Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic‐pituitary‐adrenal axis and blood pressure adaptions to high‐fat diet
Open Access
- 24 July 2008
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 22 (11), 3896-3907
- https://doi.org/10.1096/fj.08-111914
Abstract
Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GRβgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.—Michailidou, Z., Carter, R. N., Marshall, E., Sutherland, H. G., Brownstein, D. G., Owen, E., Cockett, K., Kelly, V., Ramage, L., Al-Dujaili, E. A. S., Ross, M., Maraki, I., Newton, K., Holmes, M. C., Seckl, J. R., Morton, N. M., Kenyon, C. J., Chapman, K. E. Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet.Keywords
Funding Information
- British Heart Foundation
This publication has 63 references indexed in Scilit:
- Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout miceMolecular and Cellular Endocrinology, 2007
- Conditional glucocorticoid receptor expression in the heart induces atrio‐ventricular blockThe FASEB Journal, 2007
- The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in MiceNeuropsychopharmacology, 2007
- Mice with Genetically Altered Glucocorticoid Receptor Expression Show Altered Sensitivity for Stress-Induced Depressive ReactionsJournal of Neuroscience, 2005
- The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and diseaseNeuroscience & Biobehavioral Reviews, 2005
- Feast and Famine: Critical Role of Glucocorticoids with Insulin in Daily Energy FlowFrontiers in Neuroendocrinology, 1993
- Tissue-specific nutritional regulation of angiotensinogen in adipose tissue.Hypertension, 1992
- Central 5,7‐Dihydroxytryptamine Lesions Decrease Hippocampal Glucocorticoid and Mineralocorticoid Receptor Messenger Ribonucleic Acid ExpressionJournal of Neuroendocrinology, 1990
- Two naturally‐occurring isoforms and their expression of a glucocorticoid receptor gene from an androgen‐dependent mouse tumorFEBS Letters, 1990
- Nonproportional changes in plasma renin concentration, renal renin content, and rat renin messenger RNA.Hypertension, 1985