Modeling Sex Differences in the Effects of Diuretics in Renal Epithelial Transport during Angiotensin II-induced Hypertension

Abstract

Chronic angiotensin II (AngII) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females, perhaps unexpectedly, given the rodent kidney, which plays a key role in blood pressure regulation, exhibit marked sex differences. Those sex differences include morphology, hemodynamics, and, under healthy (undrugged) conditions, solute and electrolyte transporter abundance. Notably, compared to the male rat nephron, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule, but higher Na+ transporter activities along the distal segments. AngII infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream, to different extents in the two sexes. The goals of this study are (i) to understand how the sexually dimorphic responses differentially impact segmental electrolyte transport following a 14- day AngII infusion, and (ii) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. To achieve those goals, we developed sex-specific computational models of renal epithelial transport of electrolytes and water. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with a stronger effect in males. Due to the downstream shift of Na+ transport load in hypertension, all three diuretic classes are predicted to induce stronger natriuretic and diuretic effects under hypertension compared to normotension, especially in females. New and NoteworthySex differences in the prevalence of hypertension are found in humans and animal models. The kidney, which plays an important role in blood pressure regulation, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport. Simulations results also explain sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics.