Differential maturation of Na+,K+-ATPase in the rat : transcriptional regulation by glucocorticoids

Na+,K+-ATPase is a ubiquitous transmembrane enzyme that creates the electrochemical gradient across the cell membrane. Na+,K+-ATPase activity is low in many immature tissues. Since the enzyme provides the driving force for a variety of ion transporters, it is likely that the enzyme availability is a rate-limiting step for cellular function in immature cells. In the rat, the upsurge in circulating GC that occurs during development induces enzyme maturation in many organs. Previous studies have shown that glucocorticoids (GC) contribute to the maturation of rat renal Na+,K+-ATPase. This study was therefore aimed to further investigate the mechanisms by which GC regulate maturation of Na+,K+-ATPase and other epithelial ion transporters.

We found that a saturating dose of betamethasone up-regulates Na+,K+-ATPase mRNA about 4-fold in the preweaning kidney, heart, stomach and colon as well as in the fetal lung but not in the brain. The inductive effect of GC was tissue and age dependent, it occurred with physiological doses and was observed only during a limited period of life. The maximal sensitivity of both Na+,K+-ATPase alpha1 and beta1 mRNAs to GC was found in the lung in the perinatal period and in the kidney in the preweaning period. In the preweaning heart the GC inductive effect was isoform specific. GC directly increased the Na+,K+-ATPase gene transcription rate about 3-fold and no protein synthesis was required for this action. Moreover, this study suggested that the interaction between GC receptors and Na+,K+-ATPase promoter in infant kidney may be modulated by an auxiliary factor. We then compared the effects of GC and aldosterone on the maturation of the basolateral Na+,K+-ATPase the luminal H+,K+-ATPase and the amiloride-sensitive Na+-channel. We found that the strong GC stimulation of Na+,K+-ATPase occurred more rapidly than the moderate effect on other ion transporters. The results of this study also indicated that the GC receptor and not the mineralocorticoid receptor mediates the response. Finally, we showed that in the adult kidney, in contrast to the infantone, GC mainly regulate Na+,K+-ATPase at post-translational level, most likely by modulating the enzyme incorporation in the cellular membrane.

These results suggest that the physiologic upsurge of GC that occurs at birth may stimulate the maturation of Na+,K+-ATPase to improve pulmonary function in the neonate; whereas the preweaning GC upsurge may accelerate Na+,K+-ATPase maturation and therefore enhance tissue function in the kidney, stomach and colon. GC also act as a "molecular switch" to stimulate the terminal differentiation of cardiac Na+,K+-ATPase in the preweaning period. We speculate that Na+,K+-ATPase genes are primary targets for GC during development and that this stimulation plays a central role in the postnatal maturation of epithelial ion transport capacity.