THE RENAL-SPECIFIC EXPRESSION OF ACE

ACE 的肾脏特异性表达

• 批准号: 6783436
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 14.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783436
• 关键词: angiotensin II; blood pressure; enzyme deficiency; gene expression; gene targeting; genetically modified animals; histogenesis; laboratory mouse; peptidyl dipeptidase A; phenotype; renal medulla

The renin-angiotensin system is very important in the physiologic control of blood pressure and fluid balance. That said, it is also important to realize that the physiologic actions of the renin-angiotensin system are more complex than simple blood pressure control, as evidenced by the phenotype of knockout mice that lack a functional renin-angiotensin system. Our group has created mice that lack ACE. These animals have very low systolic blood pressures and are unable to effectively concentrate urine. However, what was most dramatic and unexpected was that the mice have a marked under-development of the renal medulla. We hypothesize that part of the pathophysiology of the renal phenotype is due to the lack of the local generation of angiotensin II within the kidney. This application proposes experiments to study the renal phenotype in ACE knockout mice. Our approach will be to create new strains of genetically-altered mice expressing ACE activity in selected portions of the renal nephron. These studies are designed to discriminate between angiotensin II as a local factor necessary for renal development and function, and other pathophysiologic mechanisms that may be responsible for the renal phenotype of these animals. We also describe a second line of ACE knockout mice that lacks the tissue bound form of this enzyme. The phenotype of these animals suggests that it is expression of ACE within tissues, as opposed to plasma ACE activity, that is responsible for regulating blood pressure. Using homologous recombination to create novel strains of genetically altered mice, we will examine precisely which tissues are most responsible for blood pressure control.

肾素-血管紧张素系统在机体的生理活动中起着重要的作用 控制血压和体液平衡。也就是说， 意识到肾素-血管紧张素系统的生理作用更多 复杂的比简单的血压控制，如表型证明， 基因敲除小鼠缺乏功能性的肾素-血管紧张素系统。我们集团 制造出缺乏ACE的小鼠。这些动物的收缩期非常低 压力，不能有效地浓缩尿液。然而， 最戏剧性和意想不到的是，小鼠有一个显着的发育不足， 肾髓质的一部分我们假设，部分的病理生理学的 肾脏表型是由于缺乏局部生成的血管紧张素II 在肾脏内。本申请提出了研究肾功能的实验。 ACE基因敲除小鼠的表型。我们的方法将是创造新的菌株， 基因改变的小鼠表达ACE活性在选定的部分， 肾单位这些研究旨在区分血管紧张素 II作为肾脏发育和功能所必需的局部因素，以及其他 病理生理机制，可能是负责肾脏表型的 这些动物。我们还描述了第二种ACE基因敲除小鼠， 这种酶的组织结合形式。这些动物的表型表明 它是组织内ACE的表达，而不是血浆ACE活性， 负责调节血压。使用同源 重组，以创造新的品系的基因改变小鼠，我们将 精确地检查哪些组织对血压起主要作用 控制