Renal electrolyte handling in females vs. males over life cycle

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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.