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

Ang-(1-7) 和 ACE2 在肾小管功能中的作用

• 批准号: 7218014
• 负责人: MARK C CHAPPELL
• 金额: $ 15.53万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218014
• 关键词: angiotensin II; angiotensins; blood pressure; enzyme activity; isozymes; laboratory rat; peptide hormone metabolism; peptidyl dipeptidase A; renal tubular transport; renin angiotensin system

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.

最近发现了一种新的血管紧张素转换酶 (ACE) 同系物 ACE2，重新激发了人们对肾素-血管紧张素-醛固酮系统 (RAA) 内新型加工途径和功能活性肽多样性的兴趣。虽然 ACE 的表征显然是定义 RAAS 在血压调节中的作用的关键成就，但 ACE2 的作用可能与 ACE 一样不可或缺，可调节 RAAS 内的复杂信号传导。与 ACE 不同，ACE2 不会被卡托普利或赖诺普利等 ACE 抑制剂抑制，也不具有相同的催化特性。 ACE2 表现出单羧肽酶活性，可切割其底物羧基末端的单个氨基酸残基。尽管最初报道 ACE2 将 Ang I 裂解为 Ang-(1-9)，但动力学研究表明，高度优选将 Ang II 转化为 Ang-(1-7)。事实上，ACE2 在 Ang-(1-7) 形成酶中表现出最高的效率 (kcat/Km)，与 Ang I 相比，Ang II 的 kcat/Km 高出 500 倍。几种高血压菌株的数据表明，ACE2 的肾脏表达显着减弱。我们自己的研究表明，AT1 受体或 ACE 阻断可诱导心脏和肾脏 ACE2 的表达。此外，ACE2 在同系 mRen(2).Lewis 高血压菌株中受到抑制，并通过高盐饮食进一步降低。因此，mRen(2).Lewis 菌株提供了一个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位点尚不清楚。目前应用的总体假设是 ACE/ACE2 的差异调节可能激活 RAAS (Ang II) 的升压增殖臂并抑制降压抗增殖成分 [Ang(-1-7)]，导致 mRen(2) 中盐敏感性和肾损伤。Lewis 的特点是 RAAS 失调。该提案的总体目标是建立 mRen(2).Lewis 大鼠血压、盐敏感性和肾损伤改变的机制，重点关注肾内 ACE2 和 ACE 的调节；并确定分子对ACE2和ACE表达的影响，以及对近曲小管上皮细胞中Ang II和Ang-(1-7)的形成和代谢的影响。