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Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension. Circulation 2016 Apr 05;133(14):1360-70

Date

03/10/2016

Pubmed ID

26951843

Pubmed Central ID

PMC4819772

DOI

10.1161/CIRCULATIONAHA.115.019341

Scopus ID

2-s2.0-84960435245 (requires institutional sign-in at Scopus site)   67 Citations

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 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 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.

Author List

Evans LC, Ivy JR, Wyrwoll C, McNairn JA, Menzies RI, Christensen TH, Al-Dujaili EA, Kenyon CJ, Mullins JJ, Seckl JR, Holmes MC, Bailey MA



MESH terms used to index this publication - Major topics in bold

11-beta-Hydroxysteroid Dehydrogenase Type 2
Animals
Baroreflex
Corticosterone
Craving
Dexamethasone
Drinking Behavior
Genes, Synthetic
Hypertension
Mice
Mice, Inbred C57BL
Mice, Knockout
Mineralocorticoid Excess Syndrome, Apparent
Mineralocorticoid Receptor Antagonists
Nephrons
Nerve Tissue Proteins
Nestin
Neurons
Potassium
RNA, Messenger
Receptors, Mineralocorticoid
Reflex, Abnormal
Sodium Chloride, Dietary
Solitary Nucleus
Spironolactone