The renin-angiotensin system (RAS) in mammals is an important regulator of arterial pressure and electrolyte balance and has been proposed to play a role in the etiology of some forms of hypertension. The primary site of synthesis responsible for plasma borne renin and angiotensinogen are the kidney and liver, respectively. In addition to these sites however, both proteins are synthesized in a host of additional tissues. Expression of these proteins in some of these tissues has been found to be evolutionarily conserved suggesting they may play an important role. Nevertheless, the function of extra-renal renin or extra-hepatic angiotensinogen remains unclear. Indeed, the localization of multiple RAS components in some of these tissues has led to provocative proposals for the existence of tissue RAS providing local function. Unfortunately, much more is understood regarding the expression of these genes in rodents. This is probably explained by the paucity of human tissues and appropriate human cell lines to perform complex gene regulation studies. We therefore propose to perform experiments with the goal of understanding the expression of the human renin and human angiotensinogen genes at the molecular level. For the reasons listed above and the difficulty in performing gene regulation experiments in humans we will use transgenic mice as our experimental system. Transgenesis in whole animals provides a valuable resource for dissecting complex regulatory processes. First, we will examine a series of transgenic mice containing human renin and human angiotensinogen genomic constructs with regard to tissue- and cell-specificity with the aim of developing a consensus tissue-specific expression profile for the human genes. These studies will include examining the developmental profile of human renin expression and the regulation of human renin expression in the kidney in response to physiologic and pharmacologic perturbation. Secondly, we will molecularly dissect the 5' flanking regulatory region of the human renin gene in transgenic mice and a renin expressing kidney cell line to test the hypothesis that important tissue-specific regulatory elements controlling its expression lie in the 5' flanking region of the gene. Ultimately, we hope to use this information to design experimental animal models to investigate the significance of extra-renal renin and extra-hepatic angiotensinogen expression.
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