Renal Cell Response in Diabetes

糖尿病肾细胞反应

基本信息

批准号：
8110045
负责人：
HANNA E ABBOUD
金额：
$ 27.84万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8110045
关键词：
ATP Synthesis Pathway Accounting Antibodies Antioxidants Antisense Oligonucleotide Therapy Antisense Oligonucleotides Basement membrane Cell membrane Cells Complex Complication Complications of Diabetes Mellitus Consumption Development Diabetes Mellitus Diabetic Nephropathy Electron Transport Electrons Enzymes Epithelial Cells Extracellular Matrix Extravasation Family Fibronectins Fibrosis Gene Targeting General Population Generations Genetic Transcription Glucose Goals Growth Factor Hyperglycemia Hypertension Hypertrophy Injury Insulin-Dependent Diabetes Mellitus Intervention Isoenzymes Kidney Kidney Diseases Kidney Glomerulus Measures Mediating Mediator of activation protein Membrane Messenger RNA Mitochondria Mitochondrial DNA Modeling Morbidity - disease rate NADP NADPH Oxidase NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidants Oxidases Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Oxygen Consumption Pathogenesis Pathway interactions Positioning Attribute Production Protein Kinase C Proteins Proteinuria Rattus Reactive Oxygen Species Regulation Renal function Reporting Respiratory Chain Role Signal Transduction Pathway Source Streptozocin System Testing Tissues Tubular formation cell injury cell type cytokine glomerulosclerosis interstitial kidney cell kidney cortex mesangial cell mitochondrial dysfunction mortality prevent response transcription factor type I and type II diabetes

ATP Synthesis Pathway Accounting Antibodies Antioxidants Antisense Oligonucleotide Therapy Antisense Oligonucleotides Basement membrane Cell membrane Cells Complex Complication Complications of Diabetes Mellitus Consumption Development Diabetes Mellitus Diabetic Nephropathy Electron Transport Electrons Enzymes Epithelial Cells Extracellular Matrix Extravasation Family Fibronectins Fibrosis Gene Targeting General Population Generations Genetic Transcription Glucose Goals Growth Factor Hyperglycemia Hypertension Hypertrophy Injury Insulin-Dependent Diabetes Mellitus Intervention Isoenzymes Kidney Kidney Diseases Kidney Glomerulus Measures Mediating Mediator of activation protein Membrane Messenger RNA Mitochondria Mitochondrial DNA Modeling Morbidity - disease rate NADP NADPH Oxidase NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidants Oxidases Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Oxygen Consumption Pathogenesis Pathway interactions Positioning Attribute Production Protein Kinase C Proteins Proteinuria Rattus Reactive Oxygen Species Regulation Renal function Reporting Respiratory Chain Role Signal Transduction Pathway Source Streptozocin System Testing Tissues Tubular formation cell injury cell type cytokine glomerulosclerosis interstitial kidney cell kidney cortex mesangial cell mitochondrial dysfunction mortality prevent response transcription factor type I and type II diabetes

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项目摘要

DESCRIPTION (provided by applicant): Oxidative stress contributes to cell injury in diabetic nephropathy (DN), a major complication of type 1 and type 2 diabetes. Diabetes is characterized by mitochondrial dysfunction which results in decreased activity of the respiratory chain complexes associated with enhanced generation of reactive oxygen species (ROS). Hyperglycemia contributes to mitochondrial dysfunction and oxidative stress. We have strong evidence that high glucose enhances cell hypertrophy and fibronectin expression in mesangial cells through the NAD(P)H- oxidase isoenzyme Nox4. In addition, Nox4-dependent ROS generation is increased within the renal cortex and isolated glomeruli of rats with streptozotocin-induced diabetes. We provide strong evidence that Nox4 is present not only in cell membranes but also in mitochondria. This suggests that in addition to the mitochondrial electron-transport chain (mtETC), Nox oxidases are a source of ROS in diabetes. The central hypothesis of this proposal is that Nox4 is activated by glucose in renal glomerular cells and that an interplay exists between Nox4 and the mtETC that results in hypertrophy and matrix accumulation. Specific aim #1: to investigate the mechanisms by which glucose activates Nox4 and mtETC and the role of these two sources of ROS in the activation of protein kinase C and NFKB resulting in hypertrophy and fibronectin expression in renal cells. Specific aim #2: to explore the role of Nox4- and mtETC-derived ROS and the activation of PKC and NFKB in the structural and functional changes of diabetic nephropathy in two rat models of type 1 and type II diabetes. This project seeks to identify the cellular and subcellular source(s) of ROS and explore mechanisms by which hyperglycemia and oxidants result in kidney injury. This should help identify specific antioxidants to treat progressive diabetic nephropathy. Diabetes and diabetic nephropathy are major causes of morbidity and mortality in the general population. Euglycemia is a difficult goal to achieve. Oxidative stress contributes to diabetic complications; however, the precise sources of oxygen radicals are not completely defined. It is our hope that identifying specific sources of oxygen radicals will allow targeted therapy to prevent diabetic nephropathy.

描述（由申请人提供）：氧化应激有助于糖尿病性肾病（DN）的细胞损伤，这是1型和2型糖尿病的主要并发症。糖尿病的特征是线粒体功能障碍，导致呼吸链络合物的活性降低，与增强的活性氧（ROS）相关。高血糖有助于线粒体功能障碍和氧化应激。我们有强有力的证据表明，高葡萄糖通过NAD（P）H-氧化酶同工酶NOX4增强细胞肥大和纤连蛋白的表达。另外，在肾皮质中增加了NOX4依赖性ROS的产生，并具有链蛋白酶诱导的糖尿病的大鼠的分离肾小球。我们提供了有力的证据，表明NOX4不仅存在于细胞膜中，而且还存在于线粒体中。这表明，除了线粒体电子传输链（MTETC）之外，NOX氧化酶是糖尿病中ROS的来源。该提议的中心假设是NOX4在肾肾小球细胞中被葡萄糖激活，并且在NOX4和MTETC之间存在相互作用，从而导致肥大和基质积累。具体目的＃1：研究葡萄糖激活NOX4和MTETC的机制，以及这两个ROS来源在蛋白激酶C和NFKB激活中的作用，从而导致肾细胞中肥大和纤连蛋白表达。具体目的＃2：探索NOX4和MTETC衍生的ROS的作用，以及PKC和NFKB在糖尿病肾病的结构和功能变化中的激活在1型和II型糖尿病的两种大鼠模型中。该项目旨在鉴定ROS的细胞和亚细胞来源，并探索高血糖和氧化剂导致肾脏损伤的机制。这应该有助于确定特定的抗氧化剂来治疗进行性糖尿病性肾病。糖尿病和糖尿病性肾病是普通人群发病率和死亡率的主要原因。尤利西亚是一个艰难的目标。氧化应激导致糖尿病并发症。但是，氧自由基的精确来源并未完全定义。我们希望确定氧自由基的特定来源将允许靶向疗法预防糖尿病性肾病。