Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2

Yuri Kotelevtsev, R W Brown, S Fleming, Christopher Kenyon, Christopher R. W. Edwards, Jonathan R. Seckl, John J. Mullins

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    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.
    Original languageEnglish
    Pages (from-to)683-689
    Number of pages7
    JournalJournal of Clinical Investigation
    Volume103
    Issue number5
    DOIs
    Publication statusPublished - 1999

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    Kotelevtsev, Y., Brown, R. W., Fleming, S., Kenyon, C., Edwards, C. R. W., Seckl, J. R., & Mullins, J. J. (1999). Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2. Journal of Clinical Investigation, 103(5), 683-689. https://doi.org/10.1172/JCI4445