title: Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure.
abstract: 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.
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Eilidh
authors.initials: E
authors.lastname: Craigie
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Dawn E W
authors.initials: DEW
authors.lastname: Livingstone
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.|Stem Cell Genome Modification Laboratory, Puschino State University, Russia.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Kotelevtsev
authors.affiliation: Dietetics, Nutrition and Biological Sciences Research, Queen Margaret University, Edinburgh, Scotland, UK.
authors.forename: Emad A S
authors.initials: EAS
authors.lastname: Al-Dujaili
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D006727:Hormone Antagonists / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced* / Q000235:genetics*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D015735:Mifepristone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2