REGULATION OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE BY SEX STEROIDS IN-VIVO - FURTHER EVIDENCE FOR THE EXISTENCE OF A 2ND DEHYDROGENASE IN RAT-KIDNEY

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) catalyses the reve rsible conversion of corticosterone to inactive 11-dehydrocorticostero ne, thus regulating glucocorticoid access to mineralocorticoid and per haps glucocorticoid receptors in vivo. 11 beta-OHSD has been purified from rat liver and an encoding cDNA isolated from a liver library. How ever, several lines of indirect evidence suggest the existence of at l east two isoforms of 11 beta-OHSD, one found predominantly in glucocor ticoid receptor-rich tissues and the other restricted to aldosterone-s elective mineralocorticoid target tissues and placenta. Here we have e xamined the effects of chronic (10 day) manipulations of sex-steroid l evels on 11 beta-OHSD enzyme activity and mRNA expression in liver, ki dney and hippocampus and present further evidence for the existence of a second 11 beta-OHSD isoform in kidney. Gonadectomized male and fema le rats were given testosterone, oestradiol or blank silicone elastome r capsules, controls were sham-operated. In male liver, gonadectomy oestradiol treatment led to a dramatic decrease in both 11 beta-OHSD a ctivity (69 +/- 8% decrease) and mRNA expression (97 +/- 1% decrease). Gonadectomy and testosterone replacement had no effect on male liver 11 beta-OHSD. However, in female liver, where 11 beta-OHSD activity is approximately 50% of that in male liver, gonadectomy resulted in a ma rked increase in 11 beta-OHSD activity (120 +/- 37% rise), which was r eversed by oestradiol replacement but not testosterone treatment. In m ale kidney, gonadectomy + oestradiol treatment resulted in a marked in crease in 11 beta-OHSD activity (103 +/- 4% rise). By contrast, 11 bet a-OHSD mRNA expression was almost completely repressed (99 +/- 0.1% de crease) by oestradiol treatment. This effect of oestradiol was reflect ed in a loss of 11 beta-OHSD mRNA in all regions of the kidney showing high expression by in-situ hybridization. In female kidney, oestradio l replacement also led to an increase in 11 beta-OHSD activity (70 +/- 15% rise) while mRNA expression fell by 95 +/- 3%. None of the treatm ents had any effect on enzyme activity or mRNA expression in the hippo campus, although transcription starts from the same promoter as liver. We conclude that (i) sex steroids regulate 11 beta-OHSD enzyme activi ty and mRNA expression in a tissue-specific manner and (ii) the concur rence of increased enzyme activity with near absent 11 beta-OHSD mRNA expression in the kidney following oestradiol treatment suggests that an additional gene product is responsible, at least in part, for the h igh renal activity observed.