In adult mammals, renin is associated with the regulation of blood pressure and electrolyte homeostasis through its synthesis and release from modified smooth muscle cells known as juxtaglomerular cells along the afferent arterioles. Preliminary evidence suggests a close correspondence between expression of renin and development of the renal vasculature. Experiments are therefore proposed to define this relationship by analyzing the timing and pattern of renin expression as compared to known vascular markers, in particular smooth muscle cell markers. This will be accomplished through a combination of immunocytochemical, in situ histochemical and ultrastructural analyses. Ontological studies will be performed on normal mice and transgenic mice containing a variety of oncogenic and non- oncogenic reporter functions. To evaluate whether renin gene expression is essential and to assess its significance during fetal development, renin gene function will be ablated by homologous recombination using an embryonic stem cell approach. These experiments will permit us to determine the phenotypic effects of null mutants and determine the earliest lethal period, if any. Two types of transgenic mice containing oncogenic reporters exhibit renal vascular smooth muscle pathology at different times in kidney development. The stochastic appearance of tumors has allowed establishment of renin expressing cell lines. A determination will be made regarding the differentiated status of these cell and whether they can be used as in vitro models for smooth muscle ontogeny. These experiments will be importance to the long term goals of assessing the molecular determinants regulating smooth muscle differentiation. The significance of the renal vascular pathology will be addressed at the physiological level with the aim of defining the role of the renal renin- angiotensin system to blood pressure homeostasis in vascular disease. Experiments are proposed to address the significance of renin expression in peripheral mesenchymal connective tissue. Tumors and cell lines derived from these tissues will be evaluated to determine the renin expressing cell type and whether there is a common lineage between these cells and those in the kidney.
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