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

高血压中的肾脏钠处理：年龄、性别和膳食钾的影响

• 批准号: 10248228
• 负责人: AURELIE EDWARDS
• 金额: $ 9.78万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248228
• 关键词: Adult; Affect; Age; Age-Years; Aging; Alkalies; Anions; Attenuated; Bicarbonates; Blood Pressure; Blood Volume; Buffers; Cardiovascular system; Cessation of life; Citrates; Computer Models; Consumption; Data; Dependence; Diabetic Nephropathy; Diet; Dietary Potassium; Elderly woman; Event; Excretory function; Experimental Models; Female; Goals; Government; Grain; Homeostasis; Human; Hypertension; Incidence; Injury; Injury to Kidney; Intake; Intervention; Kidney; Lead; Limb structure; Measurement; Metabolic Diseases; Metabolic acidosis; Modeling; Modification; Natriuresis; Nephrons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Phosphotransferases; Physiology; Play; Population; Potassium; Predisposition; Proteinuria; Pump; Rattus; Regulation; Renal function; Reporting; Rodent; Role; Sex Differences; Sodium; Sodium Chloride; Sprague-Dawley Rats; Techniques; Testing; Thick; Thinness; Tubular formation; Woman; age difference; age related; base; blood pressure regulation; comorbidity; computer studies; decubitus ulcer; dietary salt; dimorphism; driving force; fruits and vegetables; global health; high salt diet; hypertension control; hypertension treatment; improved; insight; male; mathematical model; men; models and simulation; novel therapeutics; personalized medicine; pre-clinical; preclinical study; premature; pressure; prevent; response; salt sensitive hypertension; saluretic; sex; sexual dimorphism; treatment optimization; urinary; western diet; young adult

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.

项目概要 高血压 (HTN) 影响着美国 1/3 的成年人，并且在 65 岁以下的男性中比女性更普遍 年龄，但在老年女性中比男性更常见。心血管事件发生率更高且更早 男性年龄高于女性。年龄和性别相关差异的潜在机制 高血压的发病率仍知之甚少。该项目旨在提供机制见解 结合使用以下方法，研究年龄和性别差异以及膳食 Na+ 和 K+ 的影响 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。肾脏调节盐排泄的能力对于控制血压至关重要 （英国石油公司）。循环量增加可使血压升高，从而促使尿中 Na+ 和 H2O 的排泄恢复 血容量和血压。我们最近报道了沿 Na+ 转运蛋白丰度的性别差异 肾单位和女性更强大的利尿钠反应，我们使用计算模型来建立 二态性的功能含义。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高血压和肾损伤的易感性；并且这些 差异随着年龄的增长而改变。为了检验这个假设，我们将收集关键基线和实验数据 大鼠并进行模型模拟，以获得关键变量如何影响肾功能的机制见解。 我们建议调查三种引起高血压作为并发症的病理生理学条件 人类：高盐饮食 (HS)、单肾切除术 (UNX) 和 2 型糖尿病 (T2D)。目标 1. 确定 导致盐敏感性高血压易感性与年龄和性别相关的差异的机制 斯普拉格道利大鼠 (SDR)。从年轻和成年患者中收集的肾转运蛋白谱和肾功能数据 男女老少将被用来开发肾脏运输的计算模型，以了解为什么 HTN 是 在年轻女性中不太常见，以及衰老如何引发盐敏感性高血压。目标 2. 确定 UNX 后 HTN 的机制以及对性别和年龄的依赖（方法如目标 1）。 我们的目标是了解为什么很大一部分肾脏捐赠者会患上高血压和肾病 受伤。目标 3. 确定肾小管对 T2D 反应性别差异的机制 通过扩展肾脏的计算模型，在 T2D/高血压/糖尿病肾病的 ZSF1 模型中 运输。在这 3 个目标中的每一个中，确定富含钾碱的饮食对抑制 HTN 的影响，以及 模仿西方饮食喂养 2% NaCl 的大鼠肾损伤。了解年龄、性别和膳食盐的影响 HTN 期间对肾脏运输和损伤的影响有可能优化个性化治疗 和高血压的管理，这些在衰老模型中尚未得到充分研究。