Developmental effect of antenatal exposure to betamethasone on renal angiotensin II activity in the young adult sheep

Contag, Stephen; Bi, Jianli; Chappell, Mark C.; Rose, James C.

doi:10.1152/ajprenal.00497.2009

Cited by 15 publications

(14 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The enhanced response may reflect a reduction in the AT 2 -dependent signaling pathways that would normally attenuate Ang II-AT 1 receptor-coupled intracellular events23 This does not necessarily imply that the AT 1 receptor also exerts an inhibitory influence on AT2 receptor-dependent events within nuclei since losartan did not exacerbate the Ang II-AT 2 receptor pathway for NO. Nonetheless, an increased ratio of AT 1 to AT 2 receptors is consistent with the more pronounced effects of Ang II on sodium reabsorption and renal vascular resistance in the adult sheep following antenatal BMX exposure11. Moreover, the reduction in the proportion and functional response of the AT 2 receptor also supports the findings of reduced AT 2 mRNA and/or levels protein levels in the offspring of protein-restricted rats, a rodent model of fetal programming that exhibits higher glucocorticoid levels in utero 24-26.…”

Section: Discussionsupporting

confidence: 64%

Glucocorticoid-Induced Fetal Programming Alters the Functional Complement of Angiotensin Receptor Subtypes Within the Kidney

et al. 2011

Self Cite

View full text Add to dashboard Cite

Abstract-We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80 to 81 days gestation with full-term delivery. Renal nuclear and plasma membrane fractions were isolated from sheep age 1.0 to 1.5 years for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were significantly higher in the BMX-exposed adult offspring versus CON sheep. Key Words: angiotensin receptors Ⅲ kidney Ⅲ fetal programming Ⅲ hypertension G lucocorticoids have an important influence on cell maturation and differentiation, particularly in the developing lung. 1 Indeed, the treatment of mothers in immediate jeopardy of preterm delivery with synthetic glucocorticoids enhances fetal lung maturation and lessens respiratory distress syndrome, as well as substantially reduces neonatal mortality and morbidity; glucocorticoid administration is now standard care for women with preterm labor before 35 weeks gestation. However, a single course of antenatal corticosteroid is associated with higher blood pressure in adolescence and decreased insulin sensitivity and renal function in adulthood. 2,3 Experimental studies demonstrate that exposure of the fetus to elevated glucocorticoids during this critical period of gestation results in the development of elevated blood pressure once the offspring reaches adulthood. 4 In a wellcharacterized model of fetal programming, adult offspring of sheep exposed antenatally to the glucocorticoid betamethasone (BMX) exhibit increased mean arterial pressure (MAP) that is associated with reduced baroreflex sensitivity and an attenuated capacity to excrete sodium. 5-7 Furthermore, steroid-induced programming may selectively influence the enzymatic components of the renin-angiotensin system, such that the ratio of angiotensin-converting enzyme (ACE) to ACE2 is increased in the circulation and kidney favoring the Ang II-AT 1 receptor axis. 8,9 In this regard, sensitivity to Ang II and other stressors is enhanced in the offspring of glucocorticoid-exposed mothers. 9 -13 Indeed, acute treatment with an AT 1 receptor antagonist lowers blood pressure in adult exposed sheep at a therapeutic dose that does not influence pressure in the nonexposed adults. 5 We recently reported the increased expression of the angiotensin receptor subtype AT 1 , and a concomitant decrease in the AT 2 subtype within the kidney cortex of older (age 3-5 years) versus younger adult (age 1.5 years) sheep. 14 This altered receptor ratio was associated with an increased response in the Ang II-dependent release of reactive oxygen species (ROS) that was abolished by an AT 1 receptor antagonist. 14 In lieu of the functional role of glucocorticoids to influence tissue maturation, we hypothesize that antenatal exposure to glucocorticoids may influence renin-angiotensin system receptors to promote the development and/or...

show abstract

Section: Discussionsupporting

confidence: 64%

Glucocorticoid-Induced Fetal Programming Alters the Functional Complement of Angiotensin Receptor Subtypes Within the Kidney

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…All drugs were infused directly into the renal artery with syringes mounted on a multichannel pump. The dose for ANG-(1–7) and candesartan were obtained from our previous work documenting ANG II effects during intrarenal infusions in sheep (23). The dose of ANG-(1–7) was equvilent to ANG II because part of our long-term goal is to determine if antenatal betamethasone alters the relative efficacy of these two peptides in the kidney.…”

Section: Methodsmentioning

confidence: 99%

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

Contag

Carey

et al. 2012

J Renin Angiotensin Aldosterone Syst

Self Cite

View full text Add to dashboard Cite

Antenatal corticosteroid exposure reduces renal function and alters the intrarenal renin-angiotensin system to favor angiotensin activation of angiotensin type 1 receptor (AT1R) mediated responses in ovine offspring. This study aimed to assess whether antenatal steroid exposure would affect renal responses to the direct intrarenal infusion of angiotensin-(1–7) in rams and the Ang receptors involved in mediating responses to the peptide. Adult, uninephrectomized rams exposed to either betamethasone or vehicle before birth received intrarenal angiotensin-(1–7) infusions (1ng/kg/min) alone or in combination with antagonists to Ang receptors for 3 hours. Basal sodium excretion (UNa) was significantly lower and mean arterial pressure was significantly higher in betamethasone compared to the vehicle treated sheep. Angiotensin-(1–7) decreased UNa more in betamethasone than in vehicle treated sheep. Candesartan reversed the response to Angiotensin-(1–7) but D-Ala7-Angiotensin-(1–7) did not. Angiotensin-(1–7) infusion decreased effective renal plasma flow in both groups to a similar extent and the response was reversed by candesartan, but was not blocked by D-Ala7-Angiotensin-(1–7). Glomerular filtration rate increased significantly in both groups after 3h infusion of Angiotensin-(1–7) plus candesartan. These results suggest that antenatal exposure to a clinically relevant dose of betamethasone impairs renal function in rams. Moreover, Angiotensin-(1–7) appears capable of activating the AT1R in uninephrectomized rams.

show abstract

Developmental effect of antenatal exposure to betamethasone on renal angiotensin II activity in the young adult sheep

Cited by 15 publications

References 53 publications

Glucocorticoid-Induced Fetal Programming Alters the Functional Complement of Angiotensin Receptor Subtypes Within the Kidney

Glucocorticoid-Induced Fetal Programming Alters the Functional Complement of Angiotensin Receptor Subtypes Within the Kidney

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

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

Contact Info

Product

Resources

About