Renal and Hormonal Mechanisms of Perinatal Programming

描述(由申请人提供)：流行病学数据显示，早期生长模式与包括心血管疾病在内的几种成人疾病风险增加之间存在反向关系。这表明，围产期环境中影响胎儿生长发育的因素可能会增加个体的心血管风险。胎儿接触过多的母体糖皮质激素可能起到重要作用，部分原因是胎盘酶(11β-HSD)活性降低，这种酶被认为可以保护胎儿免受母体类固醇的伤害。然而，母体糖皮质激素在围产期计划中的作用，以及它们增加后代血压的机制尚不清楚。这些研究将检验最重要的假设，即发育期间过量接触母体糖皮质激素会抑制胎儿肾素-血管紧张素系统(RAS)，损害肾脏发育，从而导致肾脏结构和功能的永久性变化，从而导致成人高血压的发生。具体目标是：1)确定胎儿暴露于母亲的糖皮质激素使后代患高血压的机制，具体地说，测试母亲过量的皮质激素抑制胎儿/新生儿肾内肾素-血管紧张素系统的假设，导致肾单位数量减少、肾功能下降和高血压。还将审查由糖皮质激素治疗引起的营养不良在规划中的作用程度。2)确定子代血压对母体糖皮质激素敏感的临界期或“窗口期”及其与肾脏发生的关系。怀孕大鼠将在整个妊娠期间或仅在怀孕的前半部分(肾发生前)或后半部分(在肾发生期间)服用皮质酮(一种自然产生的糖皮质激素)、地塞米松(一种不被11β-HSD灭活的合成糖皮质激素)或甘草酮(11β-HSD的抑制剂)。将仔细注意这些制剂的剂量选择，以及配对喂养对照的使用。肾内RAS活性将在胎儿和新生动物中进行测量。动脉压、肾功能和肾单位数量将在长期使用仪器的幼年和成年后代中进行测量。

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.