The Peripheral Renin–Angiotensin System Is Not Involved In The Hypertension Of Sheep Exposed To Prenatal Dexamethasone

Peers, Arianne; Campbell, Duncan J.; Wintour, E. M.; Dodic, Miodrag

doi:10.1046/j.1440-1681.2001.03443.x

Cited by 31 publications

(20 citation statements)

References 52 publications

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“…Glucocorticoid receptors are present in the fetal sheep kidney from as early as 30 days gestation (34), and it has been shown that exposure to excess maternal glucocorticoids during early pregnancy results in a lower nephron number in the kidney in postnatal life (42,43). In the present study, there was a higher expression of renal 11␤-HSD-2 mRNA expression in PCUN singleton fetuses compared with control singletons.…”

Section: Discussionsupporting

confidence: 50%

Periconceptional undernutrition and being a twin each alter kidney development in the sheep fetus during early gestation

MacLaughlin

Walker

Kleemann

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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It has been demonstrated that kidney growth and nephrogenesis are each regulated by intrarenal factors, including the insulin-like growth factors, glucocorticoids, and the renin-angiotensin system. Therefore, we have investigated the impact of periconceptional undernutrition (PCUN; from ϳ6 wk before to 7 days after conception) in singleton (control, n ϭ 18; PCUN, n ϭ 16) and twin pregnancies (control, n ϭ 6; PCUN, n ϭ 5) on the renal mRNA expression of 11␤-hydroxysteroid dehydrogensase type 1 and type 2 (11␤-HSD-1 and -2), the glucocorticoid (GR), and mineralocorticoid receptors, angiotensinogen, angiotensin receptor type 1 (AT1R) and 2 (AT2R), IGF-1 and IGF-2, and IGF1R and IGF2R at ϳ55 days gestation. There was no effect of PCUN or fetal number on fetal weight on relative kidney weight at approximately day 55 of gestation. There was an inverse relationship between the relative weight of the fetal kidney at approximately day 55 and maternal weight loss during the periconceptional period in fetuses exposed to PCUN. Exposure to PCUN resulted in a higher expression of IGF1 in the fetal kidney in singleton and twin pregnancies. Being a twin resulted in higher intrarenal expression of IGF-1 and IGF-2, GR, angiotensinogen, AT1R, and AT2R mRNA at 55 days gestation. Renal 11␤-HSD-2 mRNA expression was higher in PCUN singletons, but not PCUN twins, compared with controls. Thus, there may be an adaptive response in the kidney to the early environment of a twin pregnancy, which precedes the fetal growth restriction that occurs later in pregnancy. The kidney of the twin fetus exposed to periconceptional undernutrition may also be less protected from the consequences of glucocorticoid exposure. nutrition; pregnancy; renal; hypertension A SERIES OF CLINICAL AND EXPERIMENTAL studies have shown that maternal nutrition and placental substrate supply during pregnancy are each important in determining the pattern of fetal kidney growth and the functional capacity of the kidney and cardiovascular system in postnatal life (23,28). In the human, nephrogenesis is complete by 32-34 wk of gestation and a nephron deficit present at birth will, therefore, persist through life (23, 28). Kidney growth is significantly slower in the intrauterine growth-restricted (IUGR) human fetus, and total nephron number is also lower in the IUGR fetus compared with normally grown fetuses (14,15,21). In the sheep, twinning, a naturally occurring form of fetal growth restriction, results in a ϳ40% lower nephron endowment compared with singleton fetuses (25). Similarly in the rat, maternal protein restriction throughout pregnancy or induction of uteroplacental insufficiency results in a decrease in kidney growth and in the number of nephrons (2,17,24,35,40,44). A low-protein diet throughout pregnancy in the rat also programs an upregulation of the renal glucocorticoid receptor (GR) and separately, administration of glucocorticoids at 15-16 days of gestation results in a reduction in glomerular number and hypertension (32,33). It has been proposed that ther...

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Section: Discussionsupporting

confidence: 50%

Periconceptional undernutrition and being a twin each alter kidney development in the sheep fetus during early gestation

MacLaughlin

Walker

Kleemann

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Finally, we cannot rule out the possibility that the observed differences in coronary artery reactivity were secondary to the development of hypertension in the glucocorticoid-exposed lambs, rather than a primary phenomenon. Regardless of the mechanisms involved, these results stress the need for further vesselspecific research in this area and highlight the possibility that the pathway connecting corticosteroids and hypertension may be different from that linking antenatal corticosteroid exposure and coronary artery disease (21,27).…”

Section: Discussionmentioning

confidence: 83%

Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity

Roghair¹,

Lamb²,

Miller³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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.-Excessive exposure of the fetus to maternally derived corticosteroids has been linked to the development of adult-onset diseases. To determine if early gestation corticosteroid exposure alters subsequent coronary artery reactivity, we administered dexamethasone (0.28 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) to pregnant ewes at 27-28 days gestation (term being 145 days). Vascular responsiveness was assessed in endothelium-intact coronary and mesenteric arteries isolated from steroid-exposed and age-matched control fetal sheep at 123-126 days gestation and lambs at 4 mo of age. Lambs exposed to maternal dexamethasone had higher mean arterial blood pressures than the age-matched controls (93 Ϯ 3 vs. 83 Ϯ 5 mmHg, P Ͻ 0.05). Mesenteric arteries from the steroid-exposed fetuses displayed diminished responses to ANG II, relative to controls. In 4-mo-old lambs, prenatal dexamethasone exposure significantly increased coronary artery vasoconstriction to ANG II, ACh, and U-46619, but not KCl. In contrast, postnatal mesenteric artery reactivity was unaltered by steroid exposure. Compared with fetal mesenteric reactivity, postnatal mesenteric reactivity to ANG II, phenylephrine, and U-46619 was diminished, whereas the response to 120 mmol/l KCl was heightened. Coronary artery ANG II receptor protein expression was not significantly altered by steroid exposure in either age group. These findings demonstrate that early-gestation glucocorticoid exposure programs postnatal elevations in blood pressure and selectively enhances coronary artery responsiveness to second messenger-dependent vasoconstrictors. Glucocorticoid-induced alterations in coronary vascular smooth muscle structure or function may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease.angiotensin II; coronary arteries; fetal programming; vascular smooth muscle THERE ARE EPIDEMIOLOGICAL links between poor fetal growth and the subsequent development of atherosclerosis. The concept of the fetal programming of adult disease found its inception through the work of Barker and colleagues (2). Their initial epidemiological data are supported by a number of international studies suggesting that lower birth weight, a potential marker for an adverse intrauterine environment, is an independent risk factor for the development of both hypertension and coronary artery disease (5,15,23).A number of animal models have been developed to ascertain the intrauterine factors that presage the development of cardiovascular disease and investigate the mechanisms involved. Protein restriction models in pregnant rats demonstrated that maternal undernutrition is associated with the development of hypertension in the offspring. Excessive fetal exposure to glucocorticoids, related to inhibition of the placental enzyme responsible for inactivation of maternal corticosteroids, 11␤-hydroxysteroid dehydrogenase, may play a role in this response (13,16). Consistent with this hypothesis, inhibition of maternal corticosteroid synthesis, produced by administration of ...

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“…Results of Wintour and colleagues (21) also indicate upregulation of angiotensinogen and AT1 centrally in fetuses at 130 days gestation, although not in offspring at 2 mo of age. In contrast, there does not appear to be an alteration in the peripheral RAS, as basal renin, angiotensinogen, ANG I, ANG II, and angiotensin-converting enzyme, as well as the response to peripheral angiotensin stimulation and AT1 receptor blockade, were identical in prenatally exposed offspring compared with controls (22,54).…”

Section: Mechanisms Of Gestational Programmingmentioning

confidence: 86%

Gestational programming: population survival effects of drought and famine during pregnancy

Ross

Desai

2005

American Journal of Physiology-Regulatory, Integrative and Comp

118

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The process whereby a stimulus or stress at a critical or sensitive period of development has long-term effects is termed "programming." Studies in humans and animals convincingly demonstrate that environmental perturbations in utero may permanently change organ structure and metabolism and/or alter homeostatic regulatory mechanisms among the offspring. These programmed changes may be the origins of adult diseases, including cardiovascular disease, obesity, and diabetes. Throughout evolution and development, humans and animals have been exposed to two common environmental stresses, drought and famine. Notably, drought-induced water deprivation is associated with dehydration anorexia and thus a concomitant potential nutrient stress. Our laboratory has performed studies among pregnant rat and sheep in which we simulate drought conditions via maternal dehydration and famine conditions via nutrient restriction. Maternal dehydration results in low-birth-weight offspring, which demonstrate gender-specific plasma hypernatremia and hypertonicity and arterial hypertension. Gestational nutrient restriction also resulted in low-birth-weight offspring. If permitted rapid catch-up growth by nutrient availability, these offspring demonstrate evidence of increased body weight and body fat, and leptin resistance as adults. Conversely, if the catch-up growth is delayed by nutrition restriction, the offspring exhibit normal body weight, body fat, and plasma leptin levels as adults. These studies indicate that osmoregulatory and cardiovascular homeostasis and phenotypic predisposition to obesity may be programmed in utero. Importantly, these results suggest that programming effects may be either potentiated or prevented by interventions during the neonatal period.

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The Peripheral Renin–Angiotensin System Is Not Involved In The Hypertension Of Sheep Exposed To Prenatal Dexamethasone

Cited by 31 publications

References 52 publications

Periconceptional undernutrition and being a twin each alter kidney development in the sheep fetus during early gestation

Periconceptional undernutrition and being a twin each alter kidney development in the sheep fetus during early gestation

Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity

Gestational programming: population survival effects of drought and famine during pregnancy

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