Renal and Hormonal Mechanisms of Perinatal Programming

围产期规划的肾脏和激素机制

• 批准号: 6798805
• 负责人: LORI L WOODS
• 金额: $ 29.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798805
• 关键词: cardiovascular disorder; corticosterone; dexamethasone; early experience; embryo /fetus pharmacology; glucocorticoids; hormone metabolism; hormone regulation /control mechanism; hypertension; laboratory rat; nephrogenesis; pregnancy; renin angiotensin system

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.

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“编程”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（11 β-HSD）活性降低，该酶被认为可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规划中的作用，以及它们增加后代血压的机制尚不清楚。这些研究将检验总体假设，即在发育过程中过量暴露于母体糖皮质激素通过抑制胎儿肾内肾素-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变化，从而使个体患成人高血压。 具体目标是：1）确定胎儿暴露于母体糖皮质激素导致后代患高血压的机制，具体而言，检验过量母体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、肾功能降低和高血压的假设。还将审查糖皮质激素给药造成的营养不良在多大程度上对方案拟订起作用。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”，以及是否与肾脏发生相吻合。 将在整个妊娠期间或仅在妊娠前半期（肾发生前）或后半期（肾发生期间）给予妊娠大鼠皮质酮（一种天然糖皮质激素）、地塞米松（一种不被11 β-HSD灭活的合成糖皮质激素）或甘珀酸（一种11 β-HSD抑制剂）。将仔细注意这些药物的剂量选择以及配对喂养对照的使用。将在胎仔和新生动物中测量肾内RAS活性。将在长期使用仪器的幼年和成年后代中测量动脉压、肾功能和肾单位数量。