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 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11ßHSD2 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 11ßHSD2 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 11ßHSD2 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 11ßHSD2-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.

Sodium homeostasis is preserved in a global 11ß-hydroxysteroid dehydrogenase type 1 knockout mouse model.

NEW FINDINGS: What is the central question of this study? Glucocorticoids act in the kidney to promote salt and water retention. Renal 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1), by increasing local concentrations of glucocorticoids, may exert an antinatriuretic effect. We hypothesized that global deletion of 11ßHSD1 in the mouse would give rise to a salt-wasting renal phenotype. What is the main finding and its importance? We subjected a mouse model of global 11ßHSD1 deletion to studies of water and electrolyte balance, renal clearance, urinary steroid excretion, renin-angiotensin system activation and renal sodium transporter expression. We found no significant effects on renal sodium or water excretion. Any effect of renal 11ßHSD1 on sodium homeostasis is subtle. Glucocorticoids act in the kidney to regulate glomerular haemodynamics and tubular sodium transport; the net effect favours sodium retention. 11ß-Hydroxysteroid dehydrogenase type 1 (11ßHSD1) is expressed in the renal tubules and the interstitial cells of the medulla, where it is likely to regenerate active glucocorticoids from inert 11-keto forms. The physiological function of renal 11ßHSD1 is largely unknown. We hypothesized that loss of renal 11ßHSD1 would result in salt wasting and tested this in a knockout mouse model in which 11ßHSD1 was deleted in all body tissues. In balance studies, 11ßHSD1 deletion had no effect on water, sodium or potassium metabolism; transition to a low-sodium diet did not reveal a natriuretic phenotype. Renal clearance studies demonstrated identical haemodynamic parameters (arterial blood pressure, renal blood flow and glomerular filtration rate) in knockout and wild-type mice, but revealed an augmented kaliuretic response to thiazides in 11ßHSD1 knockout animals. There was no effect on the natriuretic response to the amiloride analogue benzamil. Urinary excretion of deoxycorticosterone was higher in 11ßHSD1 knockout mice, and there was hypertrophy of cells in the zona fasciculata of the adrenal cortex. There was no difference in the activity of the renin-angiotensin and nitric oxide systems, no difference in renal histology and no difference in the abundance of key tubular transporter proteins. We conclude that any effect of 11ßHSD1 on renal sodium excretion is subtle.