During development, glucocorticoids (GC) are essential for organ maturation, particularly the fetal lung. In 1994 an NIH consensus panel recommended the use of glucocorticoids for enhancing fetal lung maturation in pregnancies threatened by premature labor between 24 and 34 weeks of gestation. As a consequence, the use of GC given as single or multiple doses has increased from 15 percent to more than 50 percent in such pregnancies. The possibility that GC may have adverse effects has prompted the questioning of the growing use of GC in the perinatal period. Our working hypothesis is that maternal GC therapy to promote fetal lung maturation has a fetal programming effect on the kidney that will appear as hypertension later in life. Specifically, our hypotheses are: 1) Antenatal administration of synthetic GC predisposes the individual to hypertension in adult life; 2) Exposure to synthetic GC, at critical periods during fetal life, disrupts nephrogenesis resulting in kidneys with a reduced number of nephrons; 3) Synthetic GC disrupts nephrogenesis by downregulating the fetal ReninAngiotensin-System (RAS); 4) The intrarenal mechanism involved in the effects of synthetic GC on the fetal RAS includes inhibition of COX-2 and Type I NOS in macula densa and the downregulation of angiotensin AT1 and AT2 receptors in renal tissue; 5) Reduction in nephron number during fetal life results in hypertension during adulthood. We will test these hypotheses by administering single or multiple clinically relevant doses of betamethasone to pregnant sheep at a gestational age equivalent to that used in clinical practice (0.6 of gestation). To specifically test whether reducing nephron mass at this specific stage of development produces hypertension in adults, we will perform fetal unilateral nephrectomy at 0.6 of gestation and monitor blood pressure and renal function at selected intervals after birth until adulthood. In addition, using molecular biology tools we will study potential mechanisms by which GC may alter fetal kidney development. Specifically, we will study the expression of the RAS system and of two important regulators of this system during fetal development, i.e., Type I NOS and PGHS-2. These data will provide important information on the potential impact of prenatal GC administration on blood pressure in adult life and the mechanism by which GC exerts this effect.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Berberich, Mary Anne
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Wake Forest University Health Sciences
Obstetrics & Gynecology
Schools of Medicine
United States
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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
Lee, J-H; Zhang, J; Massmann, G A et al. (2014) Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling. J Dev Orig Health Dis 5:56-62
Lee, Jeong-Heon; Zhang, Jie; Flores, Lourdes et al. (2013) Antenatal betamethasone has a sex-dependent effect on the in vivo response to endothelin in adult sheep. Am J Physiol Regul Integr Comp Physiol 304:R581-7
Shaltout, Hossam A; Chappell, Mark C; Rose, James C et al. (2011) Exaggerated sympathetic mediated responses to behavioral or pharmacological challenges following antenatal betamethasone exposure. Am J Physiol Endocrinol Metab 300:E979-85
Zhang, Jie; Massmann, G Angela; Rose, James C et al. (2010) Differential effects of clinical doses of antenatal betamethasone on nephron endowment and glomerular filtration rate in adult sheep. Reprod Sci 17:186-95
Eckman, Delrae M; Kerr, Brady A; Fuloria, Mamta et al. (2010) Antenatal betamethasone alters vascular reactivity in adult female ovine cerebral arteries. Pediatr Res 68:344-8
Connors, Ngina; Valego, Nancy K; Carey, Luke C et al. (2010) Fetal and postnatal renin secretion in female sheep exposed to prenatal betamethasone. Reprod Sci 17:239-46
Contag, Stephen A; Bi, Jianli; Chappell, Mark C et al. (2010) Developmental effect of antenatal exposure to betamethasone on renal angiotensin II activity in the young adult sheep. Am J Physiol Renal Physiol 298:F847-56
Tang, Lijun; Carey, Luke C; Bi, Jianli et al. (2009) Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep. Am J Physiol Regul Integr Comp Physiol 296:R309-17
Shaltout, Hossam A; Westwood, Brian M; Averill, David B et al. (2007) Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. Am J Physiol Renal Physiol 292:F82-91

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