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-血管紧张素系统在人体生理中非常重要 控制血压和液体平衡。也就是说，同样重要的是 认识到肾素-血管紧张素系统的生理作用更重要 血压控制比简单的血压控制复杂，如表型所证明 缺乏功能性肾素-血管紧张素系统的基因敲除小鼠。我们组有 创造了缺乏 ACE 的小鼠。这些动物的收缩压非常低 压力大，无法有效浓缩尿液。然而，什么是 最引人注目和意想不到的是小鼠的发育明显不足 肾髓质。我们假设病理生理学的一部分 肾表型是由于缺乏血管紧张素 II 的局部生成 肾内。本申请提出了研究肾脏的实验 ACE 基因敲除小鼠的表型。我们的方法是创造新的菌株 经过基因改造的小鼠，其特定部位表达 ACE 活性 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 可能导致肾表型的病理生理机制 这些动物。我们还描述了缺乏 ACE 基因敲除的第二系小鼠 该酶的组织结合形式。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， 它负责调节血压。使用同源 重组以创造新的基因改造小鼠品系，我们将 精确检查哪些组织对血压影响最大 控制。