LUNG EPITHELIAL NA CHANNEL SUBUNITS ARE DIFFERENTIALLY REGULATED DURING DEVELOPMENT AND BY STEROIDS

Because the a-subunit of the rat lung epithelial Na channel (rENaC) is not expressed until late fetal gestation, the developmental immaturity of alpha-rENaC may be involved in the premature fetal lung's inability to mount a Na-absorptive response to appropriate agonists. As previous work has shown that the beta- and gamma-rENaC subunits of the Na channel are required for maximal alpha-rENaC activity, we determined their developmental expression in the fetal lung. In addition, because thyroid and corticosteroid therapy can mature the in vivo fetal lamb lung's ability to transport Na, we wished to determine whether such treatment increased the expression of alpha-, beta-, and gamma-rENaC. Lungs were harvested from normal rat fetuses of 17 through 22 days gestation (term = 22 days), normal rat pups during the first week of life, and adult rats. Initial expression of alpha-rENaC was detected at 19 days gestation and progressively increased in utero. beta- and gamma-rENaC mRNA were not detected until 21 and 22 days gestation, and then only at very low levels. During the first week after birth, the levels of alpha-rENaC declined, whereas beta- and gamma-rENaC mRNA levels increased. This pre- and postnatal pattern of alpha-rENaC expression correlates with the endogenous glucocorticosteriod levels in the fetus and the rat pup's early postnatal corticosteroid resistance. Combined or separate treatment of pregnant rats (16 through 22 days gestational age) with thyroid-releasing hormone (TRH) and/or dexamethasone (Dex) for 48 h showed that Dex, but not TRH, could increase fetal lung alpha-rENaC mRNA levels. In addition, Dex was effective only during the canalicular stage of fetal lung development. None of these treatments increased the expression of beta- or gamma-rENaC subunits. The Dex effect on in vivo expression of alpha-rENaC occurred within 8 h. Neither combined nor separate hormonal therapy increased mRNA levels of alpha(1)- or beta(1)-isoforms of Na-K-ATPase. They also did not induce the expression of alpha(2)-, alpha(3)-, or beta(2)-isoforms of Na-K-ATPase. These results demonstrate that the ontogeny of alpha-, beta-, and gamma-rENaC is differentially regulated in the fetal and immediate postnatal lung and that the subunits similarly show differing responses to exogenous corticosteroids.