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.
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