Renal and Neural Mechanisms of Age-Related Hypertension

项目总结/摘要 高血压是中风、心肌梗死和慢性肾脏疾病的主要危险因素。的 高血压患病率随着年龄的增长而增加，从18-39岁的成年人中不到10%增加到10%以上。 60岁以上的成年人中有65%。虽然有一个证明的好处，血压降低， 高血压相关的发病率和死亡率的措施，不到一半的老年患者， 高血压实现了血压治疗控制。重要的是，年龄背后的机制- 相关的高血压尚未完全阐明。该提案旨在描述综合肾脏和 交感神经系统机制，调节钠平衡和血压在老化，与 目标是确定潜在的治疗途径，并告知当前的个性化应用 老年人的降压治疗。 我们假设年龄相关的肾传入神经减少 活动有助于交感神经兴奋，导致氯化钠协同转运蛋白介导的钠潴留 以及与年龄相关的高血压的发展。我们将使用一种新的方法来选择性地消融传入神经 肾神经和测试的年龄依赖性作用的传入肾神经介导的机械敏感性 交感神经抑制性肾-肾反射对急性和慢性钠挑战的稳态反应， 体液平衡在具体目标1中，我们将建立传入肾神经活动的年龄依赖性降低 以及不能响应于慢性高盐饮食而增加传入肾神经活动。我们将 表明完整的传入肾神经活动促进交感神经抑制，钠稳态， 正常血压对直接激活年轻人肾机械感受器的急性容量扩张的反应 Sprague-Dawley大鼠，并且传入肾神经在这些反应中的作用是年龄依赖性的。在 具体目标2，我们将证明，完整的传入肾神经活动促进交感神经抑制， 年轻Sprague大鼠对慢性高盐饮食的钠稳态和正常血压反应 道利老鼠。我们将证明，在这些反应的传入肾神经的作用是年龄 依赖性，而传入肾神经反应性降低引起年龄依赖性钠潴留 和高血压通过传出肾神经介导的α1-肾上腺素受体依赖性途径， 氯化钠协同转运蛋白我们将使用双侧肾脏去神经支配来证明， 传入和传出肾神经减弱与年龄相关的钠潴留和高血压， 机制的见解，可以告知候选人的选择正在进行的人类肾神经消融研究。我们 研究将确定新的治疗靶点，并为目前的高血压治疗模式提供信息， 老年人，满足全球人口迅速老龄化的迫切公共卫生需求。

Project Summary/Abstract Hypertension is the leading risk factor for stroke, myocardial infarction, and chronic kidney disease. The prevalence of hypertension increases with age from less than 10% among adults aged 18-39 to more than 65% among adults above the age of 60. While there is a demonstrated benefit of blood pressure reduction on measures of hypertension-related morbidity and mortality, less than one half of elderly patients with hypertension achieve therapeutic control of blood pressure. Importantly, the mechanisms underlying age- related hypertension have not been fully elucidated. This proposal seeks to delineate the integrated renal and sympathetic nervous system mechanisms that regulate sodium balance and blood pressure in aging, with the goal of identifying potential therapeutic avenues and informing the personalized application of current antihypertensive therapies in the elderly. We hypothesize that an age-related reduction in afferent renal nerve activity contributes to sympathoexcitation, leading to sodium chloride cotransporter-mediated sodium retention and the development of age-related hypertension. We will use a novel method to selectively ablate the afferent renal nerves and test the age-dependent role of the afferent renal nerve-mediated mechanosensitive sympathoinhibitory reno-renal reflex in homeostatic responses to acute and chronic challenges to sodium and fluid balance. In Specific Aim 1, we will establish an age-dependent decrease in afferent renal nerve activity and a failure to increase afferent renal nerve activity in response to a chronic high salt diet. We will demonstrate that intact afferent renal nerve activity facilitates sympathoinhibition, sodium homeostasis, and normotension in response to an acute volume expansion that directly activates renal mechanoceptors in young Sprague-Dawley rats, and that the role of the afferent renal nerves in these responses is age-dependent. In Specific Aim 2, we will demonstrate that intact afferent renal nerve activity facilitates sympathoinhibition, sodium homeostasis, and normotension in response to chronic dietary high salt intake in young Sprague- Dawley rats. We will demonstrate that the role of the afferent renal nerves in these responses is age dependent, and that decreased afferent renal nerve responsiveness evokes age-dependent sodium retention and hypertension via an efferent renal nerve-mediated α1-adrenoceptor-dependent pathway that activates the sodium chloride cotransporter. We will use bilateral renal denervation to demonstrate that removal of both the afferent and efferent renal nerves attenuates age-related sodium retention and hypertension, providing mechanistic insight that may inform candidate selection for ongoing human renal nerve ablation studies. Our studies will identify new therapeutic targets and inform current treatment paradigms for hypertension in the elderly, meeting an urgent public health need for the rapidly aging global population.