Bailey, M A and Craigie, E and Livingstone, D E W and Kotelevtsev, K V and Al-Dujaili, Emad A S and Kenyon, C J and Mullins, J J (2011) Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure. Hypertension , 57 (3). pp. 515-520. ISSN 0194911X
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Official URL: http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.163782
Salt sensitivity of blood pressure is an independent risk factor for cardiovascular morbidity. Mechanistically, abnormal mineralocorticoid action and subclinical renal impairment may blunt the natriuretic response to high sodium intake, causing blood pressure to rise. 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) controls ligand access to the mineralocorticoid receptor, and ablation of the enzyme causes severe hypertension. Polymorphisms in HSD11B2 are associated with salt sensitivity of blood pressure in normotensives. In this study, we used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2) to define the mechanisms linking reduced enzyme activity to salt sensitivity of blood pressure. A high-sodium diet caused a rapid and sustained increase in blood pressure in Hsd11b2 mice but not in wild-type littermates. During the adaptation to high-sodium diet, heterozygotes displayed impaired sodium excretion, a transient positive sodium balance, and hypokalemia. After 21 days of high-sodium feeding, Hsd11b2 mice had an increased heart weight. Mineralocorticoid receptor antagonism partially prevented the increase in heart weight but not the increase in blood pressure. Glucocorticoid receptor antagonism prevented the rise in blood pressure. In Hsd11b2 mice, high-sodium feeding caused suppression of aldosterone and a moderate but sustained increase in corticosterone. This study demonstrates an inverse relationship among 11βHSD2 activity, heart weight, and blood pressure in a clinically important context. Reduced activity causes salt sensitivity of blood pressure, but this does not reflect illicit activation of mineralocorticoid receptors by glucocorticoids. Instead, we have identified a novel interaction among 11βHSD2, dietary salt, and circulating glucocorticoids. © 2011 American Heart Association, Inc.
|Deposited On:||03 May 2011 09:16|
|Last Modified:||04 Oct 2012 09:53|
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