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

摘要 预计到2020年，高血压将成为全球导致死亡和残疾的主要原因。这个 抗高血压药物的开发成果大大低于预期，使新的 对血压调节的机械洞察力是必不可少的。这个应用程序将测试以下假设 机械感受器依赖的交感抑制传入肾神经肾-肾反射抑制交感神经 外流到肾脏减少α-1肾上腺素能受体刺激的钠重吸收和对抗 高血压。这些研究将采用我们的选择性肾传入神经消融的新技术。 高血压大鼠模型中的机械和化学敏感刺激和药理工具(目标1，2和 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人 患者样本(目标3)描述完整的肾脏和交感神经系统机制 影响肾脏钠重吸收，调节长期血压。以下是具体目标 对这一假设进行检验：具体目标1：传入肾神经肾-肾反射 抑制交感神经和排钠以防止盐敏感型高血压的发生。具体目标2： 机械感受器依赖的肾传入神经激活促进液体和电解质的动态平衡 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活动 门控WNK1-OxSR1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任务的核心 和血液研究所(NHLBI)，旨在促进心肺和血液的预防和治疗 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。这些研究还直接涉及2014年NHLBI 盐在人类健康和疾病中的作用工作组建议1)需要进一步阐明 盐可能参与的生物学机制和病理过程，以及2)鉴定 将盐敏感型高血压作为优先研究课题。具体目标1将确定传入肾的作用 急、慢性时钠排泄、交感神经流出和血压调节的神经 盐和水平衡面临的挑战。特定目标2将建立肾脏机械感受器作为 肾传入神经信号传递到大脑，以促进交感神经抑制和钠的排泄。 具体目标3将确立交感神经系统释放去甲肾上腺素的作用 通过一种新的α1-肾上腺素能受体信号转导途径调节大鼠的氯化钠共转运体 人体研究。我们的研究，由一个多学科合作研究团队进行，将有可能 确定盐敏感型高血压的新治疗目标和/或个性化治疗模式- 满足目前三分之一的美国成年人患有高血压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.