Antenatal betamethasone exposure alters renal responses to angiotensin-(1–7) in uninephrectomized adult male sheep

Bi, Jianli; Contag, Stephen; Carey, Luke C.; Tang, Lijun; Valego, Nancy K.; Chappell, Mark C.; Rose, James C.

doi:10.1177/1470320312465217

Cited by 11 publications

(14 citation statements)

References 52 publications

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“…We observed impaired sodium excretion in betamethasone-exposed adult males while glucocorticoid-treated females readily excrete a sodium load (64, 65). Also, sodium excretion is less in uninephrectomized males exposed prenatally to betamethasone than it is in vehicle-exposed males with a single kidney (7). The present findings would be consistent with the above reports.…”

Section: Discussionsupporting

confidence: 92%

“…These findings support the concept that antenatal exposure to a clinically relevant dose of betamethasone at the time of peak nephrogenesis has long-term effects on renal function (7,18,37,65), and enhances susceptibility to a second hit in a sex-dependent fashion.…”

Section: Discussionsupporting

confidence: 83%

“…Thus, we performed unilateral nephrectomy as a "second hit" in adult male and female sheep previously exposed to vehicle or betamethasone at 0.6 gestation (full term 145 days) and measured proteinuria and the excretion of 8-isoprostane as markers of renal dysfunction. Moreover, these markers were assessed under baseline conditions and during intrarenal infusions of angiotensin II (ANG II) or angiotensin-(1-7) [ANG- (1)(2)(3)(4)(5)(6)(7)] to determine whether these peptides would alter the excretion of the markers of renal dysfunction. ANG II increases oxidative stress in the kidney (32,56) while ANG-(1-7) tends to oppose the effects of ANG II (12,13,19).…”

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confidence: 99%

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Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep

Contag

Chen

et al. 2014

American Journal of Physiology-Renal Physiology

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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 sex influences increases in renal susceptibility is unclear. Therefore, we determined, in male and female adult sheep, whether 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 whether 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 did not 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 superoxide dismutase (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 the sex-specific effects 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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 83%

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confidence: 99%

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Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep

Contag

Chen

et al. 2014

American Journal of Physiology-Renal Physiology

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“…RAAS alterations include attenuated responses to Ang-(1–7), enhanced responses to Ang II, increased expression of the Ang II type 1 receptor, increased serum ACE activity, decreased serum ACE2 activity, and decreased proximal tubular ACE2 activity and expression. Together these alterations indicate an imbalance in the RAAS which promotes the actions of Ang II at the expense of Ang-(1–7) (6, 7, 24, 25). …”

Section: Discussionmentioning

confidence: 99%

Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm

et al. 2016

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Background Antenatal corticosteroid (ANCS) treatment hastens fetal lung maturity and improves survival of premature infants, but the long-term effects of ANCS are not well-described. Animal models suggest ANCS increases the risk of cardiovascular disease through programmed changes in the renin-angiotensin (Ang)-aldosterone system (RAAS). We hypothesized that ANCS exposure alters the RAAS in adolescents born prematurely. Methods A cohort of 173 adolescents born prematurely was evaluated, of whom 92 were exposed to ANCS. We measured plasma and urine Ang II and Ang-(1–7) and calculated Ang II/Ang-(1–7) ratios. We used general linear regression models to estimate the difference in the RAAS between the ANCS-exposed and unexposed groups, adjusting for confounding variables. Results In unadjusted analyses, and after adjustment for sex, race, and maternal hypertension, ANCS exposure was associated with increased urinary Ang II/Ang-(1–7) [estimate 0.27 (95% CI 0.03, 0.5), p = 0.03], increased plasma Ang-(1–7) [0.66 (0.26, 1.07), p = 0.002], and decreased plasma Ang II/Ang-(1–7) [−0.48 (−0.91, −0.06), p = 0.03]. Conclusions These alterations indicate an imbalance in the urinary RAAS, promoting the actions of Ang II at the expense of Ang-(1–7), which over time may increase the risk of renal inflammation and fibrosis and ultimately hypertension and renal disease.

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“…Women are generally thought to be protected from cardiovascular pathologies up to the time of menopause suggesting a beneficial effect of estradiol; however, several large clinical trials utilizing estrogen or combined estrogen/progesterone replacement in older women with underlying cardiovascular disease revealed adverse effects of either treatment. Experimental studies have largely focused on the role of estrogen to influence the ACE-Ang II-AT 1 -receptor axis of the RAS and generally reveal an inhibitory effect on the expression of ACE and the AT 1 receptor (135)(136)(137)(138). Estrogen depletion by ovariectomy in young mRen2.Lewis rats markedly exacerbated the hypertension and essentially abolished sex differences in blood pressure between the male and female congenics (139).…”

Section: Sex Differences In the Ang-(1-7)-mas Receptor Axismentioning

confidence: 99%

Update on the Angiotensin Converting Enzyme 2-Angiotensin (1–7)-Mas Receptor Axis: Fetal Programing, Sex Differences, and Intracellular Pathways

et al. 2014

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The renin-angiotensin-system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. Indeed, dysregulation of the RAS may lead to the development of cardiovascular pathologies including kidney injury. Moreover, the blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS that the system is comprised of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, sodium retention, and other mechanisms to maintain blood pressure, as well as increased oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the non-classical RAS composed of the ACE2-Ang-(1–7)-Mas receptor axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and oxidative stress. Thus, a reduced tone of the Ang-(1–7) system may contribute to these pathologies as well. Moreover, the non-classical RAS components may contribute to the effects of therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury. The review considers recent studies on the ACE2-Ang-(1–7)-Mas receptor axis regarding the precursor for Ang-(1–7), the intracellular expression and sex differences of this system, as well as an emerging role of the Ang1-(1–7) pathway in fetal programing events and cardiovascular dysfunction.

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Antenatal betamethasone exposure alters renal responses to angiotensin-(1–7) in uninephrectomized adult male sheep

Cited by 11 publications

References 52 publications

Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep

Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep

Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm

Update on the Angiotensin Converting Enzyme 2-Angiotensin (1–7)-Mas Receptor Axis: Fetal Programing, Sex Differences, and Intracellular Pathways

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