Renal sodium handling in hypertension: impact of age, sex, and dietary potassium

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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.