In the ovine fetus, plasma renin levels increase close to term, and renin responses to various stimuli are enhanced when compared with responses earlier in gestation. These changes are accompanied by increases in renal renin gene expression and renin content, and they occur in conjunction with elevations in fetal plasma cortisol. Thus, the purpose of this study was to test the hypothesis that a chronic, physiologic elevation in fetal plasma cortisol in early gestation would increase activity in the renin-angiotensin system prematurely. We studied fetuses (control, n = 8; cortisol infused, n = 11) at 94 ? 2 d of gestation. Fetal vessels were catheterized, and cortisol or saline solution was infused for 6 d. At the end of infusion, fetuses were hemorrhaged approximately 30% of estimated blood volume.The renin-angiotensin system undergoes marked maturational changes during development. Renin responsiveness to several physiologic and pharmacologic stimuli is greater in late-gestation fetuses than in fetuses earlier in the third trimester (1,2). In addition, renin mRNA levels significantly increase between 0.65 and 0.96 gestation, and a parallel increase in renal renin content also occurs (3). These findings indicate that in the perinatal period there is an activation of renin gene expression that is determined at least in part by events at the transcriptional level. The observed increase in renin gene expression is temporally associated with a pronounced and prolonged elevation in fetal plasma cortisol (4). Moreover, in the regulatory region of the human, rat, and mouse, renin gene glucocorticoid-responsive elements have been described (5). Therefore, in the present study, we investigated the possibility that cortisol plays a role in the activation of renin gene expression in fetal lambs. We hypothesized that chronic exposure of early-gestation fetuses (between 94 and 103 d of gestation) to cortisol levels similar to those observed in late gestation fetal lambs would cause a premature increase in renin Received March 7, 1994; accepted November 17, 1994. Correspondence: James C. Rose, Ph.D., Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Winston-Salem, NC 27157.Supported by Grant HD17644 from the National Institutes of Health.Blood samples were collected to measure plasma renin concentration. Then the animals were killed, and kidneys were removed gene expression as well as an enhancement of the renin response to hemorrhage.
METHODS
Animal Preparation and InfusionNineteen time-dated pregnant sheep were studied between 94 and 103 d of gestation (term, 145 d). Surgery was performed at 94 + 1 d of gestation. The surgical procedure has been previously described (6). Briefly, catheters were placed bilaterally in fetal femoral arteries (for blood collection and cardiovascular measurements) and veins (for infusion). Sheep were randomly assigned to one of two groups: vehicle or cortisol. One day after surgery the fetuses began receiving 6-d i.v. infusions of either vehicle (n = 8) or 0.86 pg/min/...
