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|Title: ||Role of 11βHSD2 in salt and water homeostasis|
|Authors: ||Evans, Louise Christine|
|Supervisor(s): ||Bailey, Matthew|
|Issue Date: ||30-Jun-2012|
|Publisher: ||The University of Edinburgh|
|Abstract: ||11β-Hydroxysteroid Dehydrogenase Type 2 (11βHSD2) catalyses the inactivation of
cortisol. In aldosterone target tissues co-expression of 11βHSD2 and
mineralocorticoid receptors (MR) protects the receptor from activation by
glucocorticoids. In the syndrome of Apparent Mineralocorticoid Excess, mutations
in the HSD11B2 gene cause hypertension, which is thought to be driven by volume
expansion secondary to sodium retention. 11βHSD2 mice are indeed hypertensive
but paradoxically volume contracted, suggestive of a urine-concentrating defect. The
current studies were designed to evaluate sodium and water homeostasis in
11βHSD2-/- mice developed a severe and progressive polyuric-polydipsic phenotype.
Despite basal polyuria, at <100 days 11βHSD2-/- mice had a functional concentration
response when challenged with 24 hours water deprivation. At >180 days the
exacerbated polyuria was associated with severe medullary injury in the null mice.
Basal aquaporin 2 (AQP2) abundance was reduced in the 11βHSD2-/- mice at both
<100 and >180 days. Moreover, vasopressin 2 receptor (V2R) stimulation failed to
normalize the impaired response to water deprivation in >180 day null mice.
Consequently, a renal origin to the polyuria was postulated. Indeed, mice in which
11βHSD2 had been selectively targeted in the brain had a normal water turnover. A
key finding from these studies is that functional deletion of 11βHSD2 in the brain,
specifically the nucleus of the solitary tract (NTS), resulted in an increased salt
appetite. Moreover, the mice displayed a preference for 1.5% NaCl over water. Blockade of mineralocorticoid receptors (MR) significantly reduced NaCl intake.
This is the first demonstration of an increased salt appetite in a model with normal
renal function and in the absence of sodium depletion. These data implicate
activation of MR on 11βHSD2 positive neurons in the NTS in the behavioural drive
to consume sodium.|
|Sponsor(s): ||Medical Research Council (MRC)|
British Heart Foundation
|Appears in Collections:||School of Clinical Sciences thesis and dissertation collection|
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