Role of the kallikrein-kinin system in diabetic retinopathy

激肽释放酶-激肽系统在糖尿病视网膜病变中的作用

• 批准号: 8323487
• 负责人: EDWARD P FEENER
• 金额: $ 37.94万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323487
• 关键词: Acute; Adult; Age; Angioneurotic Edema; Area; Astrocytes; Biochemical Markers; Blindness; Blood Vessels; Bradykinin; Bradykinin B2 Receptor; Bradykinin Receptor; Carbonic Anhydrase I; Characteristics; Clinical; Collaborations; Complement 1 Inactivators; Data; Development; Dextrans; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Diffuse; Edema; Endothelial Cells; Extravasation; Factor XII; Grant; Health; Hemorrhage; High-Molecular-Weight Kininogen; Hormones; Human; Image; In Vitro; Individual; Inflammation; Injection of therapeutic agent; Institutes; Kallikrein-Kinin System; Kininogenase; Kinins; Label; Lesion; Leukostasis; Mass Spectrum Analysis; Massachusetts; Measures; Mediating; Medicine; Mus; Nature; Optical Coherence Tomography; Pathogenesis; Pathway interactions; Permeability; Plasma Kallikrein; Prekallikrein; Proteolysis; Proteome; Proteomics; Publishing; Rattus; Receptor Activation; Reporting; Retina; Retinal; Retinal Edemas; Rodent; Rodent Model; Role; Streptozocin; Stroke; System; Technology; Tight Junctions; Time; Vascular Permeabilities; Work; base; carbonate dehydratase; dextran; diabetic; diabetic rat; extracellular; in vivo; intravitreal injection; macular edema; monolayer; neutralizing antibody; non-diabetic; novel; novel therapeutics; proliferative diabetic retinopathy; receptor; response; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): Excessive retinal vascular permeability contributes to the pathogenesis of diabetic macular edema (DME), a leading cause of vision loss in working-age adults. We recently reported that activation of the kallikrein-kinin system (KKS) by intravitreal injection of carbonic anhydrase 1 (CA-I) in rats resulted in a rapid increase in retinal vascular permeability (RVP) followed by the development of focal areas of increased vascular leakage to fluorecein-labeled 2x106 Dal dextran conjugate at 48 hrs post injection (Gao et al. Nature Medicine 2007, Appendix 1). In addition, we showed that in the presence of diabetes, CA-I caused intraretinal thickening, measured by 3D optical coherence tomography (OCT), at this time point. To our knowledge, this is the first report of retinal thickening in a diabetic rodent that is similar to clinically evident retinal edema. We reported that CA-I-induced retinal edema was decreased by complement 1 inhibitor, neutralizing antibody to prekallikrein, and bradykinin receptor antagonism. We demonstrated that plasma kallikrein, factor XII, and high molecular weight kininogen, are present in their activated forms in vitreous from people with diabetic retinopathy. In preliminary studies, we have shown that intravitreal injection with activated purified plasma kallikrein, kallikrein(act), induced both acute diffuse RVP at 30 min and focal areas of RVP and retinal leukostasis at 48 h post injection. In addition, we show that the effects of kallikrein(act) on the development of focal areas of leakage to fluorecein-labeled 2x106 Dal dextran are increased in both rats and mice with diabetes compared with nondiabetic controls. Using cultured retinal microvessel endothelial cells and astrocytes, we have identified both bradykinin-dependent and -independent mechanisms of kallikrein action. Although the KKS has been identified as a key pathway of vascular inflammation and vasogenic edema in stroke and angioedema, little is known regarding the actions of the KKS on the retina and its potential role in diabetic retinopathy. This grant will investigate these effects of the KKS on retinal vascular function and examine the contribution of this system to diabetic retinal edema. Our studies will examine the hypothesis that diabetes increases the actions of kallikrein on the retina and that increased kallikrein action leads to increased retinal vascular permeability and edema via a combination of B2-R activation and kallikrein's direct effect on extracellular proteolysis. We will investigate the contributions of both bradykinin receptor-dependent and -independent mechanisms of plasma kallikrein action on the retina using both in vivo studies on diabetic and nondiabetic rodents and in vitro studies using retinal microvessel endothelial cells and astrocytes. In collaboration with Dr. James Fujimoto (Massachusetts Institute of Technology), we will characterize the effects of the KKS and diabetes on retinal ultrastructure using OCT. This grant will provide critical new information on plasma kallikrein actions in the retina that contribute to both the diffuse and focal lesions of RVP, inflammation, and retinal thickening, which have been implicated as primary causal factors and characteristics of DME. PUBLIC HEALTH RELEVANCE: This grant will characterize the role of plasma kallikrein-induced inflammation in diabetic retinopathy. This grant is based on exciting new data that has identified a hormone system that triggers retinal edema in diabetic rodent models. These studies could reveal new therapeutic strategies to treat diabetic macular edema, a leading cause of vision loss.

描述（由申请人提供）：过度的视网膜血管通透性有助于糖尿病性黄斑水肿（DME）的发病机制，DME是导致工作年龄成年人视力丧失的主要原因。我们最近报道，通过在大鼠玻璃体内注射碳酸酐酶1 （CA-I）激活钾likrein-kinin系统（KKS），导致视网膜血管通透性（RVP）迅速增加，随后在注射后48小时，荧光素标记的2x106 Dal葡聚糖偶联物出现血管渗漏增加的病灶区域（Gao等）。自然医学2007，附录1)。此外，我们发现，在糖尿病存在的情况下，ca - 1引起视网膜内增厚，通过3D光学相干断层扫描（OCT）测量，在这个时间点。据我们所知，这是第一个报告视网膜增厚的糖尿病啮齿动物，类似于临床明显的视网膜水肿。我们报道了补体1抑制剂和中和抗体可以减少ca -i诱导的视网膜水肿