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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.

简介（由申请人提供）：糖尿病（DM）是一个全球性的健康问题。在美国，确诊和未确诊的糖尿病患病率正从2007年的7.8%逐步上升到2010年的14.5%，预计到2050年将从24.7%上升到32.8%。糖尿病是导致终末期肾脏疾病的最常见原因，占美国所有病例的40%以上，而且这个数字可能会继续有增无减。内皮细胞功能障碍是导致糖尿病和糖尿病肾病（DN）的主要病理生理机制。由于一氧化氮合酶（NOS）和精氨酸酶的活性和/或表达的变化，在内皮损伤中发生了精氨酸代谢的剧烈变化。精氨酸酶-2在内皮细胞和肾细胞中均可组成性表达和诱导，当精氨酸酶-2升高时，可抑制NOS活性/表达，诱导内皮细胞NOS解偶联，从而降低NO的生物利用度，抑制NO/cGMP通路。我们假设精氨酸酶促进糖尿病肾损害的发生和进展。目的1：验证精氨酸酶抑制在DN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DN发生和进展的假设。目的3：验证内皮细胞精氨酸酶-2升高导致DN组织损伤的假说。我们的实验方法将使用全动物（Ins2Akita小鼠及其野生型（WT）幼鼠，Zucker糖尿病脂肪大鼠），转基因小鼠(完全缺乏精氨酸酶-2表达的小鼠（Arg2-/-），以及在内皮细胞中特异性过表达精氨酸酶-2的转基因小鼠（Tie2Arg2）和培养细胞（肾小球微血管内皮细胞（GMVEC）和过表达精氨酸酶-2的内皮细胞）来充分确定精氨酸酶在DN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病的机制，并导致开发新的治疗策略来控制疾病过程。