ANTENATAL STEROID EXPOSURE AND THE INTRARENAL RENIN-ANGIOTENSIN

大量证据表明，产前发生的事件对发育有长期影响，包括 成人期。其中一些影响的结果是容易患上某些疾病，包括高血压。一些人 有证据表明，这些易感事件涉及胎儿暴露于高水平的糖皮质激素。 在发育的关键阶段，一个潜在的目标是肾脏。然而，我们对 糖皮质激素对肾脏的“程序化”影响的机制几乎不存在。因此， 该项目的目标是确定胎儿暴露于临床相关剂量的 妊娠初期(肾脏形成高峰期)糖皮质激素影响肾脏发育和功能 成年人的血压。我们将研究一种广泛使用的动物模型--绵羊，因为它在 关于肾脏发生的时间与妊娠阶段的关系，这些动物将提供足够的质量 用于我们的体外研究的肾组织。我们的基本假设是，产前接触糖皮质激素会减少肾单位 出生后会引起肾内肾素血管紧张素系统(RAS)代偿性改变的数字 包括血管紧张素转换酶与血管紧张素转换酶2的比值升高和不足 RAS的反馈调节。这些变化是对肾脏的排泄需求增加的结果。 出生后，他们会伴随着肾功能的改变和血压的升高。我们将使用 不同血管紧张素肽(Ang I、Ang II和Ang 1-7)的Western blotting特异性酶活性测定 和定位程序(免疫细胞化学和放射自显影)，以系统地评估 肾内和全身RAS。体外和体内研究的结合将在不同的阶段进行 成熟以建立肾功能、RAS和血压变化之间的关系。 更多地了解糖皮质激素对这些相互关系的影响是因为目前 产科应用产前类固醇促进胎儿肺成熟。

Substantial evidence suggests that events occurring prenatally have long term effects on development extending to adulthood. The outcome of some of these effects is a predisposition to certain diseases including hypertension. Some evidence indicates that these predisposing events involve exposure of the fetus to high levels of glucocorticoids at critical stages of development and that one potential target is the kidney. However, our understanding of the mechanisms involved in the "programming" effects of glucocorticoids on the kidney is almost non-existent. Therefore, the objective of this project is to define the mechanisms whereby exposure of the fetus to a clinically relavent dose of glucocorticoids at an initial period of gestation (peak of nephrogenesis) affects renal development and function and blood pressure in the adult. We will study a widely used animal model, the sheep, because it is similar to humans in terms of the timing of nephrogenesis relative to stage of gestation and these animals will provide sufficient quanties of renal tissue for our in vitro studies. Our basic hypothesis is that antenatal glucocorticoid exposure will reduce nephron number which, after birth, will cause compensatory alterations in the intrarenal renin angiotensin system (RAS) including increases in the ratio of angiotensin converting enzyme to angiotensin converting enzyme 2 and inadequate feedback regulation of the RAS. These changes are the result of increased excretory demand placed on the kidneys after birth and they will be accompanied by alterations in renal function and increased blood pressure. We will use Western blotting for the various angiotensin peptides (Ang I, Ang II and Ang 1-7) specific assays of enzyme activity and localization procedures (immunocytochemistry and autoradiography) to systematically evaluate the components of the intrarenal and systemic RAS. A combination of in vitro and in vivo studies will be employed at different stages of maturation to establish the relationships between alterations in renal function, the RAS and blood pressure. Understanding more about the impact of glucocorticoids on these inter-relationships is because of the current use of antenatal steroids in obstetrics to enhance fetal lung maturation.