DIFFERENTIAL EXPRESSION OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 ANDDEHYDROGENASE-2 IN THE DEVELOPING OVINE FETAL LIVER AND KIDNEY

In adult mammals, liver and kidney are the two major sites of biosynth esis for 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) 1 and 2 re spectively. In the present study, the expression of these two isozymes in the developing ovine fetal liver and kidney was characterized. Liv ers and kidneys were obtained from fetal sheep at days 85, 100-120 and 140-143 of gestation (term= 145 days). Tissue levels of 11 beta-HSD2 mRNA were assessed by Northern blot analysis. 11 beta-HSD dehydrogenas e and reductase activities in tissue homogenates were determined by a radiometric conversion assay using cortisol and cortisone as physiolog ical substrates respectively. The unidirectional 11 beta-HSD2 dehydrog enase activity was identified by its distinct cofactor preference (NAD ), and by its unique ability to metabolize dexamethasone (Dex). In the liver, 11 beta-HSD1 dehydrogenase and reductase activities were prese nt by day 85, and their levels did not change between days 85 and 100- 120 but increased more than twofold at days 140-143. This was consiste nt with changes we reported previously in the fetal hepatic 11 beta-HS D1 mRNA. 11 beta-HSD1 reductase activity was always higher than the de hydrogenase activity. 11 beta-HSD2 mRNA and activity were undetectable in the fetal liver at all three ages. By contrast, 11 beta-HSD2 mRNA was present in the fetal kidney by day 85, and its abundance increased progressively thereafter. There was a parallel increase in the renal 11 beta-HSD2 activity. Dex was also converted to 11-dehydro-Dex by the fetal kidney. In keeping with the absence of the full-length 11 beta- HSD1 mRNA, 11 beta-HSD1 activity was undetectable in the kidney. These results indicate that (1) 11 beta-HSD1 and 2 genes are differentially expressed and regulated in the fetal liver and kidney during developm ent, (2) since the hepatic 11 beta-HSD1 reductase activity is always h igher than the dehydrogenase activity, the fetal liver may be a potent ial extra-adrenal source of cortisol, and (3) 11 beta-HSD2 in the kidn ey may play a very important role in protecting the fetus from elevate d levels of bioactive glucocorticoids.