Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep

Abstract

posure to clinically relevant doses of glucocorticoids during fetal life increases blood pressure in adult male and female sheep. The purpose of this study was to evaluate the effects of prenatal exposure to betamethasone at 80 -81 days of gestation on renal function in ewes and rams at 1.5 yr of age. In prenatal betamethasone-exposed males, compared with the vehicle-exposed animals, basal glomerular filtration rate (GFR) (1.93 Ϯ 0.08 vs. 2.27 Ϯ 0.10 ml ⅐ min Ϫ1 ⅐ kg body wt Ϫ1 ) and the ability to excrete an acute Na ϩ load (37.1 Ϯ 4.4 vs. 53.7 Ϯ 9.7%) were reduced. (P Ͻ 0.03 and P ϭ 0.03, respectively). In contrast, prenatal betamethasone exposure had no effect on basal GFR, Na ϩ excretion, or the percentage of the Na ϩ load excreted during the experiment in females. Systemic infusions of ANG-(1-7) at 9 ng⅐ min Ϫ1 ⅐ kg Ϫ1 for 2 h had minimal effects on basal GFR, renal plasma flow, and Na ϩ excretion in males but increased Na ϩ excretion in females. However, the percentage of Na ϩ load excreted during ANG-(1-7) infusion did not change in prenatal betamethasone-exposed females (113.1 Ϯ 14.2 vs. 98.1 Ϯ 12.2%) compared with the significant increase in vehicle females (139.2 Ϯ 22.3 vs. 92.2 Ϯ 7.5%) (P ϭ 0.01). The data indicate that antenatal betamethasone exposure produces gender-specific alternations in renal function and thus suggest that different mechanisms underlie the antenatal steroid-induced elevations in blood pressure in male and female offspring. prenatal steroid exposure; sodium load; glomerular filtration rate; sodium excretion; angiotensin-(1-7) SINCE ANTENATAL STEROID TREATMENT became the standard of care for enhancing fetal lung maturation in pregnancies threatened by premature labor between 24 and 34 wk of gestation, the use of corticosteroid therapy in the United States has increased from Ͻ15% of eligible pregnancies in 1990 to Ͼ75% in 1995 (1, 3). However, clinical epidemiological studies show an association between antenatal glucocorticoid administration and altered vascular function (7,46), suggesting that exposure to excess glucocorticoids in the prenatal period may have untoward consequences in adult offspring.We and others have shown using sheep and rat experimental models that prenatal steroid exposure results in elevated blood pressure in adulthood (8,10,14,36). Although there are likely multiple targets influencing the effect of steroids on blood pressure, several recent studies have suggested that altered kidney development induced by antenatal glucocorticoids may contribute to the elevations in arterial blood pressure (35,36,53). It is well known that the kidneys play a major role in the long-term regulation of arterial pressure and that change in renal function may lead to alterations in Na ϩ and water balance and blood pressure (19). In a rat model, Ortiz et al. (35,36) observed that prenatal exposure to dexamethasone on days 15 and 16 of gestation induced 30 and 20% reductions in glomerular number in offspring compared with controls when assessed at 60 -70 days and 6 -9 mo of age, ...

Dose-dependent effects of angiotensin-(1–7) on the NHE3 exchanger and [Ca2+]iin in vivo proximal tubules

“…Therefore, our results indicate that in the S2 segment ANG- (1-7) has a biphasic effect on the Na ϩ /H ϩ exchanger, that is, the low hormonal dose inhibits and the high hormonal dose stimulates the NHE3 exchanger. Consistent with this idea is the observation that ANG 1-7 enhances sodium excretion in sheep likely through a proximal tubular mechanism coherent with the current study (41). However, this biphasic action of ANG-(1-7) we are finding is inverse to the biphasic action described for ANG II, that is, it is widely accepted that ANG II stimulates the Na ϩ /H ϩ at low doses and inhibits it at high doses (4,12,21,32,34).…”

Sex differences in developmental programming models

“…A male offspring-predominant hypertensive effect, similar to that demonstrated in rat models, has been observed in sheep exposed to excess steroids in utero (Dodic et al 2002) and in sheep fed a low-methionine and vitamin B diet in the periconceptual period (Sinclair et al 2007). In keeping with rodent data suggesting a greater sensitivity of the developing renal system to developmental insult in males than in females (Woods et al 2005, studies in sheep have also demonstrated that prenatal steroid exposure reduces glomerular filtration rate in male offspring (Tang et al 2009) and nephrogenesis is impaired in male offspring exposed to nutrient restriction (Gilbert et al 2007).…”

“…Sex-specific differences in offspring outcomes from developmental programming models are also demonstrated in farm animals, mainly sheep (Dodic et al 2002, Manikkam et al 2004, Gilbert et al 2007, Sinclair et al 2007, Tang et al 2009) and cows (Micke et al 2010). A male offspring-predominant hypertensive effect, similar to that demonstrated in rat models, has been observed in sheep exposed to excess steroids in utero (Dodic et al 2002) and in sheep fed a low-methionine and vitamin B diet in the periconceptual period (Sinclair et al 2007).…”

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

“…Betamethasone exposure in pregnant sheep that parallels the gestational age for premature infant administration of glucocorticoids results in a "fetal programming phenotype," in which the offspring exhibit reduced nephron number, glucose insensitivity, attenuated baroreflex sensitivity, and elevated blood pressure (16,42,86,87). Altered renal mechanisms that favor increased sodium retention with an enhanced response to ANG II and a reduced natriuretic effect of ANG-(1-7) are evident in this model (16,97). Moreover, renal expression of ACE2 is significantly reduced in the renal cortex and urine of adult sheep exposed to betamethasone in utero, which may influence the renal expression of ANG II and ANG-(1-7) (86).…”