Prenatal betamethasone exposure alters renal function in immature sheep: sex differences in effects

Abstract

Synthetic glucocorticoids are commonly given to pregnant women when premature delivery threatens. Antenatal administration of clinically relevant doses of betamethasone to pregnant sheep causes sex-specific compromises of renal function and increases in blood pressure in adult offspring. However, it is unclear whether such effects are present in immature lambs. Therefore, the aims of the present study were to determine whether antenatal betamethasone at 80-81 days of gestation increases blood pressure and adversely impacts renal function in adolescent ewes and rams. Prenatal steroid exposure increased blood pressure significantly in the young male (84 +/- 2 vs. 74 +/- 3 mmHg) and female sheep (88 +/- 5 vs. 79 +/- 4), but it did not alter basal glomerular filtration rate, renal blood flow (RBF), or sodium excretion in either sex. However, antenatal betamethasone exposure blocked increases in RBF (P = 0.001), and enhanced excretion of an acute Na load (P < 0.05) in response to systemic infusions of angiotensin (ANG)-(1-7) at 10 pmol.kg(-1).min(-1) in males. In females, the natriuretic response to combined ANG-(1-7), and Na load was significantly altered by prenatal betamethasone exposure. These findings indicate that blood pressure is increased in immature animals in response to antenatal steroid exposure and that sex-specific effects on renal function also exist. These changes may reflect greater risk for further loss of renal function with age.

Fig. 1.

Change in mean arterial pressure (ΔMAP) representing individual MAP changes over the baseline during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in male and female sheep prenatally exposed to vehicle (open bars, n = 5 or 6) or betamethasone (Beta; solid bars, n = 6). In males, there were effects of Beta during the control study (A), (F = 27.2, P < 0.0001) and a group × time interaction (F = 14.1, P < 0.0001). In the ANG-(1–7) study (B), there was an effect of time in both groups (F = 7.2, P = 0.003); In females, there was no change in MAP in the control study in either group (C). In the ANG-(1–7) study, there was an effect of time in both groups (D) (F = 7.1, P = 0.005).

Fig. 2.

Estimated renal blood flow (eRBF) normalized for body weight during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in male (A, B) and female (C, D) sheep prenatally exposed to vehicle (○, n = 5 or 6) or Beta (■, n = 6). In males, there was an effect of time (Na load) on RBF in the control study (F = 5.2, P = 0.01). In ANG-(1–7) study, RBF increased in the vehicle-treated animals (F = 6.1, P = 0.02), and there was an effect of Beta (F = 24.6, P < 0.0001). No effects of Beta were noted in the females.

Fig. 3.

Renal vascular resistance (RVR) during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in male (A, B) and female (C, D) sheep prenatally exposed to vehicle (□, n = 5 or 6) or Beta (▴, n = 6). In males, RVR decreased with the Na load in the control study (F = 3.8, P = 0.04). Compared with the control study, ANG-(1–7) decreased RVR in vehicle-treated animals (F = 5.0, P = 0.03). RVR was lower in vehicle than in Beta animals in the ANG-(1–7) studies (F = 26.5, P < 0.0001); In females, there was an effect of Na load in both groups in ANG-(1–7) studies (F = 6.7, P = 0.004).

Fig. 4.

Glomerular filtration rate (GFR) normalized for body weight during saline (control) (A) or ANG-(1–7) (B) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in male (A, B) and female (C, D) sheep prenatally exposed to vehicle (○, n = 5 or 6) or Beta (■, n = 6). In females, there was an effect of Na load on GFR in both the control (F = 6.6, P = 0.004) and ANG-(1–7) infusion studies (F = 5.8, P = 0.01).

Fig. 5.

Filtration fraction (FF) during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in female sheep prenatally exposed to vehicle (○, n = 5 or 6) or Beta (■, n = 6). In males, there was a Beta effect during ANG-(1–7) study (F = 13.9, P = 0.001); In females, Na load increased FF in both groups during ANG-(1–7) study (F = 7.1, P = 0.003).

Fig. 6.

Urinary sodium excretion (A and B) and fractional reabsorption of sodium (FR_Na) (C and D) during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in male sheep prenatally exposed to vehicle (○, n = 5) or Beta (■, n = 6). There was no effect of Na load on Na excretion (A) and FR_Na (B) in the control study. In the ANG-(1–7) study, the Na load increased Na excretion (C) (F = 4.0, P = 0.03), only in the vehicle-treated animals, and there was a tendency for an effect on FR_Na (F = 3.6, P = 0.09). Infusion of ANG-(1–7) in the vehicle-treated animals resulted in overall enhanced Na excretion compared with the control study (F = 17.3, P = 0.0003).

Fig. 7.

Urinary sodium excretion (A and B) and fractional reabsorption of sodium (FR_Na) (C and D) during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹) in conjunction with an acute Na load in female sheep prenatally exposed to vehicle (○, n = 6) or Beta (■, n = 6). There was a significant effect of Beta on Na excretion (A) (F = 5.8, P = 0.02) and FR_Na (B) (F =30, P = 0.005) in the control study. The Na load increased Na excretion (F = 5.3, P = 0.01) and decreased FR_Na (F = 4.1, P = 0.04) only in the vehicle-treated animals in the control study. There was an effect of ANG-(1–7) on Na excretion (C) and FR_Na (D) in vehicle- (Exc._Na: F = 11.9, P = 0.002; FR_Na: F = 4.7, P = 0.04) and Beta-exposed animals (Exc._Na: F = 12.2, P = 0.002; FR_Na: F = 4.4, P = 0.046) compared with the control study.

Fig. 8.

Ability to excrete Na in response to an acute Na load as a percentage of the sodium load in sheep prenatally exposed to vehicle (open bars, n = 5 or 6) or Beta (solid bars, n = 6) during saline (control) or ANG-(1–7) infusion (10 pmol·min⁻¹·kg body wt⁻¹). In males, there was an effect of ANG-(1–7), which was confined to the vehicle-treated animals (*P = 0.03, t-test). In females, ANG-(1–7) induced a natriuresis (F = 13.5, P < 0.002), which was attenuated by Beta (F = 5.7, P < 0.03). In addition, females excreted a higher percentage than the males for both groups (vehicle; F = 20.0, P = 0.0005; Beta: F = 6.3, P = 0.02).