REGULATION OF KIDNEY ANGIOTENSIN CONVERTING ENZYME

肾脏血管紧张素转换酶的调节

• 批准号: 2143673
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 23.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2143673
• 关键词: ACE inhibitors; blood pressure; genetic regulation; genetic transcription; genetically modified animals; homeostasis; isozymes; kidney function; laboratory mouse; laboratory rat; peptidyl dipeptidase A; testis

It is widely recognized that an elevated systemic blood pressure is associated with increased mortality and morbidity. This morbidity and the high incidence of hypertension within the US population combine to make hypertension the major indication for the use of prescription drugs and visits to physician's offices. Our work has focused on the renin- angiotensin system (RAS), one of the central physiological mechanisms that maintains pressure and volume homeostasis. The RAS relies on the sequential action of two enzymes, renin and angiotensin-converting enzyme (ACE) to produce the potent octapeptide, angiotensin II (AII). At present the blockade of AII formation is only possible using an ACE inhibitor. ACE is a cell membrane peptidase that influences blood pressure through at least two mechanisms, the conversion of angiotensin I to angiotensin II and the inactivation of the vasodilator, bradykinin. ACE inhibitors not only lower the blood pressure of hypertensives with high renin levels, but also the 85% of essential hypertensives with normal or low renin levels. Converting enzyme inhibitors, used in experimental models of diabetes to control glomerular capillary hypertension, markedly reduce progressive renal disease. Thus ACE is a central enzyme in the biology of blood pressure control. ACE has been studied for many years and there is now overwhelming evidence that the ACE protein produced by endothelium, renal tubular epithelium and other relevant somatic tissues is a single protein chain, the product of a single gene within the mouse or human genomes. This isozyme is referred to as somatic ACE. A second, smaller isozyme of ACE has been identified within germ cells of the testis and is referred to as testis ACE. These two isozymes result from two distinct promoter regions within the ACE gene and thus are the result of tissue specific regulation of RNA transcription. This grant proposes to analyze the transcription of the ACE gene, to focus on the biochemistry and molecular biology of why the kidney and other somatic tissues make a different isozyme of ACE than that produced by developing germ cells. An analysis of the control of ACE transcription will add to the understanding of tissue specific gene expression and the mechanisms of homeostatic control of systemic blood pressure.

普遍认为，全身血压升高是 与死亡率和发病率的增加有关。 这种发病率和 高血压在美国人口中的高发病率联合收割机使 高血压是使用处方药的主要适应症， 访问医生的办公室。 我们的工作集中在肾素- 血管紧张素系统（RAS），其是 维持压力和容量的稳态。 RAS依赖于 两种酶，肾素和血管紧张素转换酶的顺序作用 (ACE)产生强效的八肽血管紧张素II（AII）。 目前 AII形成的阻断仅可能使用ACE抑制剂。 Ace 是一种细胞膜肽酶， 至少有两种机制，血管紧张素I转化为血管紧张素II， 血管扩张剂缓激肽的失活 ACE抑制剂不仅 降低高血压患者的血压与高肾素水平，但也 85%的原发性高血压患者的肾素水平正常或偏低。 转化酶抑制剂，用于糖尿病的实验模型， 控制肾小球毛细血管高血压，明显减少进行性 肾脏疾病 因此，ACE是血液生物学中的中心酶 压力控制 ACE已经研究了很多年，现在有压倒性的证据表明， 血管紧张素转换酶蛋白由内皮细胞、肾小管上皮细胞和 其他相关的体细胞组织是一个单一的蛋白质链， 小鼠或人类基因组中的单个基因。 这种同工酶被称为 体细胞ACE 第二种较小的ACE同工酶已被鉴定 在睾丸的生殖细胞内，被称为睾丸ACE。 这些 两种同工酶由ACE基因内两个不同的启动子区产生 因此是RNA转录的组织特异性调节的结果。 这项资助计划分析ACE基因的转录， 在生物化学和分子生物学上为什么肾脏和其他 体细胞组织产生的ACE同工酶与 发育中的生殖细胞 ACE转录调控的分析 将增加对组织特异性基因表达的理解， 全身血压的稳态控制机制。