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.

最近发现的一种新的血管紧张素转换酶（ACE）的同系物称为ACE 2重新点燃了兴趣的新的加工途径和功能活性肽的多样性在肾素-血管紧张素-醛固酮系统（RAA）。虽然ACE的表征显然是确定RAAS在血压调节中的作用的关键成就，但ACE 2的作用可能与ACE一样不可或缺，以调节RAAS内的复杂信号传导。与ACE相反，ACE 2不被ACE抑制剂如卡托普利或赖诺普利抑制，也不具有相同的催化性质。ACE 2具有单羧肽酶活性，可切割其底物羧基末端的单个氨基酸残基。尽管最初报道ACE 2将Ang I切割成Ang-（1-9），动力学研究表明Ang II转化成Ang-（1-7）是高度优选的。实际上，ACE 2在Ang-（1-7）形成酶中表现出最高的效率（kcat/Km），并且与Ang I相比，ACE 2对Ang II表现出500倍的kcat/Km。在几个高血压株的数据显示，肾脏表达的ACE 2显着减弱。我们自己的研究表明，AT 1受体或ACE阻断均可诱导心脏和肾脏ACE 2的表达。此外，ACE 2在同类mRen（2）.刘易斯高血压品系中受到抑制，并通过高盐饮食进一步降低。因此，mRen（2）.刘易斯菌株提供了一种独特的相关模型来研究ACE 2在血压调节中的作用。然而，ACE 2影响血压的发展和维持的机制和作用部位尚不明确。本申请的总体假设是，ACE/ACE 2的差异调节可能激活 RAAS的升压-增殖性臂（Ang II）并抑制抑制剂-抗增殖组分[Ang（-1-7）]，其有助于mRen中的盐敏感性和肾损伤（2）。本研究的总体目标是建立mRen（2）.刘易斯大鼠血压、盐敏感性和肾损伤的改变机制，重点是肾内ACE 2和ACE的调节;并确定对ACE 2和ACE表达的分子影响，以及对近曲小管上皮细胞中Ang II和Ang-（1-7）的形成和代谢的后果。