Maternal Undernutrition during Early to Midgestation Programs Tissue-Specific Alterations in the Expression of the Glucocorticoid Receptor, 11β-Hydroxysteroid Dehydrogenase Isoforms, and Type 1 Angiotensin II Receptor in Neonatal Sheep*

Abstract

We have investigated the effects of maternal nutrient restriction in the sheep during the period of rapid placental growth (i.e. 28–77 days gestation; term = 147 days) on feto-placental growth and expression of the glucocorticoid receptor (GR), types 1 and 2 11β-hydroxysteroid dehydrogenase (11βHSD1, 11βHSD2), and types 1 and 2 angiotensin II receptor (AT1, AT2) in fetal and neonatal offspring. Ewes (n = 63) of similar age, body weight, and body composition were randomly allocated to a nutrient-restricted (NR) group in which they consumed 3.2 MJ/day metabolizable energy (ME; equivalent to 50% of predicted requirements) or to a control group in which they consumed 6.7 MJ/day ME (equivalent to 110% of predicted requirements). After 77 days gestation, ewes from both dietary groups consumed close to 100% of ME requirements up to term. Newborn offspring of NR ewes were of similar body weight, but had increased crown-rump length, greater placental weight, and increased placental/body weight ratio (P < 0.01) compared with controls. Their kidneys were heavier (P < 0.05), but shorter in length, with increased ratios of transverse width to length (P < 0.001). GR messenger RNA (mRNA) expression in neonatal offspring from NR ewes was increased in adrenal, kidney, liver, lung, and perirenal adipose tissue (P < 0.01). Conversely, 11βHSD1 mRNA expression was unaffected, except in perirenal adipose tissue, where it was higher in lambs born to NR ewes (P < 0.01). 11βHSD2 mRNA expression was decreased in adrenals and kidney (P < 0.001). Maternal NR also resulted in significantly increased AT1 expression in those tissues in which expression of GR was increased and/or 11βHSD2 was decreased, i.e. adrenals, kidney, liver, and lung. AT2 expression was unaffected by maternal NR. Although 11βHSD2 mRNA was undetectable in term placenta, it was abundant in midgestation placenta and was lower after maternal NR (P < 0.001). There was close agreement between levels of 11βHSD enzyme (i.e. 11β-dehydrogenase and 11-oxoreductase) activities and abundance of 11βHSD1 mRNA and 11βHSD2 mRNA expression. The persistence of tissue-specific increases in the expression of GR, 11βHSD1 and AT1 and decreases in the expression of 11βHSD2 in adrenals and kidney in newborn offspring in response to a defined period of maternal nutrient restriction during early to midgestation suggests that gene expression has been programmed by nutrient availability to the fetus before birth. These data suggest key potential mechanisms by which maternal nutrition prenatally programs physiological pathways, such as the renin-angiotensin system, in the offspring that may lead to raised blood pressure and other cardiovascular disease risk factors in later life.