The renin angiotensin system (RAS) is critically involved in the pathogenesis of hypertension, congestive heart failure and renal failure, and converting enzyme blockers of the system are one of the most important drugs used to treat these disorders. The rate limiting component of the system is renin, that cleaves angiotensinogen, to angiotensin I that is further cleaved by converting enzyme to the vasopressor, angiotensin (AII). AII generation occurs both in the plasma and in numerous tissues. The precursor to renin is prorenin whose prosegment inactivates renin. Prorenin is cleaved to renin in the kidney and some extrarenal tissue, and both prorenin and renin are released. Prorenin also has a small amount of renin activity and can be activated without removal of the prosegment by poorly defined mechanisms. Prorenin and renin are produced in the kidney, the main source of circulating renin, and in several extrarenal tissues such as the placenta (that mostly produce prorenin). The potential role of these extrarenal RASs in AII generation is a subject of intense interest. Renin mRNA is expressed in a tissue-specific manner and its levels are regulated through multiple mechanisms. Sometimes cells that ordinarily do not produce renin are recruited to do so. Renin and prorenin release, and prorenin to renin conversion can also be regulated; some tissues do not process prorenin to renin and some diabetes have defective processing of prorenin. Thus, deciphering the mechanisms of expression and control of the renin gene, of intracellular trafficking of prorenin and renin, and of proteolytic and non-proteolytic activation of prorenin is critical for understanding the RAS and its role in health and disease. We have developed several tools that should help address these issues. The first are human cell systems in culture, primary placental cells, vulvar leiomyosarcoma (SKLMS1) cells and lung fibroblasts, in which the transfected human renin promoter can be expressed in a cell-specific manner and in response to cAMP. The second employs AtT-20 cells in which prorenin is accurately targeted to the regulated secretory pathway and processed to renin. The third is the three-dimensional structure of human renin and a model for prorenin. These systems will be employed in the proposed studies using gene transfer, with native and mutated renin gene fragments, and analyses of prorenin and renin release, and other methods to define: elements in the human renin promoter that direct its tissue-specific and regulated expression, and that allow it to be activated; how the prosegment inactivates prorenin; the structures on prorenin that allow the prorenin processing enzyme (PPE) to accurately cleave renin; whether known enzymes can mimic the PPE; a human kidney PPE; the secretory pathway. The information gained should provide a much better understanding of how prorenin and renin can be controlled in extrarenal sites and in the kidney that is relevant for understanding its function in these diseases and how to intervene with this system to design new treatments.
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