THE RENAL-SPECIFIC EXPRESSION OF ACE

肾素-血管紧张素系统在生理上起着非常重要的作用。 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 比简单的血压控制更复杂，从 缺乏功能肾素-血管紧张素系统的基因敲除小鼠。我们的团队已经 创造了缺乏血管紧张素转换酶的老鼠。这些动物的收缩压很低。 压力大，不能有效地浓缩尿液。然而，到底是什么？ 最戏剧性和意想不到的是，这些小鼠的发育明显不足 肾脏的髓质。我们假设这一部分的病理生理学 肾脏的表型是由于缺乏局部产生的血管紧张素II。 在肾脏内。这项申请提出了研究肾脏的实验 ACE基因敲除小鼠的表型。我们的方法将是创造新的品系 表达血管紧张素转换酶活性的转基因小鼠 肾肾单位。这些研究旨在区分血管紧张素 作为肾脏发育和功能所必需的局部因素，以及其他 可能导致肾脏表型的病理生理机制 这些动物。我们还描述了缺乏ACE基因敲除小鼠的第二个品系 这种酶的组织结合形式。这些动物的表型表明 它是血管紧张素转换酶在组织内的表达，而不是血浆血管紧张素转换酶的活性， 它负责调节血压。使用同源 重组以创造新的转基因小鼠品系，我们将 准确检查哪些组织对血压的影响最大 控制力。

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.