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

The glucocorticoid metabolising enzymes, 11 beta -hydroxysteroid dehydrogen ases (11 beta -HSD), play a critical role in determining the availability o f glucocorticoids to activate their receptors and hence modulate target gen e transcription. There are two isozymes. 11 beta -HSD-1 and -2, which act i n opposing directions. 11 beta -HSD-2 acts as a dehydrogenase. converting a ctive corticosterone (cortisol in humans) to its inactive 11-keto derivativ e (11-dehydrocorticosterone in rodents and cortisone in humans), whereas 11 beta -HSD-1 acts as a reductase. regenerating active glucocorticoids in a tissue-specific manner, owing to the lack of specific inhibitors of these e nzymes, it has been difficult to confirm the roles and determine the import ance of these enzymes in vivo. Hence. to address this, we produced transgen ic mice with null-mutations in the genes encoding the 11 beta -HSD-1 or 11 beta -HSD-2 enzymes. 11 beta -HSD-2 -/- mice show signs of hypertension, hy potonic polyuria, hypokalemia and hypochloremia. These symptoms arise from illicit activation of mineralocorticoid receptors by glucocorticoids. in th e;absence of the protective action of 11 beta -HSD-2. The phenotype is dire ctly comparable to the Syndrome of Apparent Mineralocorticoid Excess, seen in humans, with mutations in the 11 beta -HSD-2 gene. Mice lacking 11 beta -HSD-1, however, show a more subtle phenotype with reduced activation of gl ucocorticoid-induced processes. They were unable to convert 11-dehydrocorti costerone to corticosterone in vivo, confirming 11 beta -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 attenuate d 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 11 beta -HSDs in vivo and will be a unique resource for investigating t he importance of each enzyme in the diverse actions of glucocorticoids. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.