Renal and Neural Mechanisms of Age-Related Hypertension

项目摘要/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。这个 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%增加到超过 在60岁以上的成年人中占65%。虽然降压有明显的好处，但 高血压相关发病率和死亡率的衡量标准，不到一半的老年患者患有 高血压实现治疗性血压控制。重要的是，年龄背后的机制- 与高血压相关的疾病尚未完全阐明。这项建议旨在勾勒出完整的肾脏和 交感神经系统在衰老过程中调节钠平衡和血压的机制 确定潜在治疗途径的目标并告知当前的个性化应用 老年人的降压治疗。 我们假设与年龄相关的肾传入神经减少 活性有助于交感神经兴奋，导致氯化钠共转运体介导的钠滞留 以及年龄相关性高血压的发展。我们将使用一种新的方法选择性地消融传入 并检测肾神经传入神经介导的机械敏感性的年龄依赖性作用 交感神经抑制的肾-肾反射对钠和慢性钠和钙的急性和慢性挑战的稳态反应 液体平衡。在特定的目标1中，我们将建立与年龄相关的肾传入神经活性下降。 对慢性高盐饮食未能增加肾传入神经活动。我们会 证明完整的肾传入神经活动有助于交感神经抑制、钠稳态和 直接激活年轻人肾脏机械感受器的急性容量扩张所致的血压正常 肾传入神经在这些反应中的作用与年龄有关。在……里面 具体目标2，我们将证明完整的肾传入神经活动有助于交感神经抑制， 钠稳态和正常血压对长期饮食高盐摄入量的反应年轻的斯普拉格- 道利鼠。我们将证明肾传入神经在这些反应中的作用是年龄。 依赖，而且肾传入神经反应性降低可引起年龄依赖性钠滞留 高血压通过传出肾神经介导的α1肾上腺素能受体依赖途径激活 氯化钠共转运蛋白。我们将使用双侧肾去神经来演示切除双侧肾的 传入和传出肾神经减轻与年龄相关的钠滞留和高血压，提供 可能为正在进行的人类肾神经消融研究选择候选对象的机械性洞察力。我们的 研究将确定新的治疗靶点，并为目前高血压的治疗范例提供信息 老年人，满足迅速老龄化的全球人口对公共卫生的迫切需求。

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.