Phenotypic analysis of mice bearing targeted deletions of 11beta-hydroxysteroid dehydrogenases 1 and 2 genes.

ABSTRACT

The glucocorticoid metabolising enzymes, 11beta-hydroxysteroid dehydrogenases (11beta-HSD), play a critical role in determining the availability of glucocorticoids to activate their receptors and hence modulate target gene transcription. There are two isozymes, 11beta-HSD-1 and -2, which act in opposing directions. 11beta-HSD-2 acts as a dehydrogenase, converting active corticosterone (cortisol in humans) to its inactive 11-keto derivative (11-dehydrocorticosterone in rodents and cortisone in humans), whereas 11beta-HSD-1 acts as a reductase, regenerating active glucocorticoids in a tissue-specific manner. Owing to the lack of specific inhibitors of these enzymes, it has been difficult to confirm the roles and determine the importance of these enzymes in vivo. Hence, to address this, we produced transgenic mice with null-mutations in the genes encoding the 11beta-HSD-1 or 11beta-HSD-2 enzymes. 11beta-HSD-2 -/- mice show signs of hypertension, hypotonic polyuria, hypokalemia and hypochloremia. These symptoms arise from illicit activation of mineralocorticoid receptors by glucocorticoids, in the absence of the protective action of 11beta-HSD-2. The phenotype is directly comparable to the Syndrome of Apparent Mineralocorticoid Excess, seen in humans with mutations in the 11beta-HSD-2 gene. Mice lacking 11beta-HSD-1, however, show a more subtle phenotype with reduced activation of glucocorticoid-induced processes. They were unable to convert 11-dehydrocorticosterone to corticosterone in vivo, confirming 11beta-HSD-1 as the sole 11-reductase in the mouse. They have elevated circulating levels of plasma corticosterone levels and adrenal hyperplasia, but they also have attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to fasting, and lower glucose levels in response to obesity or stress. Overall, these transgenic models have proved very useful for elucidating the roles of 11beta-HSDs in vivo and will be a unique resource for investigating the importance of each enzyme in the diverse actions of glucocorticoids.