The renin-angiotensin system (RAS) plays a key role in the maintenance of normal blood pressure through its effects on vascular tone and electrolyte metabolism. Accordingly, many of the drugs used to treat hypertension are directed at the RAS (angiotensin converting enzyme inhibitors, angiotensin II antagonists, etc). Although recent transgenic models show that hypertension may be produced by altering the expression of normal RAS gene products, derangements of the RAS that cause human hypertension are not known. The aims research conducted in this laboratory are (i) to investigate the molecular mechanisms of RAS gene expression with a view to understading normal RAS function, its role as a target of pharmacologic antihypertensive treatments, and its involvement in the pathogenesis of hypertension; and (ii) to explore novel mechanisms of renin and prorenin uptake by tissues.

Mechanisms of Cell-Specific Renin Gene Expression: Our recent studies have focused on the mechanisms that direct appropriate cell-specific expression of the human renin gene (1).

This has led to important developments in human RAS transgenic models. Such models take advantage of the species-specificity of the cleavage of angiotensinogen by renin: human renin will not cleave mouse angiotensinogen, and mouse renin will not cleave human angiotensinogen. Thus, transgenic lines harboring either the human renin (hREN) or human angiotensinogen (hAOGN) genes display no significant blood pressure (BP) phenotype. However, when mated together to yield doubly-transgenic lines expressing both hREN and hAOGN, a functional hRAS is formed. New hREN transgenic lines in which plasma human renin originates from the kidney permit studies of the regulation of synthesis and secretion of renal renin, uptake of renin by vascular tissues.

Characterization and Cloning of a Renin Binding Site: The presence of renin in some tissues and its disappearance after the removal of the kidneys suggests that it might be taken up from the circulation. The effects of renin in tissues have been implicated in cardiovascular disease and in the protective effect of drugs that act on the renin system. Recently, we identified a site in membrane preparations of several rat tissues that specifically binds both renin and its precursor, prorenin, with high (2) affinity. Studies in progress seek to determine the region(s) of the renin/prorenin molecule involved in binding in vitro and to clone the binding site. These studies will provide agonists and antagonists that will ultimately enable us to establish the relationship between renin/prorenin binding in vitro, and the site(s) that mediate the physiological effects of renin and prorenin in vivo.

e-mail: dfcatanz@med.cornell.edu

Further Information:
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