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 organ is the kidney. However, our understanding of the changes in renal function resulting from the """"""""programming"""""""" effects of glucocorticoids and the mechanisms involved is almost non-existent. Therefore, the objective of this project is to define the mechanisms whereby exposure of the fetus to a clinically relevant dose of glucocorticoids at a crucial period of gestation (peak of nephrogenesis) affects sodium handling 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. We hypothesize that: 1) Glucocorticoids exposure prenatally reduces nephron number and results in alterations in the intrarenal renin-angiotensin system (RAS) including increases in the ratio ofangiotensin converting enzyme to angiotensin converting enzyme 2, consequent changes in the Ang II to Ang-(l-7)balance and inadequate feedback regulation of the RAS later in life; and, 2) these changes will be accompanied by impaired sodium excretion resulting from alterations in sodium transport and will increase blood pressure. We will use specific assays for the various angiotensin peptides (Ang I, Ang II and Ang 1-7), assays of enzyme and sodium transporter activity, localization procedures (immunocytochemistry and autoradiography) and molecular techniques to systematically evaluate components of the intrarenal and systemic RAS and sodium handling by the kidney in control and glucocorticoid exposed groups. A combination of in vitro and in vivo studies will be employed at different stages of maturation to establish the relationships between alterations in the RAS, sodium handling, and blood pressure. Understanding more about the impact of glucocorticoids on these inter- relationships is important because of the current use of antenatal steroids in obstetrics to enhance fetal lung maturation. ? ? ?
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