Maternal Glucocorticoid Treatment Programs Alterations in the Renin-Angiotensin System of the Ovine Fetal Kidney

Moritz, Karen M.; Johnson, Kevin S.; Douglas-Denton, Rebecca Nicole; Wintour, E. M.; Dodic, Miodrag

doi:10.1210/en.2002-220534

Cited by 115 publications

(111 citation statements)

References 44 publications

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“…Despite that the intrarenal RAS is suppressed in the neonatal period in prenatally programmed hypertension in the rat, AT1R expression increases above control levels during the prehypertensive stage (97,114), without feedback suppression in kidney angiotensin I or II contents (97). In sheep that have been programmed to become hypertensive by maternal glucocorticoid treatment (115) or by maternal food restriction (70), upregulation of renal AT1R has been documented already in late gestation and at birth, respectively, perhaps reflecting the much more advanced maturation state of the ovine kidney. These findings are consistent with activation of RAS via upregulated AT1R and offer a potential role for the intrarenal RAS in the pathogenesis of prenatally programmed hypertension.…”

Section: Targets Of Programming In the Fetusmentioning

confidence: 99%

Prenatal Programming of Hypertension

Vehaskari¹,

Woods²

2005

Journal of the American Society of Nephrology

110

120

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Section: Targets Of Programming In the Fetusmentioning

confidence: 99%

Prenatal Programming of Hypertension

Vehaskari¹,

Woods²

2005

Journal of the American Society of Nephrology

110

120

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“…Thus it appears that in the sheep, as well as in the rat, the dose of dexamethasone required to program offspring hypertension is greater than the minimum dose that can impair maternal and/or fetal weight gains. Interestingly, a considerably larger dose of dexamethasone (ϳ240 g⅐kg Ϫ1 ⅐day Ϫ1 ) infused into pregnant sheep on days 26 and 27 of gestation did not significantly alter the weights of fetuses at 130 days gestation (27). Using a similar dose regimen, Dodic et al (10) showed that birth weight was not significantly different and reported that weights at 100, 300, and 560 days of postnatal age were "similar" to controls (data not given).…”

mentioning

confidence: 92%

Maternal glucocorticoids and prenatal programming of hypertension

Woods

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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can be accounted for by the corresponding reduction in food intake that these mothers experience. The present studies were designed to determine whether there is a lower dose of dexamethasone that does not reduce maternal food intake yet still causes hypertension in the adult offspring. Pregnant rats were treated with subcutaneous dexamethasone at 50 (D50) or 25 (D25) g ⅐ kg Ϫ1 ⅐ day Ϫ1 on days 15-20 of pregnancy. An additional group was untreated or received vehicle injections (control). D25 and D50 dams reduced their food intake by 17% during and after treatment and gained 31% less weight than control over the course of gestation. In adulthood (ϳ21 wk), chronically instrumented male offspring of D50 and D25 had normal blood pressures (D50: 131 Ϯ 2 mmHg and D25: 127 Ϯ 3 mmHg vs. 127 Ϯ 2 mmHg in control). Qualitatively similar results were found in female offspring. Thus neither dexamethasone per se at these doses nor the accompanying modest reductions in maternal food intake and weight gain have blood pressure programming effects. As far as has been tested, there does not appear to be a dose of dexamethasone that, given over this time period in the rat, programs offspring hypertension without reducing maternal food intake and weight gain. These data do not support the hypothesis that maternal glucocorticoids program offspring hypertension directly. prenatal dexamethasone; glomerular filtration rate; rat EVIDENCE FROM HUMAN STUDIES indicates that babies that are born smaller have a greater risk of many adult diseases than do larger babies. In particular, adult blood pressure has been shown to be inversely related to birth weight (1,8,9,20,31). Emerging evidence in animals has confirmed that factors in the prenatal environment that affect fetal growth can permanently change the structure and physiology of organ systems, thus programming the individual for various diseases, including hypertension, later in life. Yet the nature of these factors and the mechanisms by which they permanently alter morphology and physiology are still not completely understood.At least two mechanisms have been postulated to be important in prenatal programming for hypertension and other diseases. One theory is that alterations in maternal nutritional factors, particularly reduced protein intake, suppress the fetal intrarenal renin angiotensin system, which leads to impaired renal development, permanent reductions in nephron number, and adult hypertension. Indeed, several laboratories, including our own, have shown that restriction of dietary protein or total food intake in pregnant rats leads to a reduced number of nephrons and hypertension in the adult offspring (14,19,25,30,32,34,36). We have also shown that this is associated with, and likely mediated by, suppression of the intrarenal renin-angiotensin system during development (36).A second theory regarding the mechanisms by which maternal environment during pregnancy programs for adult disease invokes a role for maternal glucocorticoids (2). The fetus is normally protected from mat...

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“…We found that baseline GFR adjusted for body weight was significantly decreased in male but not female adult sheep prenatally exposed to clinically relevant doses of betamethasone. Findings from a number of studies have demonstrated lower nephron endowment, high blood pressure, and altered ANG receptor expression in glucocorticoid-exposed models of fetal programming (11,33,54,55). To date, few studies have assessed whether these changes result in impaired or altered renal function, especially in adult offspring.…”

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confidence: 99%

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

Tang¹,

Carey²,

Bi³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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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, ...

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Maternal Glucocorticoid Treatment Programs Alterations in the Renin-Angiotensin System of the Ovine Fetal Kidney

Cited by 115 publications

References 44 publications

Prenatal Programming of Hypertension

Prenatal Programming of Hypertension

Maternal glucocorticoids and prenatal programming of hypertension

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

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