11β-Hydroxysteroid dehydrogenase activity and corticosteroid hormone action

Abstract

In normal physiology 11β-hydroxysteroid dehydrogenase (11β-OHSD) protects the mineralocorticoid receptor (MR) from glucocorticoid excess. In the rat, however, 11β-OHSD mRNA and activity is widespread, suggesting that it may also play a role in regulating ligand access to the glucocorticoid receptor (GR). We have studied the role of the 11β-OHSD in modulating corticosteroid hormone action in rat pituitary GH3 cells (glucocorticoids inhibit proclactin gene transcription) and renal epithelial NRK-52E cells (mineralocorticoids increase Na-K ATPase subunit gene expression) in culture. Both cell lines express high levels of 11β-OHSD activity, and Northern/Western blod analysis using a rat cDNA probe and antisera raised against rat liver 11β-OHSD reveal a single 1.4 Kb mRNA encoding an enzyme of molecular size 34 kDa. In GH3 cells, prolactin gene transcription was unaffected by corticosterone (B) in doses of 10 −8 to 10 −6 M. When 11β-OHSD activity 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 concentration of the GR agonist RU 28362. This effect was blocked by co-incubation with the GR antagonist RU 38486. In NRK 52-E cells, co-incubation with G and GE resulted in a marked increase in α1/β1 Na-K ATPase subunit mRNA levels when compared with GE and/or B alone and ths effect could be blocked by administration of the MR antagonist RU 26752. 11β-OHSD is an important pre-receptor signalling pathway for both the GR and MR, and as such its activity must be considered in the analysis of corticosteroid hormone action.