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.

项目摘要 高血压（HTN）影响美国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，但在老年妇女比男子更普遍。心血管事件的发生率更高，更早 年龄男性多于女性。与年龄和性别相关的差异的机制 高血压发病率仍然知之甚少。该项目旨在提供机械的见解 年龄和性别的差异，以及饮食中Na+和K+的影响，结合使用 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控制血压至关重要 （英国石油公司）。循环容量增加可增加血压，促使尿Na+和H2O排泄恢复 血容量和血压。我们最近报道了Na+转运体丰度的性别差异，沿着 肾单位和更强大的利钠反应，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HTN和肾损伤的易感性;这些 差异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， 大鼠和执行模型模拟，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的病理生理条件， 人类：高盐饮食（HS）、单侧肾切除术（UNX）和2型糖尿病（T2 D）。目标1.确定 盐敏感性HTN易感性的年龄和性别相关差异的机制 Sprague道利大鼠（SDR）。从年轻人和老年人中收集的肾转运蛋白谱和肾功能数据 将使用两种性别的老年人开发肾脏转运的计算模型，以了解HTN为什么是 在年轻女性中不太普遍，以及衰老如何引起盐敏感性高血压。目标二。确定 UNX后HTN的机制以及对性别和年龄的依赖性（方法与目标1相同）。 我们的目标是了解为什么相当一部分肾脏捐献者会患上高血压和肾功能衰竭。 损伤目标3。确定T2 D肾小管反应的性别差异机制 通过扩展肾脏的计算模型， 运输在这3个目标中，确定富含钾碱的饮食对钝化HTN的影响， 用2%NaCl模拟西方饮食对大鼠的肾损伤。了解年龄、性别和饮食中的盐 HTN期间影响肾脏转运和损伤的研究有可能优化个性化治疗， 和高血压的管理，这在衰老模型中研究不足。