Is Tissue ACE Required for Diabetic Renal Damage?

糖尿病肾损伤是否需要组织 ACE？

• 批准号: 6862569
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862569
• 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.

性状（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II转化为活性血管紧张素II，在糖尿病肾病的发生和发展中起关键作用。 随机、双盲临床试验证实了ACE抑制剂在预防和改善糖尿病肾病方面的疗效。ACE抑制在减缓糖尿病肾病进展中的部分益处来自血压的降低。然而，ACE抑制剂的有益效果可能大于其他类别的降压药物（滴定至相同的血压）。尽管ACE抑制剂具有有益作用，但糖尿病患者的全身性肾素/血管紧张素系统的活性并未长期增加：糖尿病患者的血浆肾素、血管紧张素原和血管紧张素II水平受到抑制或无变化。包括肾脏在内的单个器官也含有肾素/血管紧张素系统的所有成分。糖尿病时肾脏局部的肾素/血管紧张素系统有明显的调节作用，尤其是在肾小球：动物模型和人类糖尿病患者的肾小球ACE蛋白明显增加。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，导致糖尿病肾病的肾小球损伤。 我们的假设是，内在的肾脏ACE活性产生血管紧张素II，导致糖尿病肾病的肾损害。目前还没有明确的研究分离肾脏和全身性肾素/血管紧张素系统在糖尿病肾病中的相对作用。在这个试点应用中，我们建议使用具有正常循环ACE但肾脏中ACE表达降低的转基因小鼠（ACE.3小鼠）来解决这个问题。我们的目标是描述糖尿病小鼠肾血管紧张素转换酶缺乏的肾素/血管紧张素系统，并确定肾血管紧张素转换酶缺乏的小鼠是否会对糖尿病产生肾小球损伤。我们将检查肾损伤的标志物，如胶原蛋白表达和转化生长因子表达以及蛋白尿是否因肾ACE缺乏而改变。我们相信，这种方法不仅将严格检验我们的假设，但也将奠定基础，为未来的研究ACE在糖尿病肾脏的作用。