[Show abstract][Hide abstract] ABSTRACT: Prenatal glucocorticoid administration in clinically relevant doses reduces nephron number and renal function in adulthood and is associated with hypertension. Nephron loss in early life may predispose the kidney to other insults later but whether or not sex influences increases in renal susceptibility is unclear. We determined, in male and female adult sheep, if antenatal glucocorticoid (betamethasone) exposure increased 8-isoprostane (marker of oxidative stress) and protein excretion after acute nephron reduction and intrarenal infusions of angiotensin peptides. We also examined if renal proximal tubule cells (PTCs) could contribute to alterations in 8-isoprostane excretion in a sex specific fashion. In vivo, ANG II significantly increased 8-isoprostane excretion by 49% and protein excretion by 44% in male betamethasone but not in female betamethasone or vehicle treated sheep. ANG-(1-7) decreased 8-isoprostane excretion but didn't affect protein excretion in either group. In vitro, ANG II stimulated 8-isoprostane release from PTCs of male but not female betamethasone treated sheep. Male betamethasone exposed sheep had increased p47 phox abundance in the renal cortex while SOD activity was increased only in females. We conclude that antenatal glucocorticoid exposure enhances the susceptibility of the kidney to oxidative stress induced by ANG II in a sex specific fashion and the renal proximal tubule is one target of antenatal steroids. ANG-(1-7) may mitigate the impact of prenatal glucocorticoids on the kidney. P47 phox activation may be responsible for the increased oxidative stress and proteinuria in males. The protection from renal oxidative stress in females is associated with increased SOD activity.
No preview · Article · Sep 2014 · American journal of physiology. Renal physiology
[Show abstract][Hide abstract] ABSTRACT: Cyclooxygenase 2 (COX-2) is important for development of the fetal kidney. Precisely how renal COX-2 expression is regulated in fetal life is unclear. The hypothesis that thyroid hormone positively regulates COX-2 and PGE(2) levels in the late gestation fetal kidney cortex was tested. Sham, thyroidectomized (TX), and TX + thyroid hormone replacement (R) fetal sheep were studied. TX was performed at 120 days gestational age (dGA). TX + R fetuses were continuously infused with thyroxine from 3 days after surgery until study completion. Fetal kidney cortex was obtained at 137 dGA for measurement of renal cyclooxygenase type-2 (COX-2) protein and PGE(2) metabolites. Renocortical COX-2 and PGE(2) levels were significantly lower in TX compared with sham and TX + R fetuses. There were no differences between sham and TX + R fetuses. These findings demonstrate that thyroid hormone positively regulates renal COX-2 and PGE(2) expression in the late gestation fetal sheep kidney.
No preview · Article · Aug 2008 · Reproductive sciences (Thousand Oaks, Calif.)
[Show abstract][Hide abstract] ABSTRACT: Pregnancy is characterized by a progressive increase in the different components of the renin angiotensin system (RAS) including angiotensin II, a potent vasoconstrictor. Pregnant women and experimental animals are resistant to the pressor effect of increased angiotensin II concentrations during pregnancy. In normal pregnancy, maternal blood pressure (BP) begins to fall in early gestation, reaches a nadir in midgestation, and then gradually increases to nonpregnant levels before term in both humans and C57BL/6J mice. The mechanism producing these changes is unknown. The present study investigates the roles of angiotensin II subtype receptors (AT1a and AT2) in hemodynamic regulation during pregnancy in mice. Female mice genetically or pharmacologically manipulated to alter angiotensin receptor stimulation were bred to 2 strains of males. Maternal BP was measured daily throughout pregnancy. Pup weight and number were determined. Pregnancy-induced hypertension was apparent in transgenic female mice expressing the human angiotensin gene bred with males expressing human renin. This effect was not apparent in the absence of the AT1a receptor (ie, in AT1a knockout mice). The midgestation BP decline in both C56BL/6J and AT1a(-/-) females was abolished by AT2 receptor antagonism. There was a linear, inverse relationship between average BP throughout pregnancy and the average pup weight and number per litter. In summary, these findings suggest that activation of the AT2 receptor may be an important factor in promoting the midgestation BP decline that occurs in several mammalian species and, furthermore, that angiotensin is an important modulator of BP during pregnancy.
No preview · Article · Nov 2007 · Reproductive sciences (Thousand Oaks, Calif.)
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested that thyroid hormone influences maturation of the renin-angiotensin system (RAS) and cardiovascular function in the late-gestation fetal sheep. To further examine the importance of thyroid hormone in this regard, we used the technique of thyroidectomy (TX) to remove endogenous thyroid hormone from the circulation and then replaced it with physiological amounts of exogenous thyroxine. We hypothesized that the previously observed changes in RAS activity and cardiovascular function associated with TX would be normalized. TX was performed at 120 days of gestational age (dGA), and control fetuses were sham operated. After 3 days of recovery, TX fetuses were continuously intravenously infused with thyroxine until delivery by cesarean section close to term (around 138 dGA). Immediately before necropsy, fetuses were infused with isoproterenol, and the hemodynamic responses were noted. Thyroid hormone replacement normalized not only plasma triiodothyronine (T3) and thyroxine (T4) levels but also the TX-induced decreases in renal renin mRNA and renal renin content. Renal ANG II subtype receptor expression levels were also normalized for both mRNA and protein. Decreased basal heat rate and systolic blood pressure associated with TX returned to normal following replacement; however, changes in mean blood pressure and isoproterenol-induced changes in mean blood pressure were not altered. These findings demonstrate that replacement of thyroid hormone in hypothyroid sheep fetuses can restore renal ANG II receptor and renin expression and secretion to normal.
No preview · Article · Sep 2007 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: Activity of the fetal renin-angiotensin system (RAS) is developmentally regulated, increasing in late gestation toward term. Thyroid hormone and the renal nerves are both important modulators of renal RAS maturation; however, ablation of either influence alone does not totally block the aforementioned developmental late gestation increase in RAS in fetal sheep. In the current study, we used the technique of thyroidectomy combined with bilateral renal denervation (TX+D), which removes thyroid hormone from the circulation and abolishes effects of renal nerve activity, to determine if simultaneous removal of their effects on the kidney would markedly alter renin expression and secretion in late gestation.
TX+D was performed at 120 days of gestation age (dGA). Control fetuses were sham-operated. Immediately before necropsy (approximately 138 dGA), fetuses were infused with isoproterenol to examine plasma active and prorenin changes in response to beta-adrenergic stimulation.
TX+D decreased plasma thyroid hormone concentrations, renal renin mRNA, renal active and prorenin levels, and plasma active and prorenin concentrations. Isoproterenol-induced increases in plasma active renin were also reduced in TX+D fetuses. TX+D did not alter renal angiotensin (Ang) II subtype receptor (AT2) expression close to term.
These findings suggest that TX+D synergize in the suppression of fetal renin expression.
No preview · Article · Jan 2007 · Journal of the Society for Gynecologic Investigation
[Show abstract][Hide abstract] ABSTRACT: Previous studies indicate that thyroidectomy (TX) decreases renin gene expression in ovine fetal renal cortex in late gestation. Fetal ovine renin-containing renocortical cells become increasingly responsive to beta-adrenergic stimulation as gestation proceeds. Increases in plasma thyroid hormone concentrations parallel this change, suggesting that there is a positive developmental relationship between the two. To examine this hypothesis, we determined the ontogeny of beta1-adrenergic receptor (beta1R) mRNA expression, and the effect of thyroid hormone on in vivo and in vitro expression in fetal sheep.
Renocortical tissue was obtained from naive, TX, and sham-operated fetuses to determine beta1R mRNA levels. Renin-containing renocortical cells from TX or sham fetuses were treated with isoproterenol (Iso) or forskolin (FSK) for analysis of cellular cyclic adenosine monophosphate (cAMP) levels. Renocortical cells from naive fetuses were treated with triiodothyronine (T3) to assess cellular beta1R mRNA levels. Fetal plasma thyroxine (T4) level was determined.
Renocortical beta1R mRNA expression increased significantly between 100 and 140 days' gestational age (dGA), while TX attenuated this increase (P <.01). Renocortical cellular cAMP levels were higher in sham compared to TX fetuses following incubation with Iso or FSK (P <.05). Cells incubated with T3 exhibited significantly increased beta1R mRNA expression (P <.05).
The data suggest that thyroid hormone may be involved in modulating ovine fetal renocortical beta1R gene expression during development. We speculate that the increased beta1R mRNA expression in renal cortical cells as development progresses may mediate the increases in renin gene response to beta-adrenergic stimulation in late gestation.
No preview · Article · Dec 2005 · Journal of the Society for Gynecologic Investigation
[Show abstract][Hide abstract] ABSTRACT: Fetal renin-angiotensin system (RAS) activity is developmentally regulated, increasing in late gestation toward term. At the same time, fetal hemodynamic parameters change, with blood pressure increasing and heart rate decreasing. During this period, fetal plasma thyroid hormone concentrations also increase significantly. In this study we utilized the technique of thyroidectomy (TX), which removes thyroid hormone from the circulation, to investigate the importance of thyroid hormone on the developmental changes in the RAS (in plasma, kidney, heart, and lung) and hemodynamic regulation in fetal sheep. TX was performed at 120 days of gestational age (dGA), and control fetuses were sham operated. Immediately before necropsy ( approximately 137 dGA), fetuses were infused with isoproterenol and the hemodynamic responses were noted. TX significantly decreased plasma thyroid hormone concentrations and renal renin mRNA and renal active renin levels but did not change fetal plasma active renin levels. TX decreased both angiotensin II receptor subtype 1 (AT1) mRNA and protein levels in kidney and lung but not in the left ventricle. TX also was associated with increased ANG II receptor subtype 2 (AT2) mRNA and protein at the 44-kDa band in kidney, whereas AT2 protein was decreased at the 78-kDa level in kidney and lung tissue only. TX fetuses had significantly lower basal mean arterial blood pressures (MAP) and heart rates than controls. Isoproterenol infusion decreased MAP in TX fetuses. These findings support the hypothesis that thyroid hormone is important in modulating maturation of RAS and cardiovascular function in the late-gestation fetal sheep.
Full-text · Article · Nov 2005 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: The activity of the renin-angiotensin system (RAS) increases significantly in the late-gestation fetal sheep. Fetal cortisol is also increased during this time, and it is thought that the increase in cortisol may modulate the RAS changes. Previous studies have examined the effects of cortisol infusion on RAS activity, but the effects of blocking the peripartum increase in cortisol concentrations on the developmental changes in the RAS are not known. Therefore, we utilized the technique of hypothalamic-pituitary disconnection (HPD), which prevents the cortisol surge from occurring, to investigate the importance of the late-gestation increase in cortisol on the ontogenic changes in RAS activity. HPD of fetal sheep was performed at 120 days of gestational age (dGA), and fetuses were delivered between 135 and 139 dGA. Control fetuses were sham operated. HPD blocked the late-gestation cortisol increase but did not alter renal renin mRNA, renal renin or prorenin protein content, nor plasma renin levels compared with sham operated. However, HPD fetuses had increased ANG II receptor subtype 1 (AT1) mRNA and protein expression in the kidney and lungs. ANG II receptor subtype 2 (AT2) expression was not altered in these tissues at either mRNA or protein level. HPD did not change AT1 or AT2 mRNA in the left ventricle but did result in decreased protein levels for both receptors. These studies demonstrate that blockade of the naturally occurring increase in fetal cortisol concentration in late gestation is associated with tissue-specific alterations in expression of AT1 and AT2 receptors. These changes may impact on fetal tissue maturation and hence have consequences in postnatal life.
Full-text · Article · Jun 2005 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: Angiotensin-(1-7) (Ang-[1-7]) is a bioactive component of the renin-angiotensin system, which has depressor, vasodilatory, and antihypertensive actions. In normal pregnancy, we questioned whether the known rise in plasma angiotensin II (Ang II) is counterbalanced by an increase in plasma Ang-(1-7) and whether Ang-(1-7) levels are decreased in preeclampsia and may thus be a factor involved in the development of hypertension. Nulliparous preeclamptic subjects, third-trimester normotensive pregnant subjects, and a nonpregnant group were enrolled (n = 15/group). Preeclamptic subjects had no previous history of hypertension or renal, connective-tissue, or metabolic disease, but at the time of delivery had significant hypertension (159 +/- 3/98 +/- 3 mmHg) and > or = 3+ proteinuria. Plasma Ang-(1-7) was increased by 51% in normal pregnancy (p < 0.05). Plasma Ang I, Ang II, and renin activity were also significantly elevated in normal pregnancy. In preeclamptic subjects, Ang-(1-7) was significantly decreased (p < 0.01) compared with normal pregnant subjects. All other components of the renin-angiotensin-aldosterone system, except serum angiotensin-converting enzyme, were reduced in preeclamptic subjects compared with normal pregnant subjects; only plasma Ang II remained elevated in preeclamptic compared with nonpregnant subjects. These studies demonstrate, for the first time, increased plasma Ang-(1-7) in normal pregnant subjects compared with nonpregnant subjects and decreased Ang-(1-7) in preeclamptic subjects compared with normal pregnant subjects. In preeclampsia the decreased plasma Ang-(1-7) in the presence of elevated Ang II is consistent with the development of hypertension.