Conditional Deletion Of Hsd11b2 In The Brain Causes Salt Appetite And Hypertension

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Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and HypertensionCLINICAL PERSPECTIVE | Circulation
Abstract

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 by endogenous glucocorticCongenital, acquired (licorice ingestion), or age-related deficiency in the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) promotes low-renin hypertension, hypokalemia, and sodium retention attributable to unregulated activation of the mineralocorticoid receptor (MR) by endogenous cortisol (corticosterone in rodents).1Reduced 11βHSD2 activity causes a spectrum of disease: genetic ablation of the enzyme causes the life-threatening syndrome of Apparent Mineralocorticoid Excess (AME; OMIM +218030), diagnosed in early childhood2; reduced activity causes hypertension in adults,3and loss-of-function variants in HSD11B2 are associated with increased blood pressure per se or with salt sensitivity of blood pressure.4,5oid. 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 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 11βHSD2 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 11βHSD2-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.

Congenital, acquired (licorice ingestion), or age-related deficiency in the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) promotes low-renin hypertension, hypokalemia, and sodium retention attributable to unregulated activation of the mineralocorticoid receptor (MR) by endogenous cortisol (corticosterone in rodents).1Reduced 11βHSD2 activity causes a spectrum of disease: genetic ablation of the enzyme causes the life-threatening syndrome of Apparent Mineralocorticoid Excess (AME; OMIM +218030), diagnosed in early childhood2; reduced activity causes hypertension in adults,3and loss-of-function variants in HSD11B2 are associated with increased blood pressure per se or with salt sensitivity of blood pressure.4,5
 

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