Role of Arginase in Diabetic Nephropathy

精氨酸酶在糖尿病肾病中的作用

• 批准号: 8816879
• 负责人: Alaa S Awad
• 金额: $ 12.02万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816879
• 关键词: Address; Albuminuria; Animal Experiments; Animal Model; Arginine; Biological Assay; Biological Availability; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Collaborations; Complications of Diabetes Mellitus; Core Facility; Creatinine; Cyclic GMP; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Disease; Endothelial Cells; Enzymes; Functional disorder; Funding; Future; Genetic; Glucose; Goals; Histology; Human; Hyperargininemia; In Vitro; Infiltration; Injury; Kidney; Kidney Diseases; Laboratories; Lead; Ligands; Liver; Mediating; Medical; Metabolism; Mission; Molecular Models; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Parents; Pathway interactions; Pharmaceutical Preparations; Plasma; Polyamines; Prevalence; Proline; Renal Tissue; Rodent; Role; Specificity; Testing; Therapeutic; Translational Research; Urea; Work; arginase; blood glucose regulation; diabetic; drug discovery; inhibitor/antagonist; kidney cell; kidney preservation; mRNA Expression; macrophage; molecular modeling; novel; novel therapeutic intervention; pre-clinical; prevent; public health relevance; research study; response; scaffold; small molecule; urinary

 DESCRIPTION (provided by applicant): The prevalence of diagnosed and undiagnosed diabetes in the US is progressively increasing from 7.8% in 2007, 14.5% in 2010 and expected to rise to between 24.7% and 32.8% in 2050. Diabetic nephropathy (DN) remains an important and unresolved complication of diabetes. It has become evident that endothelial cell dysfunction is a central pathophysiological mechanism contributing to diabetes and DN. Growing evidence from our work and others suggests that dramatic alterations in arginine metabolism occur during endothelial injury in response to changes in the activity and/or expression of nitric oxide synthases (NOS) and/or arginases. Arginase-2 is constitutively expressed and regulated in the kidney, but not arginase-1. Our recent work demonstrates that arginase inhibition mediates renal tissue protection in DN via an eNOS-dependent mechanism. Therefore, we hypothesize that a selective inhibitor of arginase-2 will prove to be an optimal drug for protecting against diabetic nephropathy. Such a selective agent would be a valuable adjunct to blood glucose control in mitigating this important unmet medical need. Aim 1: Modify our novel lead compound ASR-133 to render it more arginase-2 selective and potent. Aim 2: In vitro assessment of pharmacotherapeutic potential of arginase inhibitors. Identification of an arginase-2 selective inhibitor would provide a potentially important pre-therapeutic lead for the treatment of diabetic renal complications and may provide a new therapeutic approach to the management of DN.

 描述(申请人提供)：美国确诊和未确诊糖尿病的患病率从2007年的7.8%和2010年的14.5%逐渐上升，预计到2050年将上升到24.7%到32.8%之间。糖尿病肾病(糖尿病肾病)是糖尿病尚未解决的重要并发症。血管内皮细胞功能障碍是糖尿病和糖尿病肾病的重要病理生理机制。来自我们和其他人的越来越多的证据表明，在内皮损伤过程中，精氨酸代谢发生了戏剧性的变化，以响应一氧化氮合酶(NOS)和/或精氨酸酶的活性和/或表达的变化。精氨酸酶-2在肾脏中有结构性的表达和调节，而不是精氨酸酶-1。我们最近的工作表明，精氨酸酶抑制通过eNOS依赖的机制介导糖尿病肾病的肾组织保护。因此，我们假设精氨酸酶-2的选择性抑制剂将被证明是预防糖尿病肾病的最佳药物。这种选择性药物将是血糖控制的一个有价值的辅助手段，以缓解这一重要的未得到满足的医疗需求。目的1：对我们新的先导化合物ASR-133进行修饰，使其更具精氨酸酶-2的选择性和效力。目的2：体外评价精氨酸酶抑制剂的药物治疗潜力。精氨酸酶-2选择性抑制剂的鉴定将为糖尿病肾脏并发症的治疗提供一个潜在的重要的治疗前线索，并可能为治疗糖尿病肾病提供一种新的治疗方法。