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Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2.

TitleHypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2.
Publication TypeJournal Article
Year of Publication1999
AuthorsKotelevtsev Y, Brown WR, Fleming S, Kenyon CJ, Edwards CR, Seckl JR, Mullins JJ
JournalJ Clin Invest
Volume103
Issue5
Pagination683-9
Date Published1999 Mar
ISSN0021-9738
Keywords11-beta-Hydroxysteroid Dehydrogenases, Animals, Corticosterone, Female, Hydroxysteroid Dehydrogenases, Hypertension, Male, Mice, Mice, Knockout
Abstract

Deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11beta-HSD2 gene. Homozygous mutant mice (11beta-HSD2(-/-)) appear normal at birth, but approximately 50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11beta-HSD2(-/-) mice are markedly hypertensive, with a mean arterial blood pressure of 146 +/- 2 mmHg, compared with 121 +/- 2 mmHg in wild-type controls and 114 +/- 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11beta-HSD2(-/-) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension.

DOI10.1172/JCI4445
Alternate JournalJ. Clin. Invest.
PubMed ID10074485
PubMed Central IDPMC408118
Grant List / / Wellcome Trust / United Kingdom