A significant development in prenatal care over the last 30 years is the treatment of pregnant women at risk for premature delivery with synthetic corticosteroids to facilitate fetal lung maturation. However, data from experimental animals and epidemiological studies have raised concerns about the possible untoward consequences of prenatal exposure to excess glucocorticoids. During the past five years we have studied the programming effects of antenatal steroid therapy in a widely used sheep model and in a cohort of adolescents. Among the programming effects of antenatal steroids we have observed in the sheep are increases in blood pressure, reductions in nephron number, alterations in the intrarenal renin-angiotensin system (RAS) including decreased angiotensin converting enzyme 2 (ACE2), increased angiotensin type 1 receptor expression, and an increased Ang li to Ang(1-7) ratio all of which favor increased tone from Ang li stimulation of its type 1 receptor in conjunction with the altered RAS, we find impairments in the ability to excrete a sodium load, decreases in baroreflex sensitivity (SRS) and heart rate variability (HRV) and increases in insulin resistance in the animal model. In the steroid exposed adolescents there is lower urinary ACE2, an increased ratio of urinary Ang il to Ang (1-7) and higher levels of urinary albumin. Thus, there appear to be several commonalities in the responses to antenatal steroids in the animal model and the adolescents. To further establish these programming effects and their consequences, we propose a series of studies in this application to examine the mechanisms of the steroid-induced alterations in renal function (Projects 1 &4), BRS (Projects 3 &4), insulin resistance (Projects 2 &4) and the possibility that obesity acts as a "second hit" and exacerbates the effects of antenatal steroid exposure in both the animal model and the adolescents (Projects 1, 2 &4). Our hypothesis is that there will be greater impact of the adverse programming effects of antenatal steroids in offspring who are obese. If this proves to be the case our studies will identify an at risk population and a modifiable risk factor. Therefore our work may promote the identification of new, early intervention strategies to reduce the risk of hypertension as well as renal and metabolic abnormalities in antenatal steroid exposed individuals.

Public Health Relevance

Synthetic glucocorticoids are routinely given to pregnant women who threaten to deliver prematurely in order to enhance survival and reduce morbidity in their newborn infants. We now know that antenatal steroid exposure can reduce baroreflex sensitivity, increase blood pressure, impair renal development and function, and produce insulin resistance in experimental animals and we have observed some similar effects in a group of children studied at 14 years of age. Studies we propose here have a long-term goal of developing approaches for reducing the risk of developing diseases such as hypertension and metabolic syndrome in this population exposed to corticosteroids before birth.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD047584-07
Application #
8328918
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (RJ))
Program Officer
Ilekis, John V
Project Start
2004-07-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$1,432,093
Indirect Cost
$446,016
Name
Wake Forest University Health Sciences
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Washburn, Lisa K; Brosnihan, K Bridget; Chappell, Mark C et al. (2015) The renin-angiotensin-aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia. J Renin Angiotensin Aldosterone Syst 16:529-38
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2014) Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming. Peptides 52:74-81
Wilson, Bryan A; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 307:R487-9
Chappell, Mark C; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne) 4:201
Lee, J-H; Zhang, J; Massmann, G A et al. (2014) Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling. J Dev Orig Health Dis 5:56-62
Marshall, Allyson C; Pirro, Nancy T; Rose, James C et al. (2014) Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep. J Neurochem 130:313-23
Bi, Jianli; Contag, Stephen A; Chen, Kai et al. (2014) Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep. Am J Physiol Renal Physiol 307:F1013-22
Nixon, P A; Washburn, L K; O'Shea, T M (2013) Antenatal steroid exposure and pulmonary outcomes in adolescents born with very low birth weight. J Perinatol 33:806-10
Washburn, Lisa; Nixon, Patricia; Russell, Gregory et al. (2013) Adiposity in adolescent offspring born prematurely to mothers with preeclampsia. J Pediatr 162:912-7.e1
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2013) Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep. Am J Physiol Regul Integr Comp Physiol 305:R679-88

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