The focus of this application is the physiological regulation of renin gene expression during development. We believe this topic is important because the renin angiotensin system (RAS) has several extremely important roles in the developing fetus. These roles include enhancing kidney growth, renal vascular development, and regulating fetal arterial blood pressure under basal conditions and during periods of intrauterine stress. Our understanding of the maturation of this system is incomplete and there are major gaps in our knowledge of the factors that promote the marked increase in renin expression and activity in the RAS which occur in the perinatal period. Based upon data we have collected over the previous funding period and information in the literature, we believe the renal nerves and thyroid hormone are essential for this increase in activity in the RAS occurring close to term. Therefore, we wish to test the hypothesis that the renal nerves acting via beta adrenergic adenylyl cyclase- cyclic adenosine monophosphate (c-AMP) signal transduction mechanisms maintain renin gene responsiveness to beta adrenergic related stimuli and that thyroid hormone also acts on the signal transduction cascade to enhance responses to beta adrenergic stimulation and, in addition, acts directly on the renin gene to increase its expression. We will use fetal sheep to test these hypothesis because we can surgically interrupt the innervation of the kidneys in this animal model early in gestation and the kidneys of these animals are large enough to provide sufficient quantities of renin containing cells for our in vitro studies without requiring excessive numbers of animals. We will employ RNase protection assays to study the expression of renin mRNA, enzymatic assays to measure adenyly cyclase activity and radioimmunoassays for the measurement of active and prorenin concentrations. We will isolate and culture the renin containing cells from the fetal kidneys following chronic manipulations in vivo and study renin mRNA responses in them. To define the mechanisms that are involved with the renal nerve maintenance of beta adrenergic responsiveness, we will use pharmacological approaches to dissect the various steps along the beta adrenergic-adenylyl cyclase-cAMP signal transduction pathway. We will also study plasma renin responses to pharmacological and physiological interventions in order to establish the role of the renal nerves and the thyroid hormone in vivo. To our knowledge, these will be the first studies to systematically examine the importance of the renal nerves and thyroid hormone in enhancing renin expression in late gestation. Understanding more about the factors producing this developmental change could be important for understanding aspects of kidney development and maturation of renal function. Derangement of either may result in a predisposition to hypertension in the infant or the adult.
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