Renal electrolyte handling in females vs. males over life cycle

女性与男性在生命周期中的肾电解质处理

基本信息

批准号：
10539013
负责人：
AURELIE EDWARDS
金额：
$ 60.45万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539013
关键词：
4-vinylcyclohexene diepoxide Adult Age Aging Anatomy Angiotensin II Automobile Driving Blood Pressure Cardiovascular Diseases Cause of Death Cells Cessation of life Chromosomes Complex Computer Models Data Collection Data Set Dependence Development Diet Disease Progression Distal Electrolytes Equilibrium Exhibits Female Fluid Balance Four Core Genotypes Funding Genetic Models Glare Goals Gonadal Hormones Homeostasis Human Hypertension Intervention Ions Kidney Knowledge Lactation Life Cycle Stages Life Style Liquid substance Mediating Membrane Transport Proteins Menopause Modeling Modification Mus Muscle Natriuresis Nature Nephrons Outcome Output Partner in relationship Pattern Physiological Physiology Plasma Ploidies Postmenopause Pregnancy Process Production Pump Rattus Regulation Renal function Renal tubule structure Reporting Reproduction Rodent Role Saline Sex Chromosomes Sex Differences Site Skeletal Muscle Sodium Chloride Sprague-Dawley Rats Testing Tubular formation Validation blood pressure elevation complex data cost dietary dietary salt dimorphism high salt diet male man mouse development mouse genetics mouse model operation premature prepuberty pressure response salt sensitive hypertension saluretic sex sexual dimorphism therapeutic target water channel

项目摘要

PROJECT SUMMARY Kidney function is critical to maintaining effective circulating volume (ECV), electrolyte homeostasis and blood pressure (BP). Dysregulation of fluid and electrolyte transport in the kidney is central to hypertension (HTN) and cardiovascular disease (CVD) progression. Na+, K+, and volume homeostasis are maintained by regulation of renal ion and water transporters expressed in tubule specific patterns; K+ balance also depends on regulation of muscle transporters. HTN and CVD are a function of sex, age and lifestyle; less frequent in females than males below 65 yr and more common in post-menopausal females vs males over 65 yr; salt sensitivity of BP increases in both sexes with age. We have reported sex differences in the abundance of transporters along the nephron in both Sprague Dawley rats (SDR) and C57BL/6J mice, and used computational models to establish the functional implications of the dimorphisms, e.g. more robust natriuretic responses in young female vs male SDR. How kidney and muscle transporter profiles respond to life cycle transitions from development through aging and menopause is not known. Our overarching goal is to combine experimental and computational approaches to determine how kidney (and muscle) functions adapt to maintain ECV, electrolyte and fluid homeostasis in response to life cycle challenges in both male and female rats and mice: from development to aging, through the female-specific challenges of lactation and menopause, and the common challenges of dietary Na+ and K+. Aim 1. Test the hypothesis that baseline kidney function adapts during life cycle in a sex-specific manner to maintain fluid and electrolyte homeostasis. When do transporter sex differences appear? Is the more robust natriuresis in young females vs males still evident at 12 mo? Do muscle K+ transporters exhibit sex dimorphisms that impact K+ adaptation with age? We will utilize the Four Core Genotype mouse model to attribute dimorphisms along life cycle to gonadal hormones vs sex chromosome complement. Aim 2. Describe mechanisms of female kidney adaptation to lactation. Do kidney and nephron function adapt to maintain maternal homeostasis during peak lactation at minimal cost? Do kidney function, ECV and electrolyte homeostasis return to baseline after lactation cessation? Does extrarenal K+ homeostasis (skeletal muscle K+ transporters and [K+]) adapt during/after lactation? Aim 3. Test the hypothesis that menopause and age reduce sex differences and increase salt-sensitivity. Does ovotoxin-induced menopause change female kidney and muscle transporter profiles and function? Is salt-sensitive hypertension sex dependent? Exacerbated after menopause? Accomplishing these aims will fill important gaps in knowledge about sex-specific mechanisms of Na+, K+, and volume homeostasis and physiology throughout life cycle, thus, providing a better understanding of the female advantage in CVD and guiding therapeutic targets in both sexes across life cycle.

项目概要肾功能对于维持有效循环量 (ECV)、电解质稳态和血液至关重要压力（BP）。肾脏液体和电解质运输失调是高血压 (HTN) 的核心和心血管疾病（CVD）进展。 Na+、K+ 和体积稳态通过调节维持以肾小管特定模式表达的肾离子和水转运蛋白； K+ 平衡还取决于肌肉转运蛋白的调节。 HTN 和 CVD 与性别、年龄和生活方式有关；较少出现在 65 岁以下女性多于男性，绝经后女性多于 65 岁以上男性；盐男女血压的敏感性随着年龄的增长而增加。我们已经报告了丰度的性别差异 Sprague Dawley 大鼠 (SDR) 和 C57BL/6J 小鼠中沿肾单位的转运蛋白，并使用建立二态性功能含义的计算模型，例如更强大的利尿钠年轻女性与男性特别提款权的反应。肾脏和肌肉转运蛋白概况如何响应生命周期从发育到衰老和更年期的转变尚不清楚。我们的总体目标是结合实验和计算方法来确定肾脏（和肌肉）的功能适应维持 ECV、电解质和体液稳态，以应对生命周期挑战雄性和雌性大鼠和小鼠：从发育到衰老，经历雌性特有的挑战哺乳期和更年期，以及膳食 Na+ 和 K+ 的常见挑战。目标 1. 检验假设基线肾功能在生命周期中以性别特异性方式适应以维持液体和电解质稳态。转运蛋白性别差异何时出现？排钠能力更强吗年轻女性与男性在 12 个月时仍然明显吗？肌肉 K+ 转运蛋白是否表现出影响的性别二态性 K+随着年龄的增长而适应吗？我们将利用四核心基因型小鼠模型来归因二态性性腺激素与性染色体补体的生命周期。目标 2. 描述女性的机制肾脏对哺乳的适应。肾脏和肾单位功能是否适应维持母体稳态在哺乳高峰期间以最低的成本？肾功能、ECV 和电解质稳态是否恢复到基线停奶后？肾外 K+ 稳态（骨骼肌 K+ 转运蛋白和 [K+]）是否适应哺乳期间/哺乳后？目标 3. 检验更年期和年龄减少性别差异并降低性别差异的假设增加盐敏感性。卵毒素引起的更年期是否会改变女性肾脏和肌肉转运蛋白简介和功能？盐敏感性高血压是否依赖于性别？绝经后会加重吗？实现这些目标将填补有关 Na+、K+ 和 Na+、K+ 的性别特异性机制的知识空白。整个生命周期的体积稳态和生理学，从而更好地了解女性 CVD 方面的优势并指导两性整个生命周期的治疗目标。