曲小管细胞系（Aim 3）和正常血压和高血压的人 患者样本（目标3），以描绘整合的肾脏和交感神经系统机制， 影响肾脏钠重吸收，从而调节长期血压。以下具体目标将 具体目的1：传入肾神经肾-肾反射介导 交感神经抑制和尿钠排泄，以防止盐敏感性高血压的发生。具体目标2： 机械感受器依赖性传入肾神经激活促进体液和电解质稳态， 血压调节具体目标3：去甲肾上腺素通过α1-肾上腺素受体调节NCC活性 门控WNK 1-OxSR 1信号转导通路，介导钠稳态和长期血液 压力调节这些以高血压为重点的研究是国家心肺中心使命的核心。 和血液研究所（NHLBI），这是为了促进预防和治疗心脏，肺和血液 疾病，并直接支持NHLBI战略计划的目标1，即提高对 健康和疾病的分子和生理基础。这些研究还直接针对2014年NHLBI 盐对人类健康和疾病的影响工作组建议：1）需要进一步阐明 盐可能导致的生物机制和病理过程，以及2）识别 盐敏感性高血压作为优先研究课题。具体目标1将建立传入肾的作用， 神经在钠排泄，交感神经流出和血压调节在急性和慢性 盐和水平衡的挑战。具体目标2将确立肾机械感受器作为 传入肾神经信号传播到大脑，以促进交感神经抑制和钠排泄。 具体目标3将确定交感神经系统释放去甲肾上腺素的作用， 调节氯化钠协同转运蛋白，通过一种新的α1-肾上腺素受体信号转导途径在大鼠， 人类研究我们的研究，由一个多学科的合作研究小组进行，将有可能 确定盐敏感性高血压的新治疗靶点和/或个性化治疗范例- 满足目前患有原发性高血压的三分之一美国成年人的紧急公共卫生需求。

ABSTRACT Hypertension is predicted to be the leading global cause of death and disability by the year 2020. The development of antihypertensive drugs has been dramatically less productive than expected, making new mechanistic insights into blood pressure regulation essential. This application will test the hypothesis that mechanoreceptor dependent sympathoinhibitory afferent renal nerve reno-renal reflexes suppress sympathetic outflow to the kidney to reduce α1-adrenoceptor stimulated NCC-mediated sodium reabsorption and counter hypertension. These studies will employ our novel technique of selective afferent renal nerve ablation, direct mechano- and chemosensitive stimuli, and pharmacological tools in rat models of hypertension (Aims 1, 2 & 3), a unique mouse distal convoluted tubule cell line (Aim 3) and normotensive and hypertensive human patient samples (Aim 3) to delineate the integrated renal and sympathetic nervous system mechanisms that influence renal sodium reabsorption to regulate long term blood pressure. The following Specific Aims will be conducted to test this hypothesis: Specific Aim 1: The afferent renal nerve reno-renal reflex mediates sympathoinhibition and natriuresis to prevent the initiation of salt-sensitive hypertension. Specific Aim 2: That mechanoreceptor-dependent afferent renal nerve activation facilitates fluid and electrolyte homeostasis and blood pressure regulation. Specific Aim 3: That norepinephrine regulates NCC activity, via an α1-adrenoceptor gated WNK1-OxSR1 signal transduction pathway, to mediate sodium homeostasis and long-term blood pressure regulation. These hypertension focused studies are central to the mission of the National Heart Lung and Blood Institute (NHLBI), which is to promote the prevention and treatment of heart, lung and blood disease, and directly support Goal 1 of the NHLBI Strategic Plan, which is to improve understanding of molecular and physiological basis of health and disease. These studies also directly address the 2014 NHLBI Salt in Human Health and Sickness Working Group recommendations for 1) a need to further illuminate the biological mechanisms and pathological processes to which salt may contribute, and 2) the identification of salt-sensitive hypertension as a priority research topic. Specific Aim 1 will establish a role of the afferent renal nerves in sodium excretion, sympathetic outflow and blood pressure regulation during acute and chronic challenges to salt and water balance. Specific Aim 2 will establish the renal mechanoreceptors as the site of afferent renal nerve signal propagation to the brain to facilitate sympathoinhibition and sodium excretion. Specific Aim 3 will establish the actions of the sympathetic nervous system release of norepinephrine to regulate the sodium chloride cotransporter, via a novel α1- adrenoceptor signal transduction pathway in rat and human studies. Our studies, performed by a multidisciplinary collaborative research team, will potentially identify new therapeutic targets and/or personalized treatment paradigms for salt-sensitive hypertension – meeting an urgent public health need for the 1 in 3 US adults currently living with essential hypertension.