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Publication : Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension.

First Author  Evans LC Year  2016
Journal  Circulation Volume  133
Issue  14 Pages  1360-70
PubMed ID  26951843 Mgi Jnum  J:244690
Mgi Id  MGI:5913469 Doi  10.1161/CIRCULATIONAHA.115.019341
Citation  Evans LC, et al. (2016) Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension. Circulation 133(14):1360-70
abstractText  BACKGROUND: The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11betaHSD2 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 11betaHSD2 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 the 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 11betaHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11betaHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.
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