Antenatal corticosteroid (ANCS) treatment is recommended for all pregnant women expected to deliver between 24 and 34 weeks gestation, and over 100,000 fetuses are exposed to ANCS in the United States each year. ANCS significantly decreases neonatal mortality and morbidity, but has been associated with elevated blood pressure, insulin resistance, and reduced renal funcfion in adolescents and young adults. Our data indicate that 14 year olds who were born with very low birth weight (<1500g) and were exposed to ANCS show physiological differences that might predispose them to elevated blood pressure later in life. Specifically, the ANCS-exposed adolescents had lower levels of urinary Angiotensin Converting Enzyme 2, higher rafios of urinary Angiotensin II (Ang 11) to Angiotensin (1-7), lower urinary sodium levels, and higher urinary albumin levels. Thesefindingsin humans correspond to our colleagues'findingsthat ANCS-exposed sheep have reduced nephron number and sodium excretion, alterations in the renin-angiotensin system (RAS) favoring increased Ang 11 tone, increased blood pressure, insulin resistance, and increased leptin. ANCS-exposed sheep also have alterations in the central RAS that were associated with decreased heart rate variability and baroreflex sensitivity, and these alterations preceded the blood pressure elevation. In addifion, the effects of ANCS in sheep are exacerbated by obesity, which has important implications for our cohort in which >34% are ovenweight. In the current application, we propose to study our human cohort at age 19 years, to assess the relationship of ANCS exposure to the following: 1) autonomic balance as reflected in heart rate variability and baroreflex sensitivity, 2) renal sodium handling, as indicated by stress-induced pressure natriuresis, 3) insulin sensitivity as assessed by oral glucose tolerance testing, 4) levels of circulating adipokines (leptin, adiponecfin, and resistin), and 5) blood pressure. We hypothesize that young adults who had very low birth weight and were exposed to ANCS will have decreased baroreflex sensitivity, decreased ability to excrete sodium, decreased insulin sensitivity, increased leptin levels, and increased blood pressure, and that these findings will be associated with alterations in the RAS that promote increased Ang II tone. We will collect data on known modifiable correlates, such as physical activity, adiposity, and diet. Our studies may identify a population at increased risk for cardiometabolic disease and inform approaches for monitoring and eariy intervention that will improve health outcomes of ANCS-exposed individuals as they mature.

Public Health Relevance

Corticosteroids are commonly given to pregnant women with threatened preterm delivery to improve the survival of the infant. Exposure to antenatal steroids may have adverse long-term consequences. These studies will investigate the long-term effects of antenatal steroid exposure on cardiovascular and metabolic risk factors with a goal of prevenfing and treafing hypertension and metabolic disease in individuals born with very low birth weight and exposed prenatally to steroids.

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 #
8381685
Study Section
Special Emphasis Panel (ZHD1-DSR-Z)
Project Start
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$478,021
Indirect Cost
$136,354
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

Showing the most recent 10 out of 56 publications