Substantial evidence demonstrates that prenatal events have effects on development resulting in pathophysiological consequences in adulthood. The outcome of some of these effects is a predisposition to certain diseases including hypertension. Our data from the previous funding period demonstrate that prenatal exposure to clinically relevant doses of glucocorticoids at a critical stage of gestafion (peak of nephrogenesis) reduces nephron number, impairs excretion of a salt load (that is gender dependent) and elevates blood pressure in adulthood. Although knowledge of the mechanisms whereby sodium excretion is altered is nearly nonexistent, alterations in the intrarenal renin-angiotensin system (RAS) which we have reported may be involved. In addition, it is not known if the alterations in renal development and the intrarenal RAS result in greater susceptibility to renal damage and greater loss of funcfion following a second insult. Therefore this proposed project has two objectives. The first is to determine if the mechanisms responsible for the reduced ability to excrete a sodium load involve alterafions in the receptors/signaling pathways that respond to the angiotensin peptides in the kidney. The second is to ascertain if prenatal betamethasone exposure results in higher risk for additional renal damage from an adverse event after birth. We will study sheep, because they are similar to humans in terms of the fiming of nephrogenesis relative to stage of gestation and because these animals provide sufficient quantifies of renal tissue for our in vitro studies. We hypothesize that: 1) the mechanisms involved in the reduced ability to excrete a sodium load include reducfions in the ability of Ang peptides to activate signaling pathways associated with natriuresis;and, 2) prenatal betamethasone exposure results in greater risk for renal damage and reductions in function following a second insult afterbirth. We will use specific assays to measure the angiotensin peptides and key components in the signaling pathways activated by them associated with natriuresis. Binding assays will be used to assess receptors for these pepfides. We will use unilateral nephrectomy or obesity (induced by voluntary overeafing) as second """"""""hits"""""""" and evaluate renal funcfion and markers of renal damage to establish if there is a predisposing relafionship between prenatal betamethasone and subsequent renal injury. Understanding more about the impact of antenatal glucocorticoids on renal funcfion and suscepfibility to renal damage in adulthood is important because of the widespread use of glucocorticoids in Obstetrics today. Our studies may identify a population at greater risk for renal disease and hypertension as they mature which could result in approaches for monitoring this at risk population and eariy inten/ention to prevent premature deterioration of renal function in adulthood.

Public Health Relevance

(See Instructions): We now know that antenatal glucocorticoids, which are commonly used to enhance fetal lung maturity in pregnant women threatening to deliver prematurely, have programming effects on blood pressure and kidney function. This project focuses on defining the mechanisms involved in the steroid-induced reducfion in ability to excrete a sodium load and in determining if an adverse condition after birth will produce greater renal damage and loss of renal funcfion in steroid exposed animals. Our results may identify a population at greater risk for renal disease as they mature and thus lead to approaches for monitoring and early interventions in this population. PROJECT/PERFORIVIANCE SITE(S) (If additional space is needed, use Project/Perfomiance Site Format Page) Project/

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Wake Forest University Health Sciences
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Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
Su, Yixin; Bi, Jianli; Pulgar, Victor M et al. (2017) Antenatal betamethasone attenuates the angiotensin-(1-7)-Mas receptor-nitric oxide axis in isolated proximal tubule cells. Am J Physiol Renal Physiol 312:F1056-F1062
South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2017) Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm. Pediatr Res 81:88-93
Washburn, Lisa K; Nixon, Patricia A; Snively, Beverly M et al. (2017) Antenatal corticosteroids and cardiometabolic outcomes in adolescents born with very low birth weight. Pediatr Res 82:697-703
Massmann, G Angela; Zhang, Jie; Seong, Won Joon et al. (2017) Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system. Am J Physiol Regul Integr Comp Physiol 312:R1029-R1038
Nixon, Patricia A; Washburn, Lisa K; Michael O'Shea, Thomas et al. (2017) Antenatal steroid exposure and heart rate variability in adolescents born with very low birth weight. Pediatr Res 81:57-62
Sigmund, Curt D; Diz, Debra I; Chappell, Mark C (2017) No Brain Renin-Angiotensin System: Déjà vu All Over Again? Hypertension 69:1007-1010
Wilson, Bryan A; Chappell, Mark C (2017) Assessment of the Renin-Angiotensin System in Cellular Organelle: New Arenas for Study in the Mitochondria. Methods Mol Biol 1614:99-121
Wilson, Bryan A; Cruz-Diaz, Nildris; Su, Yixin et al. (2017) Angiotensinogen import in isolated proximal tubules: evidence for mitochondrial trafficking and uptake. Am J Physiol Renal Physiol 312:F879-F886
Chen, Kai; Bi, Jianli; Su, Yixin et al. (2016) Sex-Specific Changes in Renal Angiotensin-Converting Enzyme and Angiotensin-Converting Enzyme 2 Gene Expression and Enzyme Activity at Birth and Over the First Year of Life. Reprod Sci 23:200-10

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