Bailey, Matthew A.

Mullins, John J.

Craigie, Eilidh

Medical Research Council (MRC)

2011-10-10T14:41:59Z

2011-10-10T14:41:59Z

2011-07-05

The mineralocorticoid hormone, aldosterone, classically acts via the Mineralocorticoid Receptor (MR) to promote sodium transport in aldosterone target tissues, such as the kidney, thereby controlling long-term electrolyte homeostasis and blood pressure (BP). Aldosterone biosynthesis by the adrenal gland is regulated by a negative feedback loop called the Renin Angiotensin Aldosterone System (RAAS). The glucocorticoid cortisol (corticosterone in rodents), which has a very similar structure to aldosterone, shares with aldosterone an equal affinity for the MR. Typically, plasma cortisol levels are approximately 1000-fold higher than plasma aldosterone, and so the ligand specificity for aldosterone must be imposed on MR by other, non-structural, means. This specificity is important in order to retain electrolyte and BP balance within the control of the RAAS. The co-localisation of the enzyme 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) with the MR in aldosterone target tissues provides the MR with the aldosterone specificity it inherently lacks. 11β-HSD2 achieves this by converting active cortisol to its inactive 11-keto metabolite, cortisone (dehydrocorticosterone in rodents). In humans with the monogenetic Syndrome of Apparent Mineralocorticoid Excess (SAME), inactivating mutations in the HSD11B2 gene allows cortisol unregulated access to the MR. Resultant symptoms include severe hypertension and life-threatening hypokalemia. Individuals heterozygous for SAME display no overt phenotypes. However, some studies have associated SAME heterozygosity and loss-of-function polymorphisms within the HSD11B2 gene with essential and/or salt-sensitive hypertension in the general population. Targeted disruption of the Hsd11b2 gene in mice (Hsd11b2-/-) faithfully reproduces with all the major phenotypes of SAME patients. Mice heterozygote for the targeted gene (Hsd11b2+/-) have no phenotype and display a normal BP. In the present study, Hsd11b2+/- mice were used to explore the relationship between reduced 11β-HSD2 enzyme activity and salt-sensitive hypertension. On a high salt diet, Hsd11b2+/- mice were found to have increased BP and impaired natriuresis, compared to wild-type controls (Hsd11b2+/+). Further studies used pharmacological blockade of the Epithelial Sodium Channel (ENaC) and MR to ascertain the contributions of these pathways towards the observed phenotypes. These identified a deregulation of ENaC activity pertaining to an inability to regulate sodium appropriately. Investigations into the contributions of the RAAS and the Hypothalamus Pituitary Adrenal (HPA) axis have revealed valuable insights into their roles in this model. There is an implication that the RAAS has increased sensitivity in Hsd11b2+/-, further exacerbated by increased dietary sodium, and that the regulation of corticosteroids may also be altered. Novel observations have suggested that oxidative stress in response to a high salt diet could also be involved, as a study administering an antioxidant drug in conjunction with a high salt diet prevented the manifestation of a phenotype in Hsd11b2+/-. Finally, the generation of a floxed Hsd11b2 targeting construct for tissue-specific deletion of 11β-HSD2 will allow future studies into the contributions of specific 11β-HSD2 expression sites (such as the kidney) towards the phenotypes of both homozygous and heterozygous mice

http://hdl.handle.net/1842/5565

en

The University of Edinburgh

Webster, S.P., Ward, P., Binnie, M., Craigie, E., McConnell, K.M., Sooy, K., Vinter, A., Seckl, J.R., Walker, B.R., 2007. Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors. Bioorg Med Chem Lett 17, 2838-2843.

Craigie, E., Mullins, J.J., Bailey, M.A. “Chronic ENaC Blockade Rescues Na+ Induced High Blood Pressure in 11β-Hydroxysteroid Dehydrogenase Type 2 Heterozygote Mice.” J Physiol (2009) Proc Physiol Soc 15 C29.

Craigie, E., Bailey, M.A. “11β-hydroxysteroid Dehydrogenase Type 2 Heterozygous Mice Display Blunted Naturesis, Increased Blood Pressure and Impaired ENaC Regulation on a High Sodium Diet.” J Physiol (2008) Proc Physiol Soc 11 C37.

Craigie, E., Bailey, M.A., Mullins, J.J. (2008). “Glucocorticoids and Mineralocorticoids.” Chapter 1, pp 3-38 IN Cardiovascular Hormone Systems: from molecular mechanisms to novel therapeutics. Editor M. Bader. Wiley-Blackwell.

Craigie, E., Bailey, M.A., Livingstone, D.E.W., Kotelevtsev, Y.V., Al-Dujaili, E.A.S., Kenyon, C.J., Mullins, J.J. (2011). “Hsd11b2 Haploinsufficiency in Mice Causes Salt Sensitivity of Blood Pressure”. Hypertension, 57, 515 - 520 (see Appendix 2 full publication).

hypertension

salt

11β-HSD2

Epithelial Sodium Channel

ENaC

steroids

Investigating mechanisms of salt-sensitive hypertension in 11β-HSD2 heterozygote mice

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy