Role of Arginase in Diabetic Nephropathy

 描述（由申请人提供）：美国已诊断和未诊断糖尿病的患病率从2007年的7.8%逐渐增加，2010年为14.5%，预计2050年将上升至24.7%至32.8%。糖尿病肾病（DN）是糖尿病的重要并发症之一。内皮细胞功能障碍是糖尿病和DN的重要病理生理机制。越来越多的证据表明，精氨酸代谢的显着变化发生在内皮损伤的活性和/或表达的一氧化氮合酶（NOS）和/或NOS的变化。精氨酸酶-2在肾脏中组成型表达和调节，但精氨酸酶-1不表达和调节。我们最近的工作表明，抑制β-淀粉酶介导的DN通过eNOS依赖性机制的肾组织保护。因此，我们推测，选择性抑制剂的β-淀粉样蛋白酶-2将被证明是一个最佳的药物，以防止糖尿病肾病。这种选择性试剂将是血糖控制的有价值的辅助剂，以减轻这一重要的未满足的医疗需求。目的1：修饰我们的新型先导化合物ASR-133，使其具有更高的选择性和有效性。目的2：体外评价辅酶Ⅱ酶抑制剂的药理活性。确定一个选择性的β-淀粉样蛋白酶-2抑制剂将提供一个潜在的重要的治疗前领导糖尿病肾脏并发症的治疗，并可能提供一个新的治疗方法来管理DN。

 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.