Role of Arginase in Diabetic Nephropathy

精氨酸酶在糖尿病肾病中的作用

基本信息

批准号：
9107444
负责人：
Alaa S Awad
金额：
$ 14.73万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
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/9107444
关键词：
Albuminuria Allergens Angiotensin-Converting Enzyme Inhibitors Animals Arginine Attenuated Autoimmune encephalitis Biological Availability Blood Glucose Blood Pressure Blood Urea Nitrogen Blood Vessels Citrulline Cultured Cells Cyclic GMP Cysteine Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Diagnosis Disease Dose End stage renal failure Endothelial Cells Functional disorder Genetic Glucose Gold Histology Hyperargininemia Hypertension Infiltration Injury Kidney Kidney Diseases Lead Metabolism Modality Mus NOS3 gene Nitric Oxide Synthase Ornithine Outcome Pathogenesis Pathway interactions Plasma Prevalence Primary Prevention Process Publications Rattus Renal Tissue Renal function Reperfusion Injury Role Secondary Prevention Streptozocin Sum Supplementation System Testing Tissues Transgenic Mice airway obstruction arginase base diabetic global health improved in vivo inhibitor/antagonist kidney cell kidney preservation liver ischemia mRNA Expression macrophage mouse model novel therapeutic intervention novel therapeutics overexpression prevent

项目摘要

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.

描述（由申请人提供）：糖尿病（DM）是全球健康问题。美国被诊断和未诊断的糖尿病的患病率从2007年的7.8％逐渐增加，2010年的14.5％，预计将上升到2050年的24.7％到32.8％。糖尿病是终止阶段肾脏疾病的最常见原因，造成终止阶段的肾脏疾病，造成美国的40％以上，这一数字可能会增加，并且可能会持续增长。内皮细胞功能障碍是一种中央病理生理机制，有助于糖尿病和糖尿病性肾病（DN）。由于一氧化氮合酶（NOS）和精氨酸酶的活性和/或表达的变化，精氨酸代谢的急剧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也可诱导，并且在升高时可以抑制NOS活性/表达并诱导内皮NOS脱偶联，从而降低了无生物利用度并抑制NO/CGMP途径。我们假设精氨酸酶促进了糖尿病肾脏损伤的发育和发展。目标1：检验精氨酸酶抑制作用将在DN的初级和次要预防中有效的假设。目标2：检验以下假设：血浆精氨酸生物利用度的降低有助于DN的发展和发展。 AIM 3：检验以下假设：内皮细胞中精氨酸酶-2升高会导致DN的组织损伤。 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）和过表达精氨酸酶-2的内皮细胞完全定义了精氨酸酶在DN中的作用。