A link between fertility and K+ homeostasis: role of the renal H,K-ATPase type 2

Abstract

Renal K(+) retention is activated during pregnancy through a mechanism unknown to date. Here, we showed that the renal stimulation of H,K-ATPase type 2 (HKA2), whose expression was recently identified to be progesterone-dependent, is part of the mechanism favoring K(+) accumulation during gestation. Moreover, investigation of the gestational phenotype of HKA2-null mice compared to their wild-type (WT) littermate revealed a decrease in fertility (gestation was successful in 33 % of HKA2-null mice vs. 83 % of WT mice) and in litter size (6.5 ± 0.6 and 7.8 ± 0.4 fetuses per litter, respectively). We also observed that urinary K(+) excretion decreased by 20 % and plasma K(+) concentration rose slightly (11 %) in WT mice during gestation (relative to basal conditions). In contrast, the renal excretion of K(+) and plasma K(+) levels in HKA2-null mice remained constant during gestation, whereas fecal K(+) excretion increased. As a consequence, HKA2-null mice did not accumulate K(+) in their extracellular compartment as efficiently as WT mice did. Finally, the link between inefficient K(+) balance adaptations and gestational complications was established when we observed that these complications could be reversed with an increased K(+) uptake. Altogether, these results define a novel physiological role for the HKA2 transporter and uncover a link between K(+) metabolism and fertility.

H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K+ restriction

“…As already observed [22,33], the dietary K + restriction induced profound physiological changes (Table 1) that differ in their kinetics between WT and HKA2-null mice, including parallel loss of weight and food intake. HKA2-null mice have been shown to loose K + in their feces [22,33,34] thus accelerating the development of hypokalemia that is already present after only 4 days of K + restriction whereas WT mice remained normokalemic (3.16 ± 0.11 vs 3.60 ± 0.09 mM, p = 0.005).…”

“…This last process has been challenged by the lack of renal phenotype in HKA2-null mice fed a low-K + diet [22]. More recently, however, we have discovered that HKA2-null mice do not retain K + correctly during gestation [34] and exhibit circadian defects in urinary excretion of K + that affects plasma K + levels [33]. Moreover, when we acutely inhibited the K + -restriction-induced stimulation of HKA2 by blocking the nuclear progesterone receptor, the mice displayed a higher loss of K + in their urine and a lower plasma K + level [12].…”

H-K-ATPase type 2: relevance for renal physiology and beyond

“…The finding that progesterone is a hormonal regulator of HKA2 expression led us to investigate the putative role of this transporter in the renal adaptation to gestation (76). Gestation has been shown to induce renal K ϩ retention, as needed to cope with fetal development (54), when many factors favor renal K ϩ loss instead (increase of glomerular filtration, stimulation of aldosterone production, etc.).…”

P2C-Type ATPases and Their Regulation

“…High K + concentrations are needed for some functions of H + /K + -ATPase; for example, during fetal development, a HKα 2 -null mice may have problems with placental perfusion or even partial abortion. These may result from failure of compartment volume adjustment, most likely because of a high plasma K + concentration [48]. Both benign prostate hyperplasia and prostatic tumor tissue had increased non-gastric H + /K + -ATPase compared with normal prostate cells, not only in the basal cells and membrane but also along the epithelium and cytosol [49].…”