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Glucocorticoid Effects on the Programming of AT1b Angiotensin Receptor Gene Methylation and Expression in the Rat.

Bogdarina, I; Haase, A; Langley-Evans, S; Clark, AJ (2010) Glucocorticoid Effects on the Programming of AT1b Angiotensin Receptor Gene Methylation and Expression in the Rat. PLOS ONE, 5 (2). e9237. ISSN 1932-6203
SGUL Authors: Clark, Adrian John L

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Adverse events in pregnancy may 'programme' offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11beta-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.

Item Type: Article
Additional Information: ©2010 Bogdarina et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Animal Nutritional Physiological Phenomena, Animals, Animals, Newborn, Blood Pressure, DNA Methylation, Dexamethasone, Dietary Proteins, Enzyme Inhibitors, Female, Gene Expression Regulation, Developmental, Glucocorticoids, Male, Metyrapone, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Rats, Wistar, Receptor, Angiotensin, Type 1, Reverse Transcriptase Polymerase Chain Reaction, Steroid 11-beta-Hydroxylase, Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, LOW-PROTEIN DIET, ISCHEMIC-HEART-DISEASE, ADULT-BLOOD PRESSURE, PRENATAL EXPOSURE, DIFFERENTIAL EXPRESSION, EPIGENETIC MODIFICATION, INDUCED HYPERTENSION, LATER LIFE, FETAL, CONSEQUENCES
Journal or Publication Title: PLOS ONE
ISSN: 1932-6203
16 February 2010Published
Web of Science ID: WOS:000274590500018
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