: The primary goal of this program project application is to investigate the long-term effects of antenatal exposure to synthetic glucocorticoids on renal functional and blood pressure postnatally. This topic has major significance today because of the widespread clinical use of synthetic glucocorticoids in the perinatal period to enhance lung maturation. The proposed studies encompass three projects in the same, widely used animal model (the sheep at different stages of development) to examine specific systems and mechanisms mediating the effects of antenatal steroid treatment on aspects of kidney development and function, the neural control of the cardiovascular system and blood pressure. They are coupled with a clinical project to document in children between 10-16 years of age, the effects of glucocorticoid exposure on blood pressure, blood pressure responsivity and indices of renal function. Specifically, Project 1 examines the impact of prenatal steroid exposure on the intra-renal renin-angiotensin system, renal function in vivo and blood pressure at different stages of development. Project 2 focuses on the effects of prenatal steroid exposure on sodium handling by the kidney using both in vitro and in vivo approaches. Project 3 establishes the impact of antenatal glucocorticoids on the brain renin angiotensin system, baroreceptor function and the regulation of sympathetic outflow. Finally, Project 4 establishes, in a well-defined patient population, the impact of prenatal steroid exposure on blood pressure, the responsiveness of blood pressure to stimulation and on indices of renal functional in children and how this impact is modulated by factors such as growth and fitness. Thus, all the animal projects have a high level of scientific integration and the results of the clinical project will provide a high level of relevance for the work in the animal model. The data obtained will improve our understanding of the consequences of the use of glucocorticoids antenatally and may help to identify a population of children at risk for the development of high blood pressure as adults. This outcome would obviously serve as a stimulus for the development of monitoring and early intervention strategies to be used in children exposed to glucocorticoids prior to birth. Thus, a long-term benefit of the proposed studies may be to reduce the overall morbidity associated with elevations in blood pressure in such a population. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD047584-01A1
Application #
6970583
Study Section
Special Emphasis Panel (ZHD1-DSR-A (JR))
Program Officer
Ilekis, John V
Project Start
2005-08-20
Project End
2010-06-30
Budget Start
2005-08-20
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$908,407
Indirect Cost
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
South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2018) Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm. J Pediatr :
South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2018) Association between preterm birth and the renin-angiotensin system in adolescence: influence of sex and obesity. J Hypertens 36:2092-2101
Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
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
Sigmund, Curt D; Diz, Debra I; Chappell, Mark C (2017) No Brain Renin-Angiotensin System: Déjà vu All Over Again? Hypertension 69:1007-1010
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
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
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
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

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