The mechanism by which glucocorticoids program the cardiometabolic impairment is not completely understood. Although one final common pathway may involve the kidney, the decrease in nephron number, by itself, does not explain the elevation in blood pressure. In this project we will address an additional mechanism by which prenatal steroids cause cardiometabolic impairment, i.e., a functional alterafion in the local adipose tissue renin angiotensin system (RAS) and that these alterafions are amplified by obesity, a """"""""second hit"""""""" that tilts the balance towards insulin resistance and further elevations in blood pressure. The working hypothesis is that antenatal steroid exposure has a """"""""programming effect"""""""" on white adipose tissue development and funcfion and predisposes the individual for developing insulin resistance and hypertension. We further hypothesize that 1) antenatal steroid exposure alters the function of a local renin-angiotensin system (RAS) within the white adipose tissue, 2) the abnormal adipose tissue RAS function predisposes the individual for developing cardiovascular and metabolic alterations, 3) Obesity exaggerates the functional derangement of adipose tissue, thus increasing the impact antenatal steroid exposure has on cardiovascular and metabolic regulafion. Obesity will be induced using a standard ruminant formula, thus fat composifion of the diet is removed as a confounding factor. Sheep of both sexes will be randomly allocated to be fed 100% of recommended nutritional allowance or ad libitum for three months. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine if obesity, a modifiable risk factor, has a significant contribution in the development of cardiovascular diseases in animals exposed antenatally to steroids. We will test these hypotheses with the following specific aims:
Specific Aim 1 : To study the effects of antenatal glucocorticoid exposure on the expression of critical components of the RAS and inflammatory mediators in white adipose fissue depots (subcutaneous, omental and perirenal) and the consequences these changes have on adipose fissue function.
Specific Aim 2 : To determine which component(s) of the adipose tissue RAS mediate(s) the cardiometabolic dysregulafion in animals exposed antenatally to glucocorticoids.
Specific Aim 3 : To study the mechanism by which superimposed obesity exaggerates the cardiovascular and metabolic abnormalities induced by antenatal steroid exposure.

Public Health Relevance

(See Instructions): Antenatal glucocorticoids remain the single alternative to reduce the risk of respiratory distress syndrome in premature newborns. Considering the functional upregulafion of the RAS system in steroid-treated animals and the role of the RAS in the regulation of blood pressure in obese and diabetic humans, results from this proposal will pave the way for establishing if obesity in adulthood magnifies the alterations already present in animals exposed prenatally to glucocorticoids.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
2P01HD047584-06A1
Application #
8212814
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (RJ))
Project Start
2011-07-01
Project End
2016-08-31
Budget Start
2011-09-15
Budget End
2012-08-31
Support Year
6
Fiscal Year
2011
Total Cost
$198,875
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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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