A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess

Matthew A Bailey, Janice M Paterson, Patrick W F Hadoke, Nicola Wrobel, Christopher O C Bellamy, David G Brownstein, Jonathan R Seckl, John J Mullins

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The syndrome of apparent mineralocorticoid excess arises from nonfunctional mutations in 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. Loss of 11betaHSD2 permits glucocorticoids to activate the mineralocorticoid receptor, and the hypertension in the syndrome is presumed to arise from volume expansion secondary to renal sodium retention. An 11betaHSD2 null mouse was generated on an inbred C57BL/6J genetic background, allowing survival to adulthood. 11betaHSD2(-/-) mice had BP approximately 20 mmHg higher on average compared with wild-type mice but were volume contracted, not volume expanded as expected. Initially, impaired sodium excretion associated with increased activity of the epithelial sodium channel was observed. By 80 days of age, however, channel activity was abolished and 11betaHSD2(-/-) mice lost salt. Despite the natriuresis, hypertension remained but was not attributable to intrinsic vascular dysfunction. Instead, urinary catecholamine levels in 11betaHSD2(-/-) mice were double those in wild-type mice, and alpha1-adrenergic receptor blockade rescued the hypertensive phenotype, suggesting that vasoconstriction contributes to the sustained hypertension in this model. In summary, it is proposed that renal sodium retention remains a key event in apparent mineralocorticoid excess but that the accompanying hypertension changes from a renal to a vascular etiology over time.
Original languageEnglish
Pages (from-to)47-58
Number of pages12
JournalJournal of the American Society of Nephrology
Volume19
Issue number1
Early online date21 Nov 2007
DOIs
Publication statusPublished - Jan 2008

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