Endocrine Abstracts (2015) 38 FP6 | DOI: 10.1530/endoabs.38.FP6

The role of 11[beta]-hydroxysteroid dehydrogenase type 2 in the central regulation of blood pressure and salt appetite

Julie McNairn1, Matthew Bailey1, Carmel Moran1, Lorraine Work2 & Megan Holmes1

1Edinburgh University, QMRI, Edinburgh, UK; 2Glasgow University, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK.

Increased intake of sodium is postulated to be controlled by aldosterone-sensitive cells in a select region of the adult mouse brain, the nucleus of the solitary tract (NTS). These cells express the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) which inactivates glucocorticoids, allowing selective activation of mineralocorticoid receptors by aldosterone. However in the developing brain, HSD2 is widely expressed to protect against adverse glucocorticoid action, which increases susceptibility to affective and cognitive disorders as adults. To determine the role of developmental versus adult expression of brain HSD2, we investigated the phenotype of mice with lifelong deletion of brain HSD2 (HSD2f/f.nestin-cre) and mice with adult deletion of HSD2 in the NTS using lentiviral delivery (HSD2f/f.v-CRE) compared to their respective controls. The phenotypes (salt appetite, BP, baroreceptor response (BRR) and cognition), can be categorized as either due to glucocorticoid fetal programming effects, or unregulated activation of 11β-HSD2 expressing neurons in the NTS.

Salt appetite increased in both HSD2f/f.nestin-cre and HSD2f/f.v-cre cohorts (percentage increase of 65% n=8 and 46% n=6, respectively), leading to an increased blood pressure in both groups (percentage increase of 12% and +8%, respectively). Similarly, the BRR is impaired in brain HSD2 KO mice, indicating all phenotypes are mediated by NTS neurons. However, spatial recognition memory (Object-in-Place task) is abolished in HSD2f/f.nestin-cre mice. Whereas, HSD2f/f.v-cre mice have a marginally reduced memory, but still retain short-term memory.

Our data suggests that neural HSD2 protects against inappropriate activation of MR by corticosterone to regulate salt appetite and salt-induced rises in blood pressure in the adult mouse. However, spatial recognition memory is not influenced by deletion of 11β-HSD2 in the adult brain, confirming this phenotype is underpinned by developmental programming by glucocorticoids.

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