What do dietary K+ restriction and pregnancy share in common?

Modern dietary habits are characterized by high‐Na+ and low‐K+ intakes, each of which has been correlated with a higher risk for hypertension. In this study, we examined whether long‐term variations in the intake of Na+ and K+ induce lasting changes in the plasma concentration of circulating steroids. We first developed a mathematical model of steroidogenesis in mice that predicted that mice increase their plasma progesterone levels specifically in response to K+ depletion. This prediction was confirmed by experimental measurements in both male mice and men. Further investigations revealed that progesterone regulates renal K+ handling by stimulating the expression of H,K‐ATPase type 2 (HKA2) under K+ restriction conditions. This new pathway linking progesterone, HKA2 expression and K+ retention was then investigated in the context of pregnancy, a condition in which progesterone is elevated and K+ retained. We showed that, during the late part of gestation in mice, the decrease in urinary K+ excretion is accompanied by overexpression of HKA2. Conversely, HKA2 knock‐out mice are unable to efficiently retain K+ during gestation. This occurs in parallel with a higher mortality rate during gestation in this strain compared to wild‐type mice. All together, our results suggest the existence of a hereto unknown regulatory process involving progesterone, its nuclear receptor, the HKA2 and renal K+ retention.