Effect of pregnancy and hypertension on kidney function in female rats: Modeling and functional implications

Abstract

During pregnancy, major adaptations in renal morphology, hemodynamics, and transport occur to achieve volume and electrolyte retention required to support a healthy pregnancy. Additionally, during pregnancies complicated by chronic hypertension, altered renal function from normal pregnancy occurs. The goal of this study is to analyze how inhibition of key transporters impacts gestational kidney function as well as how altered renal function during chronic hypertension impacts renal function during pregnancy. To do this, we developed epithelial cell-based computational models of solute and water transport in the kidneys of a female rat in mid- and late pregnancy. We simulated the effect of key individual pregnancy-induced changes on renal Na⁺ and K⁺ transport: proximal tubule length, Na⁺/H⁺ exchanger isoform 3 (NHE3) activity, epithelial Na⁺ channel activity (ENaC), K⁺ secretory channel expression, and H⁺-K⁺-ATPase activity. Additionally, we conducted simulations on the effects of inhibition and knockout of the ENaC and H⁺-K⁺-ATPase transporters on virgin and pregnant rat kidneys. Our simulation results predicted that the ENaC and H⁺-K⁺-ATPase transporters are essential for sufficient Na⁺ and K⁺ reabsorption during pregnancy. Last, we developed models to capture changes made during hypertension in female rats and considered what may occur when a rat with chronic hypertension becomes pregnant. Model simulations predicted that in hypertension for a pregnant rat there is a similar shift in Na⁺ transport from the proximal tubules to the distal tubules as in a virgin rat.