DHEA induces 11β-HSD2 by acting on CCAAT/enhancer-binding proteins

Abstract

11β-Hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2 catalyze the interconversion of inactive and active glucocorticoids. Impaired regulation of these enzymes has been associated with obesity, diabetes, hypertension, and cardiovascular disease. Previous studies in animals and humans suggested that dehydroepiandrosterone (DHEA) has antiglucocorticoid effects, but the underlying mechanisms are unknown. In this study, DHEA treatment markedly increased mRNA expression and activity of 11β-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice and Sprague-Dawley rats. DHEA-treated rats tended to have reduced urinary corticosterone to 11-dehydrocorticosterone ratios. It was found that CCAAT/enhancer-binding protein-α (C/EBP-α) and C/EBP-β regulated HSD11B2 transcription and that DHEA likely modulated the transcription of 11β-HSD2 in a phosphatidylinositol-3 kinase/Akt-dependent manner by increasing C/EBP-β mRNA and protein expression. Moreover, it is shown that C/EBP-α and C/EBP-β differentially regulate the expression of 11β-HSD1 and 11β-HSD2. In conclusion, DHEA induces a shift from 11β-HSD1 to 11β-HSD2 expression, increasing conversion from active to inactive glucocorticoids. This provides a possible explanation for the antiglucocorticoid effects of DHEA. Copyright © 2008 by the American Society of Nephrology.