Renal and Hormonal Mechanisms of Perinatal Programming

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DESCRIPTION (provided by applicant): Epidemiologic data have shown an inverse relationship between early growth patterns and increased risk for several adult diseases, including cardiovascular disease. This indicates that factors in the perinatal environment that affect fetal growth can "program" the individual for increased cardiovascular risk. Fetal exposure to excess maternal glucocorticoids may play an important role, in part by reduced activity of a placental enzyme (11beta-HSD) which is thought to protect the fetus from maternal steroids. However, the role of maternal glucocorticoids in perinatal programming, and the mechanisms by which they increase offspring blood pressure, are not known. These studies will test the overarching hypothesis that excess exposure to maternal glucocorticoids during development programs an individual for adult hypertension by suppressing the fetal intrarenal renin-angiotensin system (RAS) and impairing renal development, thus causing permanent changes in renal structure and function. The Specific Aims are: 1) to determine the mechanisms by which exposure of the fetus to glucocorticoids from the mother programs the offspring for hypertension, and specifically, to test the hypothesis that excess maternal corticoids suppress the intrarenal renin-angiotensin system in the fetus/newborn, leading to a reduced number of nephrons, reduced renal function, and hypertension. The extent to which undernutrition caused by glucocorticoid administration plays a role in programming will also be examined. 2) To determine the critical period or "window" of sensitivity of offspring blood pressure to maternal glucocorticoids and whether it coincides with nephrogenesis. Corticosterone (a naturally-occurring glucocorticoid), dexamethasone (a synthetic glucocorticoid not inactivated by 11beta-HSD), or carbenoxolone (an inhibitor of 11beta-HSD) will be given to pregnant rats either throughout gestation or for only the first half (pre-nephrogenesis) or second half (during nephrogenesis) of pregnancy. Careful attention will be given to choice of doses of these agents, as well as to use of pair-fed controls. Intrarenal RAS activity will be measured in fetal and newborn animals. Arterial pressure, renal function, and nephron number will be measured in chronically instrumented juvenile and adult offspring.