Role of Arginase in Diabetic Nephropathy

描述（由申请人提供）：糖尿病（DM）是一个全球性的健康问题。在美国，已诊断和未诊断糖尿病的患病率从2007年的7.8%逐渐增加到2010年的14.5%，预计到2050年将在24.7%至32.8%之间上升。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，并且这一数字可能会继续增加。内皮细胞功能障碍是导致糖尿病和糖尿病肾病（DN）的重要病理生理机制。由于一氧化氮合酶（NOS）和精氨酸合酶的活性和/或表达的变化，精氨酸代谢的显著改变发生在内皮损伤中。精氨酸酶-2在内皮细胞以及肾细胞中组成型表达并且也是可诱导的，并且当升高时，可以抑制NOS活性/表达并诱导内皮NOS解偶联，从而降低NO生物利用度并抑制NO/cGMP途径。我们推测，胰蛋白酶促进糖尿病肾损害的发展和进展。目的1：检验抑制胰蛋白酶对DN的一级和二级预防有效的假设。目的2：验证血浆精氨酸生物利用度降低有助于DN发生和进展的假设。目的3：验证DN时内皮细胞中升高的β-淀粉样蛋白酶-2参与组织损伤的假设。我们的实验方法将使用整个动物（Ins 2秋田小鼠及其野生型（WT）同窝仔，Zucker糖尿病肥胖大鼠），遗传改变小鼠（完全不存在精氨酸酶-2表达的小鼠（Arg 2-/-），以及在内皮细胞中特异性过表达β-内酰胺酶-2的转基因小鼠（Tie 2Arg 2）和培养的细胞（肾小球微血管内皮细胞（GMVEC）和过表达β-淀粉样蛋白酶-2的内皮细胞）来充分确定β-淀粉样蛋白酶在DN中的作用。了解糖尿病和糖尿病肾病之间的相互作用可能有助于阐明糖尿病肾病的机制，并导致新的治疗策略的发展，以管理疾病的过程。

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.