Role of Arginase in Diabetic Nephropathy

描述(申请人提供)：糖尿病(DM)是一个全球性的健康问题。美国已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年将从24.7%上升到32.8%。糖尿病是终末期肾病最常见的原因，占美国所有病例的40%以上，而且这一数字可能会有增无减。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。在内皮损伤中，由于一氧化氮合酶(NOS)和精氨酸酶的活性和/或表达的变化，精氨酸代谢发生了戏剧性的变化。精氨酸酶-2在血管内皮细胞和肾脏细胞中有结构性表达和诱导作用，升高时可抑制一氧化氮合酶活性/表达，诱导内皮细胞一氧化氮合酶解偶联，从而降低NO的生物利用度，抑制NO/cGMP途径。我们假设精氨酸酶促进糖尿病肾损害的发生和发展。目的1：验证精氨酸酶抑制在糖尿病肾病一级和二级预防中有效的假设。目的2：验证血浆精氨酸生物利用度降低有助于糖尿病肾病发生发展的假说。目的：验证内皮细胞内精氨酸酶-2升高参与糖尿病肾病组织损伤的假说。我们的实验方法将使用完整的动物(Ins2Akita小鼠及其野生型(WT)胎鼠，Zucker糖尿病肥胖大鼠)，转基因小鼠(完全不表达精氨酸酶-2的小鼠(Arg2-/-)，以及在内皮细胞(Tie2Arg2)和培养细胞(肾小球微血管内皮细胞)和高表达精氨酸酶-2的内皮细胞中过表达精氨酸酶-2的转基因小鼠)来全面确定精氨酸酶在糖尿病肾病中的作用。了解糖尿病和精氨酸酶之间的相互作用可能有助于阐明糖尿病肾脏疾病的机制，并导致开发新的治疗策略来管理疾病过程。

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is a global health problem. 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 between 24.7% to 32.8% in 2050. Diabetes is the most common cause of end stage renal disease, responsible for more than 40% of all cases in the US, and this number are likely to continue to increase unabated. Endothelial cell dysfunction is a central pathophysiological mechanism that contributes to diabetes and diabetic nephropathy (DN). Dramatic alterations in arginine metabolism occur in endothelial injury due to changes in the activity and/or expression of nitric oxide synthases (NOS) and arginases. Arginase-2 is constitutively expressed and also inducible in endothelial cells as well as in kidney cells and, when elevated, can inhibit NOS activity/expression and induce endothelial NOS uncoupling, thus reducing NO bioavailability and inhibiting the NO/cGMP pathway. We hypothesize that arginases promote the development and progression of diabetic kidney damage. Aim 1: Test the hypothesis that arginase inhibition will be effective in the primary and secondary prevention of DN. Aim 2: Test the hypothesis that reduction in plasma arginine bioavailability contributes to the development and progression of DN. Aim 3: Test the hypothesis that elevated arginase-2 in endothelial cells contributes to tissue damage in DN. Our experimental approach will use both whole animals (Ins2Akita mice and their wild type (WT) littermates, Zucker diabetic fatty rats), genetically altered mice (mice with complete absence of arginase-2 expression (Arg2-/-), and transgenic mice that overexpress arginase-2 specifically in endothelial cells (Tie2Arg2) and cultured cells (glomerular microvascular endothelial cells (GMVEC) and endothelial cells that overexpress arginase-2) to fully define the role of arginases in DN. An understanding of the interaction between diabetes and arginases may help to elucidate mechanisms involved in diabetic renal disease and lead to the development of new therapeutic strategies to manage the disease process.