Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin II receptor inneonatal sheep

We have investigated the effects of maternal nutrient restriction in the sh eep during the period of rapid placental growth (i.e. 28-77 days gestation; term = 147 days) on fete-placental growth and expression of the glucocorti coid receptor (GR), types 1 and 2 11 beta -hydroxysteroid dehydrogenase (11 beta HSD1, 11 beta HSD2), and types 1 and 2 angiotensin II receptor (AT1, AT2) in fetal and neonatal offspring. Ewes (n = 63) of similar age, body we ight, and body composition were randomly allocated to a nutrient-restricted (NR) group in which they consumed 3.2 MJ/day metabolizable energy (ME; equ ivalent to 50% of predicted requirements) or to a control group in which th ey consumed 6.7 MJ/day ME (equivalent to 110% of predicted requirements). A fter 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 simil ar body weight, but had increased crown-romp length, greater placental weig ht, and increased placental/body weight ratio (P < 0.01) compared with cont rols. Their kidneys were heavier (P < 0.05), but shorter in length, with in creased ratios of transverse width to length (P < 0.001). GR messenger RNA (mRNA) expression in neonatal offspring from NR ewes was i ncreased in adrenal, kidney, liver, lung, and perirenal adipose tissue (P < 0.01). Conversely, 11 beta HSD1 mRNA expression was unaffected, except in perirenal adipose tissue, where it was higher in lambs born to NR ewes (P < 0.01). 11 beta HSD2 mRNA expression was decreased in adrenals and kidney ( P < 0.001). Maternal NR also resulted in significantly increased AT1 expres sion in those tissues in which expression of GR was increased and/or 11 bet a HSD2 was decreased, i.e. adrenals, kidney, liver, and lung. AT2 expressio n was unaffected by maternal NR. Although 11 beta HSD2 mRNA was undetectabl e 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 11 beta HSD enzyme (i.e. 11 beta -dehydrogenase and 11-oxoreductase) activi ties and abundance of 11 beta HSD1 mRNA and 11 beta HSD2 mRNA expression. The persistence of tissue-specific increases in the expression of GR, 11 be ta HSD1 and AT1 and decreases in the expression of 11 beta HSD2 in adrenals and kidney in newborn offspring in response to a defined period of materna l nutrient restriction during early to midgestation suggests that gene expr ession has been programmed by nutrient availability to the fetus before bir th. 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 c ardiovascular disease risk factors in later life.