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Title: Tissue-specific regulation of 11β-hydroxysteroid dehydrogenase by adrenal steroids, sex steroids and growth hormone
Author: Low, Susan C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1994
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I have found that 11β-OHSD activity and mRNA expression are regulated by glucocorticoids, but not mineralocorticoids, in rat hippocampus and liver, but not kidney. Hippocampal 11β-OHSD activity and mRNA expression are elevated by dexamethasone and stress suggesting a role for 11β-OHSD in modulating glucocorticoid access to neuronal MR. In agreement with this hypothesis, development of a double in-situ hybridisation technique demonstrated cellular co-localisation of 11β-OHSD mRNA with MR and GR mRNAs in rat hippocampus. I have also demonstrated that 11β-OHSD activity exhibits a sexually-dimorphic pattern of expression in rat liver due to repression of activity in female rats by oestradiol which could not be explained by a direct action of oestradiol. In order to understand the cellular role of the 'liver-type' 11β-OHSD, a plasmid containing the coding region of the rat liver 11β-OHSD cDNA linked to an SV40 promoter was transfected into COS-7 and CV-1 cells, and the conversion of [3H] 11-dehydrocorticosterone or [3H] 11-dehydrocorticosterone to [3H] corticosterone, monitored in the medium over a 24 hour period. Interestingly, it was found that in intact cells, the 'liver-type' 11β-OHSD did not act as a dehydrogenase, but instead as a reductase (activating glucocorticoids), and therefore is highly unlikely to be the enzyme responsible for protecting MR in kidney tubules from exposure to glucocorticoids. This was confirmed at a molecular level using cells transfected with 11β-OHSD, GR and MMTV-luciferase reporter plasmids, which showed activation of otherwise inert 11-dehydrocorticosterone to induce the GR-dependent reporter gene. In conclusion, this thesis demonstrates tissue-specific regulation of 11β-OHSD by adrenal steroids, sex steroids and growth hormone, provides evidence for the existence of a second dehydrogenase in rat kidney, and indicates that the 'liver-type' 11β-OHSD is unlikely to be responsible for protecting renal MR from exposure to glucocorticoids.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available