Is Tissue ACE Required for Diabetic Renal Damage?

糖尿病肾损伤是否需要组织 ACE？

• 批准号: 6720984
• 负责人: HAROLD A FRANCH
• 金额: $ 15.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720984
• 关键词: angiotensin II; biomarker; blood chemistry; collagen; diabetic nephropathy; disease /disorder model; enzyme activity; gene expression; genetically modified animals; immunocytochemistry; kidney; laboratory mouse; pathologic process; peptidyl dipeptidase A; proteinuria; renal glomerulus; renin angiotensin system; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): Angiotensin converting enzyme (ACE), a carboxyl-peptidase that converts the inactive precursor angiotensin linto the active angiotesion II, plays a crucial role in the development and progression of diabetic nephropathy. Randomized, double blinded clinical trials demonstrate the efficacy of ACE inhibitors in preventing and ameliorating diabetic nephropathy. Part of the benefit from ACE inhibition in slowing the progression of diabetic nephropathy arises from the reduction of blood pressure. However, the beneficial effect of ACE inhibitors may be greater than that of other classes of antihypertensive medications (titrated to the same blood pressure. Despite the beneficial effects of ACE inhibitors, the activity of the systemic renin/angiotensin system in diabetes is not chronically increased: plasma levels of rennin, angiotensinigen and angiotensin II are either suppressed or unchanged in diabetes. Individual organs, including the kidney, also contain all components of the renin/angiotensin system. There is apparent regulation of the local renal renin/angiotensin system during diabetes mellitus especially in the glomerulus: glomerular ACE protein increases markedly in both animal models and human diabetic. This activated glomerular rennin/angiotensin system could produce the angiotensin II that causes glomerular damage in diabetic nephropathy. Our hypothesis is that intrinsic renal ACE activity generates the angiotensin II which causes the renal damage in diabetic nephropathy. There have been no well-defined studies separating the relative roles of kidney and systemic renin/angiotensin systems in diabetic nephropathy. In this pilot application, we propose to address this issue using transgenic mice with normal circulating ACE, but decreased ACE expression in the kidney (ACE.3 mice). Our goals are to characterize the renin/angiotensin system in diabetic mice deficient in renal ACE and to determine if mice deficient in renal ACE develop glomerular damage in response to diabetes mellitus. We will examine if markers of kidney damage, such a collagen expression and transforming growth factor expression as well as proteinuria are altered by lack of renal ACE. We believe that this approach will not only critically test our hypothesis, but will also lay the ground work for future studies into the role of ACE in the diabetic kidney.

描述（由申请人提供）：血管紧张素转换酶（ACE）是一种羧基肽酶，可将无活性的前体血管紧张素i转化为活性血管紧张素II，在糖尿病肾病的发生和进展中起着至关重要的作用。随机、双盲临床试验证明了ACE抑制剂在预防和改善糖尿病肾病方面的疗效。抑制ACE减缓糖尿病肾病进展的部分益处来自于血压的降低。然而，ACE抑制剂的有益作用可能比其他类型的降压药更大（滴定到相同的血压）。尽管ACE抑制剂有有益的作用，但糖尿病患者全身肾素/血管紧张素系统的活性并没有长期升高：糖尿病患者血浆中肾素、血管紧张素和血管紧张素II的水平要么受到抑制，要么保持不变。单个器官，包括肾脏，也包含肾素/血管紧张素系统的所有组成部分。糖尿病患者局部肾素/血管紧张素系统有明显的调节，尤其是在肾小球：肾小球ACE蛋白在动物模型和人类糖尿病患者中均显著升高。这种激活的肾小球肾素/血管紧张素系统可以产生血管紧张素II，导致糖尿病肾病肾小球损伤。