The recent discovery of a new homolog of angiotensin converting enzyme (ACE) termed ACE2 has re-ignited the interest in the diversity of novel processing pathways and functionally active peptides within the renin-angiotensin-aldosterone system (RAA). While the characterization of ACE was clearly a pivotal achievement in defining the role of the RAAS in the regulation of blood pressure, the role of ACE2 may be as integral as ACE to modulate the complex signaling within the RAAS. In contrast to ACE, ACE2 is not inhibited by ACE inhibitors such as captopril or lisinopril nor shares the same catalytic properties. ACE2 exhibits mono-carboxypeptidase activity cleaving a single amino acid residue at the carboxy terminus of its substrate. Although ACE2 was originally reported to cleave Ang I to Ang-(1-9), kinetic studies suggest that the conversion of Ang II to Ang-(1-7) is highly preferred. Indeed, ACE2 exhibits the highest efficiency (kcat/Km) among Ang-(1-7)-forming enzymes and a 500-fold greater kcat/Km for Ang II as compared to Ang I. Data in several hypertensive strains reveal that the renal expression of ACE2 is significantly attenuated. Our own studies demonstrate that either AT1 receptor or ACE blockade induces expression of cardiac and renal ACE2. In addition, ACE2 is suppressed in the congenic mRen(2).Lewis hypertensive strain and further reduced by a high salt diet. Thus, the mRen(2).Lewis strain presents a unique and relevant model to investigate the role of ACE2 in the regulation of blood pressure. However, the mechanisms and the site of action for ACE2 to influence the development and maintenance of blood pressure are not defined. The overall hypothesis oft he present applicaaon is that the differential regulation of ACE/ACE2 may activate the pressor-praliferative arm of the RAAS (Ang II) and suppress the depressor-antiproliferative component [Ang(-1-7)] contributing to the salt sensitivity and renal injury in the mRen(2).Lewis marked by dysregulation of the RAAS. The overall aims in this proposal will establish the mechanisms for alteration of blood pressure, salt-sensitivity and renal injury in the mRen(2).Lewis rats focusing on the regulation of intra-renal ACE2 and ACE; and determine the molecular influences on the expression of ACE2 and ACE, as well as the consequences on the formation and metabolism of Ang II and Ang-(1-7) in the proximal tubule epithelial cells.
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