Renal and Hormonal Mechanisms of Perinatal Programming

描述（由申请人提供）：流行病学数据显示，早期生长模式与几种成人疾病（包括心血管疾病）风险增加之间存在反比关系。这表明围产期环境中影响胎儿生长的因素可以“程序化”个体增加心血管风险。胎儿暴露于过量的母体糖皮质激素可能起重要作用，部分原因是胎盘酶（11β - hsd）活性降低，而胎盘酶被认为可以保护胎儿免受母体类固醇的影响。然而，母体糖皮质激素在围产期程序中的作用，以及它们增加后代血压的机制，尚不清楚。这些研究将验证在发育过程中过量暴露于母体糖皮质激素会抑制胎儿肾内肾素血管紧张素系统（RAS）和损害肾脏发育，从而导致肾脏结构和功能的永久性改变，从而导致成人高血压个体。具体目的是：1)确定胎儿暴露于母亲的糖皮质激素对后代高血压的影响机制，特别是，验证过量的母亲糖皮质激素抑制胎儿/新生儿肾内肾素-血管紧张素系统，导致肾单位数量减少、肾功能下降和高血压的假设。还将审查糖皮质激素引起的营养不良在规划中所起的作用。2)确定子代血压对母体糖皮质激素敏感的关键期或“窗口期”，是否与肾发生相吻合。皮质酮（一种天然存在的糖皮质激素）、地塞米松（一种合成的糖皮质激素，未被11β - hsd灭活）或卡贝诺酮（11β - hsd的抑制剂）将在妊娠期间或仅在妊娠的前半期（肾前期）或后半期（肾发生期间）给予妊娠大鼠。将仔细注意这些药物剂量的选择，以及使用成对喂养对照。将在胎儿和新生动物中测量肾内RAS活性。动脉压，肾功能和肾单位数将测量长期仪器的青少年和成年后代。

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.