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

Throughout pregnancy, the kidneys undergo significant adaptations in morphology, hemodynamics, and transport to achieve the 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 critical transporters affects gestational kidney function as well as how renal function is affected during chronic hypertension in pregnancy. To do this, we developed epithelial cell-based multi-nephron computational models of solute and water transport in the kidneys of a female rat in mid- and late pregnancy. We simulated the effects 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 to predict 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.