Strategies for ACE2 Amplification to Treat Diabetic Kidney Disease

ACE2 扩增治疗糖尿病肾病的策略

• 批准号: 7932763
• 负责人: DANIEL BATLLE
• 金额: $ 32.61万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932763
• 关键词: Affect; Albuminuria; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Attenuated; Blood Vessels; Carboxypeptidase; Catalytic Domain; Companions; Complement; Complication; Conflict (Psychology); Coupled; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diuresis; Down-Regulation; Effectiveness; Enzymes; Face; Figs - dietary; Fostering; Generations; Genes; Hormones; Injury; Integral Membrane Protein; Kidney; Kidney Diseases; Knock-out; Lesion; MLN4760; Mediating; Metabolism; Metalloproteases; Modeling; Mus; Natriuresis; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Patients; Pattern; Peptides; Play; Proteinuria; Protocols documentation; Recombinants; Relative (related person); Renin-Angiotensin System; Role; Series; Serum; Streptozocin; System; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Model; Transgenic Organisms; Up-Regulation; angiotensin I (1-7); atrial natriuretic factor prohormone (31-67); base; db/db mouse; diabetic; diabetic patient; editorial; hemodynamics; inhibitor/antagonist; insight; new therapeutic target; novel; overexpression; podocyte; prevent; public health relevance; receptor; research study; therapy development; tool; type I and type II diabetes

DESCRIPTION (provided by applicant): ACE2 is a type 1 integral membrane protein that shares 42% homology with the metalloprotease catalytic domains of ACE. Whereas ACE promotes the formation of angiotensin II, ACE2 promotes the degradation of angiotensin (ANG) II to angiotensin-(1-7). Strategies geared at increasing ACE2 activity may provide a novel therapeutic target within the renin-angiotensin system by enhancing angiotensin II degradation that may complement the current approach of either inhibiting angiotensin II formation using ACE inhibitors or blocking its action using specific AT1 receptor antagonists. We hypothesize that decreased ANG II degradation coupled with decreased ANG-(1-7) formation owing to ACE2 downregulation may play an important role in diabetic kidney disease. This hypothesis is based on our recent findings of a distinctive pattern of ACE and ACE2 expression in kidneys from diabetic mice such that glomerular ACE2 expression is decreased and ACE is increased in the db/db mice. In keeping with this hypothesis, we have recently found that ACE2 inhibition using a specific pharmacologic agent, MLN-4760, worsens albuminuria and induces glomerular injury in two different models of nephropathy in diabetic mice. We propose that ACE2 upregulation will emerge as a target of new therapies aimed at reducing albuminuria and glomerular injury. We now have the tools to test this hypothesis directly by different approaches: the administration of murine recombinant ACE2, lentiviral ACE2 delivery and a novel ACE2 activator to diabetic mice. The postulated mechanism of local ACE2 protection will be further studied using a podocyte-specific ACE2 transgenic. The specific objectives of this proposal are: Aim 1) To produce murine recombinant ACE2 and establish protocols for delivery to mice that achieve a sustained increase in serum ACE2 activity that effectively increases ANG II degradation and ANG-(1-7) formation. Aim 2) To create a system for lentiviral murine ACE2 expression and establish protocols for delivery to mice that achieve a sustained increase in serum and tissue ACE2 activity that effectively increases ANG II degradation and ANG-(1-7) formation systemically and at the kidney level. Aim 3) To examine the effect of the administration of murine recombinant (r)ACE2, lentiviral ACE2 delivery, and a novel ACE2 activator, XNT, on albuminuria and glomerular lesions in the db/db model of type 2 diabetes (C57BLK and FVB backgrounds). The relative contribution of ANG II and ANG-(1-7) following ACE2 amplification by these various approaches on these parameters will be examined in additional experiments using a specific blocker of the ANG-(1- 7)/Mas receptor. Aim 4) To test the hypothesis that in diabetic (db/db) with glomerular ACE2 over-expression albuminuria and the glomerular lesions of diabetes can be prevented and that this protection can be accomplished with isolated glomerular ACE2 overexpression even in the face of systemic ACE2 deficiency. PUBLIC HEALTH RELEVANCE: Kidney disease is a frequent complication of both type 1 and type 2 diabetes. The renin- angiotensin system (RAS) has been widely implicated in the development of diabetic kidney disease. It has been recently found that an enzyme called ACE2 plays a role in the disposal of angiotensin II, a hormone that may be responsible for the progression of diabetic kidney disease. This proposal will provide a better understanding of angiotensin II and, in particular, ACE2 in diabetic kidney disease and has the promise to offer novel insights into ways to treat patients afflicted with diabetes and kidney damage. We surmise that results from this proposal will be proof of concept for the development of therapies aimed at enhancing the activity of ACE2 to treat diabetic kidney disease much the same way that ACE inhibitors were developed to prevent the formation of angiotensin II and are now widely used in patients with diabetes and kidney disease.

描述(申请人提供)：ACE2是一种1型完整的膜蛋白，与ACE的金属蛋白酶催化结构域有42%的同源性。血管紧张素转换酶促进血管紧张素II的形成，而血管紧张素转换酶2促进血管紧张素II降解为血管紧张素-(1-7)。旨在增加ACE2活性的策略可能通过促进血管紧张素II的降解在肾素-血管紧张素系统中提供一个新的治疗靶点，这可能是对目前使用ACE抑制剂抑制血管紧张素II形成或使用特定AT1受体拮抗剂阻断其作用的补充。我们推测血管紧张素转换酶II降解减少和血管紧张素转换酶2下调导致的血管生成减少可能在糖尿病肾病中起重要作用。这一假说是基于我们最近发现的糖尿病小鼠肾脏中ACE和ACE2表达的独特模式，即db/db小鼠肾小球ACE2表达减少，ACE表达增加。为了符合这一假设，我们最近发现，在糖尿病小鼠两种不同的肾病模型中，使用特定的药理学药物MLN-4760抑制ACE2会加重蛋白尿并导致肾小球损伤。我们建议，ACE2上调将成为旨在减少蛋白尿和肾小球损伤的新疗法的靶点。我们现在有工具通过不同的方法直接验证这一假设：给糖尿病小鼠注射重组小鼠血管紧张素转换酶2，慢病毒血管紧张素转换酶2和一种新的血管紧张素转换酶激活剂。ACE2局部保护的假设机制将使用足细胞特异的ACE2转基因进一步研究。这项建议的具体目标是：目的1)生产小鼠重组ACE2并建立给小鼠的方案，以实现血清ACE2活性的持续增加，从而有效地增加Ang II的降解和Ang-(1-7)的形成。目的2)建立慢病毒小鼠血管紧张素转换酶2(ACE2)表达系统，并建立给药方案，实现血清和组织ACE2活性的持续增加，有效促进Ang II的系统降解和Ang-(1-7)在肾脏水平的形成。目的3)观察小鼠重组血管紧张素转换酶2(R)、慢病毒血管紧张素转换酶2载体和新型血管紧张素转换酶激活剂XNT对2型糖尿病模型(C57BLK和FVB背景)蛋白尿和肾小球病变的影响。这些不同的方法扩增ACE2后，Ang II和Ang-(1-7)对这些参数的相对贡献将在使用Ang-(1-7)/mAs受体的特定阻断剂的附加实验中进行检验。目的4)验证糖尿病(db/db)合并肾小球ACE2过度表达的蛋白尿和糖尿病肾小球病变可以预防的假说，以及即使在系统性ACE2缺乏的情况下，这种保护也可以通过孤立的肾小球ACE2过度表达来实现。公共卫生相关性：肾脏疾病是1型和2型糖尿病的常见并发症。肾素-血管紧张素系统(RAS)与糖尿病肾病的发生发展密切相关。最近发现，一种名为ACE2的酶在处理血管紧张素II方面发挥了作用，血管紧张素II是一种可能导致糖尿病肾病进展的激素。这项提案将更好地了解血管紧张素II，特别是血管紧张素转换酶2在糖尿病肾脏疾病中的作用，并有望为治疗患有糖尿病和肾脏损害的患者提供新的见解。我们推测，这项提议的结果将为旨在增强ACE2活性以治疗糖尿病肾脏疾病的疗法的开发提供概念证明，与开发ACE抑制剂以防止血管紧张素II形成并目前广泛用于糖尿病和肾脏疾病患者的方式非常相似。