Renal electrolyte handling in females vs. males over life cycle

项目摘要 肾功能对于维持有效循环容量（ECV）、电解质稳态和血液循环至关重要。 压力（BP）。肾脏中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。Na+、K+和容量稳态通过调节维持 肾离子和水转运蛋白以肾小管特异性模式表达; K+平衡也取决于 调节肌肉转运蛋白。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，绝经后女性多于65岁以上男性;盐 血压的敏感性随着年龄的增长而增加。我们已经报道了在丰富的性别差异， 在Sprague道利大鼠（SDR）和C57 BL/6 J小鼠中，沿着肾单位沿着转运蛋白，并使用 计算模型，以建立二态性的功能含义，例如更强大的利钠剂 年轻女性与男性SDR的反应。肾脏和肌肉转运蛋白谱如何响应生命周期 从发育到衰老和更年期的转变是未知的。我们的首要目标是 结合联合收割机实验和计算方法来确定肾脏（和肌肉）的功能 适应维持ECV，电解质和液体稳态，以应对生命周期中的挑战， 雄性和雌性大鼠和小鼠：从发育到衰老，通过女性特有的挑战， 哺乳期和绝经期，以及饮食Na+和K+的共同挑战。目标1.检验这一假设 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， 电解质稳态什么时候会出现转运蛋白的性别差异？尿钠排泄越强， 12个月时，年轻女性与男性相比仍然明显？肌肉K+转运蛋白是否表现出影响 随着年龄的增长，K+的适应性如何？我们将利用四个核心基因型小鼠模型来归因二态性沿着 生命周期与性腺激素和性染色体互补的关系。目标二。描述女性的机制 肾脏对泌乳的适应。肾脏和肾单位功能是否适应维持母体内环境稳定 以最小的成本在哺乳高峰期生产？肾功能、ECV和电解质稳态是否恢复至基线 哺乳期停止后？肾外K+稳态（骨骼肌K+转运体和[K+]）是否适应 哺乳期/哺乳期后？目标3：检验更年期和年龄减少性别差异的假设， 增加盐敏感性。卵毒素诱导的绝经改变女性肾脏和肌肉转运蛋白吗 配置文件和功能？盐敏感性高血压是性别依赖性的吗？绝经后病情加重？ 实现这些目标将填补关于Na+、K+和Na+的性别特异性机制的知识空白。 体积稳态和生理学在整个生命周期，因此，提供了一个更好的了解女性 在CVD中的优势，并在整个生命周期中指导两性的治疗靶点。

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.