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 reversible conversion of corticosterone to inactive 11-dehydrocorticosterone, thus regulating glucocorticoid access to mineralocorticoid and perhaps glucocorticoid receptors in vivo. 11 beta-OHSD has been purified from rat liver and an encoding cDNA isolated from a liver library. However, several lines of indirect evidence suggest the existence of at least two isoforms of 11 beta-OHSD, one found predominantly in glucocorticoid receptor-rich tissues and the other restricted to aldosterone-selective mineralocorticoid target tissues and placenta. Here we have examined the effects of chronic (10 day) manipulations of sex-steroid levels on 11 beta-OHSD enzyme activity and mRNA expression in liver, kidney and hippocampus and present further evidence for the existence of a second 11 beta-OHSD isoform in kidney.

Gonadectomized male and female rats were given testosterone, oestradiol or blank silicone elastomer capsules, controls were sham-operated. In male liver, gonadectomy + oestradiol treatment led to a dramatic decrease in both 11 beta-OHSD activity (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 marked increase in 11 beta-OHSD activity (120 +/- 37% rise), which was reversed by oestradiol replacement but not testosterone treatment.

In male kidney, gonadectomy + oestradiol treatment resulted in a marked increase in 11 beta-OHSD activity (103 +/- 4% rise). By contrast, 11 beta-OHSD mRNA expression was almost completely repressed (99 +/- 0.1% decrease) by oestradiol treatment. This effect of oestradiol was reflected in a loss of 11 beta-OHSD mRNA in all regions of the kidney showing high expression by in-situ hybridization. In female kidney, oestradiol replacement also led to an increase in 11 beta-OHSD activity (70 +/- 15% rise) while mRNA expression fell by 95 +/- 3%. None of the treatments had any effect on enzyme activity or mRNA expression in the hippocampus, although transcription starts from the same promoter as liver.

We conclude that (i) sex steroids regulate 11 beta-OHSD enzyme activity and mRNA expression in a tissue-specific manner and (ii) the concurrence 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 high renal activity observed.