Role of Ang-(1-7) and ACE2 in Kidney Tubular Function

最近发现的一种新的血管紧张素转换酶（ACE）的同源物ACE2重新点燃了人们对肾素-血管紧张素-醛固酮系统（RAA）中新的加工途径和功能活性肽多样性的兴趣。虽然ACE的表征在确定RAAS在调节血压中的作用方面显然是一项关键成就，但ACE2在调节RAAS内复杂信号传导方面的作用可能与ACE一样不可或缺。与ACE相反，ACE2不受ACE抑制剂如卡托普利或赖诺普利的抑制，也不具有相同的催化性质。ACE2表现出单羧基肽酶活性，在其底物的羧基端切割单个氨基酸残基。虽然ACE2最初被报道将Ang I裂解为Ang-(1-9)，但动力学研究表明，Ang II更倾向于转化为Ang-(1-7)。事实上，在Ang-(1-7)形成酶中，ACE2表现出最高的效率（kcat/Km），而Ang II的kcat/Km是Ang i的500倍。几种高血压菌株的数据显示，ACE2在肾脏中的表达显著减弱。我们自己的研究表明，AT1受体或ACE阻断均可诱导心脏和肾脏ACE2的表达。此外，ACE2在基因mRen中被抑制(2)。高盐饮食进一步降低了刘易斯高血压的压力。因此，mRen(2)。Lewis菌株提供了一种独特且相关的模型来研究ACE2在血压调节中的作用。然而，ACE2影响血压发展和维持的机制和作用部位尚不明确。本研究的总体假设是ACE/ACE2的差异调控可能被激活

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.