Renal sodium handling in hypertension: impact of age, sex, and dietary potassium

项目摘要 高血压(HTN)影响美国三分之一的成年人，65岁以下的男性比女性更普遍 年龄，但在老年女性中比男性更普遍。心血管事件的发生率更高且发生得更早 男性年龄大于女性。年龄和性别差异背后的机制 高血压的发病率仍然知之甚少。这个项目旨在提供机械性的洞察 年龄和性别差异，以及饮食中Na+和K+的影响，使用以下组合 实验和数学建模技术，以优化高血压的治疗 取决于年龄和性别。肾脏调节盐分排泄的能力对控制血压至关重要 (BP)。循环容量增加会使血压升高，从而促使尿钠和水的排泄恢复 血容量和血压。我们最近报道了钠离子转运体丰度的性别差异。 女性的肾单位和更强健的利钠反应，我们使用计算模型来建立 二态词的功能含义。我们的中心假设是性别和年龄相关的差异 肾小管功能有助于降低女性对HTN的易感性和肾脏损伤；这些 不同之处随着年龄的增长而变化。为了验证这一假设，我们将收集关键的基线和实验数据 并进行模型模拟，以获得对关键变量如何影响肾功能的机械性见解。 我们建议调查引起高血压的三种病理生理条件作为高血压的共同发病率。 人类：高盐饮食(HS)、单肾切除(UNX)和2型糖尿病(T2D)。目标1.确定 盐敏感型HTN易感性与年龄和性别相关的机制 SD大鼠(SDR)。来自肾脏转运体和肾功能的数据收集在年轻和 老年男性和女性将被用来开发肾脏转运的计算模型，以了解为什么HTN 在年轻女性中不太常见，以及衰老如何引发盐敏感型高血压。目标2.确定 UNX后HTN的机制以及对性别和年龄的依赖(方法与Aim1相同)。 我们的目标是了解为什么有很大一部分肾脏捐赠者会患上高血压和肾脏。 受伤。目的3.确定肾小管对T2D反应的性别差异的机制 在T2D/高血压/糖尿病肾病ZSF1模型中扩展肾脏计算模型 运输。在这三个目标中的每一个中，确定富含钾碱的饮食对钝化HTN和 用2%氯化钠模拟西方饮食造成大鼠肾脏损伤。了解年龄、性别和饮食盐 HTN期间对肾脏的影响和损伤有可能优化个体化治疗 以及高血压的管理，这些都是在老龄化模型中研究不足的。

Project Summary Hypertension (HTN) affects 1/3 of adults in USA, and is more prevalent in men vs. women under 65 years of age, but more prevalent in elderly women vs. men. Cardiovascular events occur at a higher rate and earlier age in males than females. The mechanisms underlying age- and sex-related differences in hypertension incidence remain poorly understood. This project aims to provide mechanistic insight into age- and sex- differences, and the influence of dietary Na+ and K+, using a combination of experimental and mathematical modeling techniques, in order to optimize treatments for hypertension depending on age and sex. The kidney's ability to regulate salt excretion is critical to control of blood pressure (BP). Increased circulating volume can increase BP which drives urinary excretion of Na+ and H2O to restore blood volume and BP. We recently reported sex differences in the abundance of Na+ transporters along the nephron and more robust natriuretic responses in females, and we used computational models to establish the functional implications of the dimorphisms. Our central hypothesis is that sex- and age-related differences in renal tubular function contribute to reduced susceptibility to HTN and renal injury in females; and that these differences change with aging. To test this hypothesis, we will collect key baseline and experimental data in rats and perform model simulations to gain mechanistic insights into how key variables impact kidney function. We propose to investigate three pathophysiological conditions that provoke hypertension as a co-morbidity in humans: high-salt diet (HS), uninephrectomy (UNX) and type 2 diabetes (T2D). Aim 1. Determine mechanisms responsible for age- and sex-related differences in susceptibility to salt sensitive HTN in Sprague Dawley rats (SDR). Data from renal transporter profiles and renal function collected in young and old of both sexes will be used to develop computational models of renal transport to understand why HTN is less prevalent in young females, and how aging provokes salt-sensitive hypertension. Aim 2. Determine mechanisms responsible for HTN following UNX and dependence on sex and age (approach as in Aim1). Our objective is to understand why a significant fraction of kidney donors develop hypertension and renal injury. Aim 3. Determine mechanisms responsible for sex- differences in renal tubular responses to T2D in the ZSF1 model of T2D/hypertension/diabetic nephropathy by extending computational models of renal transport. In each of these 3 aims, determine the impact of a potassium-alkali rich diet to blunt HTN and renal injury in rats fed 2% NaCl to mimic Western diet. Understanding how age, sex, and dietary salts impact renal transport and injury during HTN has the potential to optimize personalized therapies for treatment and management of hypertension, which are understudied in aging models.