ANTENATAL STEROID EXPOSURE AND THE INTRARENAL RENIN-ANGIOTENSIN

产前类固醇暴露与肾内肾素-血管紧张素

• 批准号: 7714597
• 负责人: JAMES C ROSE
• 金额: $ 6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714597
• 关键词: Adult; Affect; Agonist; Angiotensin Receptor; Angiotensinogen; Angiotensins; Animal Model; Animals; Autoradiography; Betamethasone; Biological Assay; Birth; Blood Pressure; Cells; Data; Development; Discipline of obstetrics; Disease; Dose; Enzymes; Event; Exposure to; Feedback; Fetal Development; Fetal Lung; Fetus; Forskolin; Glucocorticoids; Hour; Human; Hypertension; Impaired Renal Function; In Vitro; Isoproterenol; Kidney; Life; Link; Literature; Long-Term Effects; Nephrons; Numbers; Outcome; PTGS2 gene; Peptides; Peptidyl-Dipeptidase A; Perinatal Exposure; Plasma; Predisposition; Pregnancy; Procedures; Process; Production; Prostaglandins; Regulation; Relative (related person); Renal Tissue; Renal function; Renin; Renin-Angiotensin System; Sheep; Staging; Steroids; Testing; Time; Western Blotting; base; enzyme activity; immunocytochemistry; in vivo; lung maturation; mature animal; nephrogenesis; prenatal; prenatal exposure; programs; receptor; receptor expression; young adult

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.

大量证据表明，产前发生的事件对发育有长期影响， 成年其中一些影响的结果是易患某些疾病，包括高血压。一些 有证据表明，这些诱发事件涉及胎儿暴露于高水平的糖皮质激素， 发展的关键阶段，一个潜在的目标是肾脏。然而，我们对 参与糖皮质激素对肾脏的“编程”作用的机制几乎不存在。因此，我们认为， 本项目的目的是确定胎儿暴露于临床相关剂量的 妊娠初期（肾发生高峰期）的糖皮质激素影响肾发育和功能， 成人的血压。我们将研究一种广泛使用的动物模型，绵羊，因为它在 这些动物将提供足够数量的 肾脏组织进行体外研究我们的基本假设是产前糖皮质激素暴露会降低肾单位 出生后将导致肾内肾素血管紧张素系统（RAS）代偿性改变的数量 包括血管紧张素转化酶与血管紧张素转化酶2的比率增加， RAS的反馈调节。这些变化是肾脏排泄需求增加的结果 出生后，它们将伴随着肾功能的改变和血压的升高。我们将使用 用于酶活性的各种血管紧张素肽（Ang I、Ang II和Ang 1-7）特异性测定的Western印迹 和定位程序（免疫细胞化学和放射自显影），以系统地评价 肾内和全身RAS。将在不同阶段采用体外和体内研究的组合， 成熟，以建立肾功能，RAS和血压的变化之间的关系。 了解更多关于糖皮质激素对这些相互关系的影响是因为目前使用的 产前类固醇在产科提高胎儿肺成熟。