During fetal life, the renin-angiotensin system (RAS) has multiple vital roles including influencing kidney growth, renal vascular development and regulating fetal arterial blood pressure under basal conditions and in times of intrauterine stress. Currently, our understanding of the ontogeny of this system is incomplete. In particular, there are major gaps in our understanding of the maturation of local mechanisms which modulate renin secretion. One local modulator which may be quite important in this regard is nitric oxide (NO) produced by type l nitric oxide synthase in the macula densa. In this application, we will test three inter-related hypotheses concerning the role of NO. Briefly, these hypothesis are: i) that NO is a positive modulator of renin secretion in the mature fetus with a minimal role in the immature animal; 2) that NO exerts its effects by two pathways, a direct one involving inhibition of phosphodiesterase III in juxtaglomerular cells and an indirect one involving endoperoxide synthetase in the macula densa; and 3) that chronic manipulations of the macula densa in the immature fetus will promote the stimulatory effect of NO. We will use fetal sheep to test these hypotheses because we can study this model in utero in the absence of stress and anesthesia. Also the kidneys of these animals are large enough to provide sufficient amounts of renal cortical tissue for our in vitro studies without requiring excessive numbers of animals. We will use western blotting, immunocytochemistry, assays of enzyme activity and RNase protection assays to study the expression of NOS-l, COX-2, and renin in fetal kidneys at two stages of development and following chronic manipulations in vivo. We will study plasma renin responses to pharmacological and physiological interventions in order to establish a role for NO in vivo. We will use pharmacological approaches in vitro to define the mechanisms whereby NO can stimulate the RAS. To our knowledge, these will be the first studies to systematically examine the maturation of the ability of NO to modulate renin secretion and mechanisms by which this modulation is accomplished. Thus, the studies will provide important new information on the role of NO in the modulation of renin secretion during development and, by extension on the maturation of the macula densa as a regulator of renin expression. Understanding more about the development of these inter- relationships is important because derangement of the timely establishment of the stimulatory influence of NO could have adverse effects on kidney development. Impaired fetal kidney growth and maturation of renal function can result later in hypertension in both the infant and adult.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037885-04
Application #
6521213
Study Section
Special Emphasis Panel (ZRG1-MET (01))
Program Officer
Ilekis, John V
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$344,627
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
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Pulgar, Victor M; Zhang, Jie; Massmann, G Angela et al. (2007) Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion. Brain Res 1176:18-26
Pulgar, Victor M; Zhang, Jie; Massmann, G Angela et al. (2006) Prolonged mild hypoxia alters fetal sheep electrocorticogram activity. J Soc Gynecol Investig 13:404-11
Mertz, Heather L; Liu, Jingfang; Valego, Nancy K et al. (2003) Inhibition of cyclooxygenase-2: effects on renin secretion and expression in fetal lambs. Am J Physiol Regul Integr Comp Physiol 284:R1012-8
Pryor, Elizabeth C; Zhang, Jie; Massmann, G Angela et al. (2002) Prolonged mild fetal hypoxia up-regulates type I nitric oxide synthase expression in discrete areas of the late-gestation fetal sheep brain. Am J Obstet Gynecol 187:164-70