Transgenic animals offer the opportunity to test specific pathogenetic hypotheses within a physiologically relevant context. The control of blood pressure and volume homeostasis involves the interaction of complex hormonal systems. Two important regulators which have opposing effects and act at the adrenal are atrial naturetic peptide (ANP) and the renin-angiotensin (RA) system. Recently it has become clear that many tissues make the components of the RA system. It is unclear what relationship these local RA systems have to the classical circulating RA system. The situation is complicated by the existence of two functional renin genes, ren-1 and ren-2, in some strains of mice. The different functions that may be attributable to these two genes in tissues such as the adrenal is unknown. ANP is a hormone which can oppose the effects of vasoconstriction and aldosterone stimulation mediated by the RA system. The role of ANP in relation to the other hormones is also unknown. Using oocyte injection and homologous recombination with blastocyst-mediated transgenesis, we propose to investigate the contributions of the local adrenal RA system, the two murine renin genes, and ANP in the control of blood pressure and the physiology of the adrenal. We will produce 1) transgenic murine model which over-expresses renin specifically in the adrenal to test the significance of the local renin-angiotensin system, 2) through targeted mutagenesis strains of mice that lack either a functional ren-1 or ren-2 gene in order to test the contributions of each, and 3) also through targeted mutagenesis a strain lacking function ANP. We have chosen to alter these genes because of their hypothesized important roles in the regulation of blood pressure and the regulation of adrenal function by dietary manipulations of Na+ and K+. By testing these strains of mice under different dietary conditions, we hope to dissect out the individual roles played by these genes. We will primarily test the alterations in blood pressure, major hormones that affect blood pressure (aldosterone, ANP, renin, angiotensin II), and the effects on adrenal physiology (rates of aldosterone synthesis, sensitivity to angiotensin II, ACTH, K+).
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