Prenatal Events-Postnatal Consequences

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DESCRIPTION (provided by the applicant): The primary goal of this program project application is to investigate the long-term effects of antenatal exposure to synthetic glucocorticoids on renal functional and blood pressure postnatally. This topic has major significance today because of the widespread clinical use of synthetic glucocorticoids in the perinatal period to enhance lung maturation. The proposed studies encompass three projects in the same, widely used animal model (the sheep at different stages of development) to examine specific systems and mechanisms mediating the effects of antenatal steroid treatment on aspects of kidney development and function, the neural control of the cardiovascular system and blood pressure. They are coupled with a clinical project to document in children between 10-16 years of age, the effects of glucocorticoid exposure on blood pressure, blood pressure responsivity and indices of renal function. Specifically, Project 1 examines the impact of prenatal steroid exposure on the intra-renal renin-angiotensin system, renal function in vivo and blood pressure at different stages of development. Project 2 focuses on the effects of prenatal steroid exposure on sodium handling by the kidney using both in vitro and in vivo approaches. Project 3 establishes the impact of antenatal glucocorticoids on the brain renin angiotensin system, baroreceptor function and the regulation of sympathetic outflow. Finally, Project 4 establishes, in a well-defined patient population, the impact of prenatal steroid exposure on blood pressure, the responsiveness of blood pressure to stimulation and on indices of renal functional in children and how this impact is modulated by factors such as growth and fitness. Thus, all the animal projects have a high level of scientific integration and the results of the clinical project will provide a high level of relevance for the work in the animal model. The data obtained will improve our understanding of the consequences of the use of glucocorticoids antenatally and may help to identify a population of children at risk for the development of high blood pressure as adults. This outcome would obviously serve as a stimulus for the development of monitoring and early intervention strategies to be used in children exposed to glucocorticoids prior to birth. Thus, a long-term benefit of the proposed studies may be to reduce the overall morbidity associated with elevations in blood pressure in such a population.