11-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY AND CORTICOSTEROID HORMONE ACTION

In normal physiology 11 beta-hydroxysteroid dehydrogenase (11 beta-OHS D) protects the mineralocorticoid receptor (MR) from glucocorticoid ex cess. In the rat, however, 11 beta-OHSD mRNA and activity is widesprea d, suggesting that it may also play a role in regulating ligand access to the glucocorticoid receptor (GR). We have studied the role of the 11 beta-OHSD in modulating corticosteroid hormone action in rat pituit ary GH3 cells (glucocorticoids inhibit prolactin gene transcription) a nd renal epithelial NRK-52E cells (mineralocorticoids increase Na-K AT Pase subunit gene expression) in culture. Both cell lines express high levels of 11 beta-OHSD activity, and Northern/Western blot analyses u sing a rat cDNA probe and antisera raised against rat liver 11 beta-OH SD reveal a single 1.4 Kb mRNA encoding an enzyme of molecular size 34 kDa. In GH3 cells, prolactin gene transcription was unaffected by cor ticosterone (B) in noses of 10(-8) to 10(-6) M. When 11 beta-OHSD acti vity was inhibited with the licorice derivative, glycyrrhetinic acid ( GE); however, 10(-6) M B inhibited prolactin (PRL) mRNA levels to the same degree as an equimolar concentration of the GR agonist RU 28362. This effect was blocked by co-incubation sith the GR antagonist RU 384 86. In NRK 52-E cells, co-incubation with B and GE resulted in a marke d increase in alpha 1/beta 1 Na-K ATPase subunit mRNA levels when comp ared with GE and/or B alone and this effect could be blocked by admini stration of the MR antagonist RU 26752. 11 beta-OHSD is an important p re-receptor signaling pathway for both the GR and MR, find as such its activity must be considered in the analysis of corticosteroid hormone action.