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, ...
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.
This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen.
There are sex-related differences in the development of renal-converting enzyme activities that may have functional implications in terms of the regulation of blood pressure and renal function in men and women. The difference in the patterns of gene expression and enzyme activity indicates that changes in gene expression may not accurately reflect changes in activity.
We have shown a sex-specific effect of fetal programming on Na(+) excretion in adult sheep. The site of this effect in the kidney is unknown. Therefore, we tested the hypothesis that renal proximal tubule cells (RPTCs) from adult male sheep exposed to betamethasone (Beta) before birth have greater Na(+) uptake than do RPTCs from vehicle-exposed male sheep and that RPTCs from female sheep similarly exposed are not influenced by antenatal Beta. In isolated RPTCs from 1- to 1.5-yr-old male and female sheep, we measured Na(+) uptake under basal conditions and after stimulation with ANG II. To gain insight into the mechanisms involved, we also measured nitric oxide (NO) levels, ANG II receptor mRNA levels, and expression of Na(+)/H(+) exchanger 3. Basal Na(+) uptake increased more in cells from Beta-exposed male sheep than in cells from vehicle-exposed male sheep (400% vs. 300%, P < 0.00001). ANG II-stimulated Na(+) uptake was also greater in cells from Beta-exposed males. Beta exposure did not increase Na(+) uptake by RPTCs from female sheep. NO production was suppressed more by ANG II in RPTCs from Beta-exposed males than in RPTCs from either vehicle-exposed male or female sheep. Our data suggest that one site of the sex-specific effect of Beta-induced fetal programming in the kidney is the RPTC and that the enhanced Na(+) uptake induced by antenatal Beta in male RPTCs may be related to the suppression of NO in these cells.
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