A role for mineralocorticoid receptors in the physiology of the ovine fetus: effects on ACTH and lung liquid composition.

In the human and ovine fetus, the presence of 11ß-hydroxysteroid dehydrogenase 1 allows cortisol and other corticosteroids to act at mineralocorticoid receptors (MRs) in lung and brain. To test the physiologic role of MRs in the late gestation fetus, fetal lambs were infused with a specific MR antagonist for 12 h. Infusion of the MR antagonist significantly increased plasma ACTH and cortisol concentrations. Infusion of the MR antagonist also significantly increased fetal Pco2 and hematocrit, and decreased fetal pH, but did not alter fetal heart rate or blood pressure. Infusion of the MR antagonist altered the ratio of Na⁺ to K⁺ in lung fluid but did not alter the rate of production of lung liquid or the expression of the epithelial sodium channel α or of the Na,K ATPaseα1 in lung. These results suggest that corticosteroids act at MR to regulate ACTH and blood volume and modulate lung fluid composition in the fetus, but basal levels of corticosteroids do not alter lung liquid production rate through effects on MR.

Expression of ENaC subunits, chloride channels, and aquaporins in ovine fetal lung: ontogeny of expression and effects of altered fetal cortisol concentrations.

Transition of the epithelium of the fetal lung from fluid secretion to fluid reabsorption requires changes in the expression of ion channels. Corticosteroids regulate expression of several of these channels, including the epithelium sodium channel (ENaC) subunits and aquaporins (AQP). We investigated the ontogenetic changes in these ion channels in the ovine fetal lung during the last half of gestation, a time of increasing adrenal maturation. Expression of the mRNAs for the chloride channels, cystic fibrosis transmembrane conductance regulator (CFTR), and chloride channel 2 (CLCN2) decreased with age. Expression of mRNAs for AQP1, AQP5, and for subunits of ENaC (alpha, beta, gamma) increased with age. In the fetal sheep the expression of ENaCbeta mRNA was dramatically higher than the expression of ENaCalpha or ENaCgamma, but expression of ENaCbeta protein decreased with maturation, although the ratio of the mature (112 kDa) to immature (102 kDa) ENaCbeta protein increased with age, particularly in the membrane fraction. In contrast, ENaCalpha mRNA and protein both increase with maturation, and the mature form of ENaCalpha (68 kDa) predominates at all ages. A modest increase in fetal cortisol, within the range expected to occur naturally in late gestation but prior to active labor, increased ENaCalpha mRNA but not ENaCbeta, ENaCgamma, or AQP mRNAs. We conclude that in the ovine fetal lung, appearance of functional sodium channels is associated with induction of ENACalpha and ENaCgamma, and that ENaCalpha expression may be induced by even small, preterm increases in fetal cortisol.