Mechanisms of microvascular damage in acute kidney injury

急性肾损伤微血管损伤机制

• 批准号: 7991697
• 负责人: Timothy Alan Sutton
• 金额: $ 8.09万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991697
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; American; Animals; Attention; Basement membrane; Biochemical; Biological Assay; Biology; Blood Vessels; Cell Adhesion; Cells; Chronic; Chronic Kidney Failure; Clinical; Complex; Coupled; Critical Pathways; Data; Development; Dropout; Edema; Endothelial Cells; Environment; Functional disorder; Funding; Gelatinase A; Gelatinase B; Gelatinases; Generations; Goals; Health; Healthcare; Hospitals; Human; Hypoxia; Image; Imaging Techniques; Inflammation; Injury; Intercellular Junctions; Intervention; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Life; Literature; Long-Term Effects; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Methods; Microscopic; Microscopy; Microvascular Permeability; Modeling; Molecular; Outcome; Pericytes; Play; Prevention; Public Health; Renal function; Renal tubule structure; Research; Research Personnel; Resource Sharing; Resources; Role; Severities; Structure; Syndrome; Techniques; Testing; Therapeutic Intervention; Tissues; Transgenic Animals; Tubular formation; Vascular Permeabilities; Work; angiogenesis; base; body system; density; experience; in vivo; innovation; new therapeutic target; novel; prevent; programs

DESCRIPTION (provided by applicant): Project Summary: Acute kidney injury (AKI) is a tremendous burden on human health and health care resources. Acute alterations of the kidney microvasculature significantly contribute to kidney dysfunction during AKI. In addition, there is growing evidence that chronic alterations of the kidney microvasculature following an episode of AKI are directly related to long-term kidney dysfunction and a propensity towards chronic kidney disease. There is a fundamental gap in understanding the mechanisms responsible for these acute and chronic microvascular alterations. The long term goal is to understand the cellular and molecular basis of renal microvascular alterations associated with AKI and to develop novel and specific therapeutic interventions targeting these mechanisms. The objective of this application, which is a step toward attainment of the long term goal, is to determine how matrix metalloproteinases (MMP)-2 and -9, known collectively as gelatinases, alter renal microvascular function and structure in AKI. The central hypothesis of this application is that gelatinase activation is essential for the increased microvascular permeability and increased microvascular loss observed in AKI. The central hypothesis will be tested and the overall objective of this application will be accomplished by pursuing two specific aims. Aim 1 will test the hypothesis that gelatinase activation in cells resident to the kidney promotes increased vascular permeability in AKI through degradation of the endothelial cell contacts and breakdown of the vascular basement membrane. To accomplish this aim, multiphoton microscopy will be employed to examine in vivo alterations in microvascular permeability, endothelial cell adhesion complexes, and vascular basement membranes in animals deficient in MMP-2 or MMP-9 using a model of AKI. Aim 2 will test the hypothesis that gelatinase activation in AKI effects long term microvascular loss via generation of angiostatic factors. To accomplish this aim, biochemical and advanced microscopic techniques will be utilized to examine alterations in microvascular density and generation of angiostatic factors in animals deficient in MMP-2 or MMP-9 using a model of AKI. This proposed work is innovative because it applies novel methods of live-animal imaging in transgenic animals. The proposed research is significant because it is expected to provide a detailed understanding of novel mechanisms for two critical microvascular alterations associated with AKI and pinpoint innovative pharmacological interventions for ameliorating the short-term and long-term consequences of AKI. Relevance to Public Health: The proposed research will have an important positive impact because it is expected to provide novel therapeutic targets for the prevention and treatment of the serious clinical syndrome of acute kidney injury, as well as, the progression to chronic kidney disease that has become increasingly appreciated to be an important long term clinical consequence of acute kidney injury.

描述（由申请人提供）：项目摘要：急性肾脏损伤（AKI）是人类健康和保健资源的巨大负担。肾脏微脉管系统的急性改变显着导致AKI期间的肾功能障碍。此外，越来越多的证据表明，AKI发作后肾脏微脉管系统的慢性改变与长期肾功能障碍和慢性肾脏病的倾向直接相关。理解负责这些急性和慢性微血管改变的机制存在根本的差距。长期目标是了解与AKI相关的肾脏微血管改变的细胞和分子基础，并开发针对这些机制的新型和特定的治疗干预措施。该应用的目的是实现长期目标的一步，是确定基质金属蛋白酶（MMP）-2和-9如何统称为明胶酶，改变AKI的肾脏微血管功能和结构。该应用的中心假设是，明胶酶活性对于增加的微血管通透性和在AKI中观察到的微血管损失增加至关重要。将测试中心假设，并通过追求两个具体目标来实现本应用的总体目标。 AIM 1将检验以下假设：居住在肾脏中的细胞中的明胶激活通过降解内皮细胞接触和血管基底膜的分解而促进AKI中血管通透性的增加。为了实现这一目标，将使用多光子显微镜检查微血管通透性，内皮细胞粘附复合物和使用AKI模型中缺乏MMP-2或MMP-9中缺乏的动物的血管基底膜的体内改变。 AIM 2将检验以下假设：AKI中的明胶激活会通过产生血管静脉因子的长期微血管丧失。为了实现这一目标，将利用生化和先进的微观微观技术来检查微血管密度的变化以及使用AKI模型在MMP-2或MMP-9中缺乏动物的血管静脉因子的产生。这项提出的工作具有创新性，因为它采用了转基因动物中活动画成像的新方法。拟议的研究之所以重要，是因为预计它将对与AKI相关的两种关键微血管变化的新机制提供详细的理解，并确定了创新的药理干预措施，以改善AKI的短期和长期后果。与公共卫生的相关性：拟议的研究将产生重要的积极影响，因为它有望为预防和治疗严重的急性肾脏损伤临床综合征提供新的治疗靶标，以及慢性肾脏疾病的进展，越来越多地欣赏到急性急性肾肾脏损伤的重要临床后果。