Cortisol at MR Mediate Fetal Physiologic/Genomic Effects

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The overall goal of these studies is to test the hypothesis that for most of gestation, the concentrations of free cortisol in the fetus exert physiologic actions via the high affinity (corticosteroid type I) mineratocorticoid receptors (MR) rather than the lower affinity, but higher capacity, glucocorticoid receptors (GR). It is well established that the high levels of cortisol produced by the fetal adrenal at the time of delivery are important for normal organ maturation, and that these effects are mediated by GR. The presence of MR in fetal tissues as early as mid-gestation suggests that there may be effects of low concentrations of cortisol via MR, even before the time of fetal maturation. We will test whether cortisol action at MR receptors mediates effects on fetal volume through specific MR-target genes in the lung and/or kidney, and on hypothalamo- pituitary-adrenal function via MR-target genes in the hippocampus. The relative activity of corticosteroids in the tissues will be related to plasma levels of corticosteroids, activity of 11 t_ hydroxysteroid dehydrogenase and reductase activities (1ll3HSD), levels of MR and GR in the tissue, and transactivation to alter gene expression. MR target genes, including the early response genes, Sgk and K-Ras, and more slowly induced genes for ENaC, Na/K ATPase and 5HT1A, MR and GR will be tested. To test this hypothesis, experiments were designed to: 1) quantitate the protein, mRNA and relative occupancy by endogenous steroids of MR and GR, and activity of 1I_HSD in fetal tissues such as lung, kidney, heart, hippocampus, brainstem and pituitary in late gestation fetuses both before and after the time of fetal adrenal maturation (120-140d); 2) test the effect of blockade of fetal MR receptors on physiologic actions known in the adult to be MR-mediated, renal function and ACTH secretion, and on a possible MR-mediated function in the fetus, lung liquid reabsorption; 3) test for a relation between MR occupancy and these physiologic effects, and on the proposed target genes for MR action in hippocampus, kidney, and by analogy, fetal lung; 4) to compare the effect of combined MR and GR occupancy on these genes and physiologic actions.