Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

Abstract

Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 ± 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10-11 pm, with dexamethasone (2 × 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment.

Figure 1.

Plasma concentrations of angiotensinogen, renin, and ACE in the fetuses (A) and ewes (B) sampled at 10 hours after the second daily injection of either saline (□, n = 5) or dexamethasone (, n = 5). Data are presented as mean values (±SEM). Significant difference from saline-treated group: *, P < .05; †, P = .06.

Figure 2.

Pulmonary ACE mRNA and concentration in the fetus (A) and ewe (B) at 10 hours after saline (□, n = 5) or dexamethasone (, n = 5) treatment. Data are presented as mean values (±SEM); transcript data are presented as fold changes relative to the saline-treated group. Significant difference from saline-treated group: *, P < .05.

Figure 3.

Renal ACE mRNA and concentration in the fetus (A) and ewe (B) at 10 hours after saline (□, n = 5) or dexamethasone (, n = 5) treatment. Data are presented as mean values (±SEM); transcript data are presented as fold changes relative to the saline-treated group. Significant difference from saline-treated group: *, P < .05.

Figure 4.

Cardiac ACE (A) and AT₂R (B) mRNA levels in the fetus at 10 hours after saline (□, n = 5) or dexamethasone (, n = 5) treatment. Data are presented as mean fold changes (±SEM) relative to the saline-treated group. Significant difference from saline-treated group: *, P < .05.