Renal electrolyte handling in females vs. males over life cycle

项目总结 肾功能是维持有效循环容量(ECV)、电解质平衡和血液的关键 压力(BP)。肾脏内液体和电解质转运的失调是高血压(HTN)的核心 和心血管疾病(CVD)进展。通过调节来维持Na+、K+和容量的动态平衡 肾小管中离子和水转运蛋白的表达；K+平衡也依赖于 对肌肉转运蛋白的调节。HTN和CVD是性别、年龄和生活方式的函数； 65岁以下女性多于男性，在绝经后女性比65岁以上男性更常见；盐 男性和女性的血压敏感性均随年龄增长而增加。我们已经报道了性别差异在丰度上 在SD大鼠(SDR)和C57BL/6J小鼠中沿肾单位的转运蛋白，并使用 建立二态的功能含义的计算模型，例如更健壮的利钠药 年轻女性与男性SDR的反应。肾脏和肌肉转运蛋白对生命周期的反应 从发育到衰老和更年期的转变尚不清楚。我们的首要目标是 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、电解质和液体的动态平衡，以应对生命周期的挑战 雄性和雌性大鼠和小鼠：从发育到衰老，通过雌性特有的挑战 哺乳和更年期，以及饮食中Na+和K+的共同挑战。目标1.检验假设 基线肾功能在生命周期中以性别特有的方式进行适应，以维持液体和 电解质动态平衡。运输者的性别差异什么时候出现？是更强健的利钠作用 年轻的女性和男性在12个月时仍然明显吗？肌肉K+转运体是否表现出影响 K+适应随年龄增长？我们将利用四核心基因型鼠模型将二态现象归因于 性腺激素与性染色体互补的生命周期。目标2.描述女性的生理机制 肾脏对哺乳的适应。肾脏和肾单位功能适应于维持母体内环境平衡吗？ 在哺乳高峰期，以最低的成本？肾功能、ECV和电解质平衡是否恢复到基线水平 在停止哺乳之后？肾外K+稳态(骨骼肌K+转运体和[K+])适应吗 哺乳期间/哺乳后？目的3.检验更年期和年龄减少性别差异和性别差异的假设 增加对盐的敏感性。卵毒素诱导的更年期是否会改变女性肾脏和肌肉转运体 配置文件和功能？盐敏感型高血压是性别依赖吗？更年期后病情恶化？ 实现这些目标将填补关于Na+，K+和 整个生命周期的体量动态平衡和生理学，从而提供了对女性更好的理解 在心血管疾病方面的优势，并在生命周期中指导男女治疗靶点。

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.