Substantial evidence suggests that events occurring prenatally have long term effects on development extending to adulthood. The outcome of some of these effects is a predisposition to certain diseases including hypertension. Some evidence indicates that these predisposing events involve exposure of the fetus to high levels of glucocorticoids at critical stages of development and that one potential target organ is the kidney. However, our understanding of the changes in renalfunction resulting from the """"""""programming"""""""" effects of glucocorticoids and the mechanisms involved is almost non-existent. Therefore, the objective of this project is to define the mechanisms whereby exposure of thefetus to a clinically relavent dose of glucocorticoids at a crucialperiod of gestation (peak of nephrogenesis) affects sodium handling and blood pressure in the adult. We will study a widely used animal model, the sheep, because it is similar to humans in terms of the timing of nephrogenesis relative to stage of gestation and these animals will provide sufficient quanties of renal tissue for our in vitro studies. Wehypothesize that: 1) Glucocorticoid exposure prenatally reduces nephron number and results in alterations in the intrarenal renin-angiotensin system (RAS) including increases in the ratio ofangiotensin converting enzyme to angiotensin converting enzyme2, consequent changes in theAngII to Ang-(l-7)balance andinadequatefeedback regulation of the RASlater in life;and, 2) these changes will be accompanied by impaired sodium excretion resulting from alterations in sodium transport and will increase blood pressure. We will use specific assays for the various angiotensin peptides (Ang I, Ang II and Ang 1-7), assays of enzyme and sodium transporter activity, localization procedures (immunocytochemistry and autoradiography) and molecular techniques to systematically evaluate components of the intrarenal and systemic RAS and sodium handling by the kidney in control and glucocorticoid exposed groups. A combination of in vitro and in vivo studies will be employed at different stages of maturation to establish the relationships between alterations in the RAS, sodium handling, and blood pressure. Understanding more about the impact of glucocorticoids on these inter- relationships is important because of the current use of antenatal steroids in obstetrics to enhance fetal lung maturation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD017644-25
Application #
8004065
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (05))
Program Officer
Ilekis, John V
Project Start
1984-01-01
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2013-11-30
Support Year
25
Fiscal Year
2011
Total Cost
$254,326
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
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
Su, Yixin; Bi, Jianli; Pulgar, Victor M et al. (2015) Antenatal glucocorticoid treatment alters Na+ uptake in renal proximal tubule cells from adult offspring in a sex-specific manner. Am J Physiol Renal Physiol 308:F1268-75
Wilson, Bryan A; Cruz-Diaz, Nildris; Marshall, Allyson C et al. (2015) An angiotensin-(1-7) peptidase in the kidney cortex, proximal tubules, and human HK-2 epithelial cells that is distinct from insulin-degrading enzyme. Am J Physiol Renal Physiol 308:F594-601
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
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
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
Marshall, Allyson C; Shaltout, Hossam A; Nautiyal, Manisha et al. (2013) Fetal betamethasone exposure attenuates angiotensin-(1-7)-Mas receptor expression in the dorsal medulla of adult sheep. Peptides 44:25-31
Bi, Jianli; Contag, Stephen A; Carey, Luke C et al. (2013) Antenatal betamethasone exposure alters renal responses to angiotensin-(1-7) in uninephrectomized adult male sheep. J Renin Angiotensin Aldosterone Syst 14:290-8
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
Shaltout, Hossam A; Rose, James C; Chappell, Mark C et al. (2012) Angiotensin-(1-7) deficiency and baroreflex impairment precede the antenatal Betamethasone exposure-induced elevation in blood pressure. Hypertension 59:453-8

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