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: 7386019
• 负责人: MARK C CHAPPELL
• 金额: $ 22.49万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386019
• 关键词: Achievement; Amino Acids; Angiotensin-Converting Enzyme Inhibitors; Attenuated; Blood Pressure; Captopril; Carboxypeptidase; Cardiac; Cardiovascular Diseases; Cell Nucleus; Cells; Characteristics; Chromosomes, Human, Pair 10; Chronic; Cleaved cell; Complex; Data; Development; Diet; Diuresis; Diuretics; Enzymes; Epithelial Cells; Epithelium; Equilibrium; Estrogens; Event; Exhibits; Feedback; Female; Heart; Homologous Gene; Hypertension; Hypotension; Injury; Intake; Kidney; Kinetics; Knockout Mice; Lisinopril; MAS1 Protein; Maintenance; Maps; Membrane; Messenger RNA; Metabolism; Modeling; Molecular; Mono-S; Not Defined; Nuclear; Nuclear Envelope; Omapatrilat; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Phenotype; Process; Property; Protein Overexpression; Proteinuria; Proximal Kidney Tubules; Quantitative Trait Loci; Rattus; Receptor Signaling; Regulation; Renal Hypertension; Renal function; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Reporting; Research Personnel; Role; Signal Transduction; Site; Sodium; Sodium Chloride; Testing; Testis; Time; Tissues; Tubular formation; Upper arm; Water consumption; Work; blood pressure regulation; congenic; density; extracellular; hypertension treatment; improved; inhibitor/antagonist; interest; kidney epithelial cell; male; normotensive; novel; programs; protective effect; protein expression; receptor; receptor binding; response; salt sensitive; therapeutic target

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.

最近发现的称为ACE2的血管紧张素转化酶（ACE）的新型同源物重新点燃了对肾素 - 血管紧张素 - 醛固酮系统（RAA）中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RAA在血压调节中的作用方面的关键成就，但ACE2的作用可能与ACE一样不可或缺，在调节RAAS内的复杂信号传导。与ACE相反，ACE2不受Captopril或Lisinopril等ACE抑制剂的抑制，也没有具有相同的催化特性。 ACE2表现出单羧肽酶活性，可在其底物的羧基末端切断单个氨基酸残基。尽管最初报告了ACE2向Ang-（1-9）裂解，但动力学研究表明，Ang II向Ang-（1-7）的转化是高度首选的。实际上，与ANG I相比，ANG II的ACE2在ANG-（1-7）形成酶中表现出最高的效率（KCAT/KM），而ANG I的kCAT/km则表现出500倍的KCAT/KM。我们自己的研究表明，AT1受体或ACE封锁诱导心脏和肾ACE2的表达。此外，ACE2在先天的MREN中被抑制（2）。刘易斯高血压菌株，并通过高盐饮食进一步降低。因此，MREN（2）。LEWIS菌株提出了一个独特且相关的模型，以研究ACE2在调节血压中的作用。但是，ACE2影响血压发育和维持的机制和作用部位尚未定义。目前的总体假设是，ACE/ACE2的差分调节可能会激活 RAAS（ANG II）的压力促进臂并抑制抑制剂 - 抗抗增殖成分[ANG（-1-7）]在MREN中有助于盐敏感性和肾脏损伤（2）.LEWIS。由RAAS失调标记的LEWIS。该提案中的总体目的将确定MREN血压，盐敏感和肾损伤改变的机制（2）。Lewis大鼠着重于调节肾脏内ACE2和ACE；并确定分子对ACE2和ACE表达的影响，以及对近端小管上皮细胞中Ang II和Ang-（1-7）形成和代谢的后果。