Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension
Background—The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss of function mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), allowing inappropriate activation of the mineralocorticoid receptor (MR) by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron but 11βHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11βHSD2 brain-specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults.
Methods and Results—Basal blood pressure, electrolytes and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3-times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing intrinsic salt-resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt-sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals.
Conclusions—Reduced 11βHSD2 activity in the brain does not intrinsically cause hypertension but promotes a hunger for salt and a transition from salt-resistance to salt-sensitivity. Our data suggest that 11βHSD2-positive neurons integrate salt-appetite and the blood pressure response to dietary sodium through an MR-dependent pathway. Therefore, central MR antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.
- Received September 24, 2015.
- Revision received February 3, 2016.
- Accepted February 12, 2016.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.