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 gestation (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 function 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 alterations 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 timing of nephrogenesis relative to stage of gestation and because these animals provide sufficient quantities 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 reductions 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 peptides. We will use unilateral nephrectomy or obesity (induced by voluntary overeating) as second """"""""hits"""""""" and evaluate renal function and markers of renal damage to establish if there is a predisposing relationship between prenatal betamethasone and subsequent renal injury. Understanding more about the impact of antenatal glucocorticoids on renal function and susceptibility 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 early intervention to prevent premature deterioration of renal function in adulthood.

Public Health Relevance

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 reduction 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 function 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.

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 (2016) Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol 310:H137-52
Nixon, Patricia A; Washburn, Lisa K; Michael O'Shea, Thomas et al. (2016) Antenatal steroid exposure and heart rate variability in adolescents born with very low birth weight. Pediatr Res :
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
Washburn, Lisa K; Brosnihan, K Bridget; Chappell, Mark C et al. (2015) The renin-angiotensin-aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia. J Renin Angiotensin Aldosterone Syst 16:529-38
Washburn, Lisa K; Nixon, Patricia A; Russell, Gregory B et al. (2015) Preterm Birth Is Associated with Higher Uric Acid Levels in Adolescents. J Pediatr 167:76-80
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
Chappell, Mark C; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne) 4:201
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

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