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)同系物，称为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多肽的多样性的兴趣。虽然ACE的特性在明确RAAS在血压调节中的作用方面是一项关键的成就，但ACE2可能与ACE一样在调节RAAS内的复杂信号方面发挥着不可或缺的作用。与血管紧张素转换酶不同，血管紧张素转换酶2不被血管紧张素转换酶抑制剂卡托普利或赖诺普利抑制，也不具有相同的催化特性。ACE2显示出单羧基肽酶活性，在底物的羧基末端裂解单一氨基酸残基。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向Ang-(1-7)的转化是非常可取的。事实上，在Ang-(1-7)形成酶中，ACE2表现出最高的效率(kcat/Km)，Ang II的Kcat/Km比Ang I高500倍。在几个高血压菌株中的数据显示，ACE2的肾脏表达显著减弱。我们自己的研究表明，AT1受体或ACE阻断都能诱导心脏和肾脏ACE2的表达。此外，ACE2在同源基因MREN(2)中被抑制。Lewis高血压株并通过高盐饮食进一步减少。因此，MREN(2).Lewis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影响血压形成和维持的机制和作用部位尚未确定。目前应用的总体假设是，ACE/ACE2的差异调节可能激活 RAAS的升压-增殖臂(Ang II)和抑制降压-抗增殖成分[Ang(-1-7)]参与了MREN的盐敏感性和肾脏损伤(2)。本方案的总体目标是在MREN(2)中建立血压改变、盐敏感性和肾脏损伤的机制，重点是肾内ACE2和ACE的调节；并确定对ACE2和ACE表达的分子影响，以及对近端小管上皮细胞Ang II和Ang-(1-7)形成和代谢的影响。