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Bradykinin, Nitric Oxide and Mitochondrial DNA Damage in Diabetic Complications

糖尿病并发症中的缓激肽、一氧化氮和线粒体 DNA 损伤

基本信息

批准号：
7287830
负责人：
OLIVER SMITHIES
金额：
$ 29.06万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7287830
关键词：
Affect Apoptosis Bradykinin Bradykinin B1 Receptor Bradykinin B2 Receptor Bradykinin Receptor Cardiovascular system Cells Complications of Diabetes Mellitus DNA DNA Damage DNA polymerase gamma Data Defect Deoxyguanosine Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Endothelial Cells Frequencies Generations Genes Genetic Glucose Goals Human In Vitro Kidney Knowledge Lead Measures Methods Mitochondria Mitochondrial DNA Modification Molecular Mus Mutation NG-Nitroarginine Methyl Ester Neuraxis Nitric Oxide Organ Oxidative Stress Participant Patients Peripheral Phenotype Play Point Mutation Preventive Principal Investigator Process Production Reading Research Design Research Personnel Retina Role Severities Skin Staging Streptozocin Susceptibility Gene TP53 gene Testing Therapeutic Tissues Work base connective tissue growth factor diabetic genetic risk factor inhibitor/antagonist mitochondrial DNA mutation mouse model programs protective effect receptor research study senescence synuclein

项目摘要

DESCRIPTION (provided by applicant): In our previous work we have demonstrated that genetic factors controlling the production of bradykinin (BK) and nitric oxide (NO) influence greatly the development of renal complications in mice made diabetic with streptozotocin (STZ) or by the Akita diabetogenic C86Y mutation in Ins 2. We also showed that diabetic nephropathy and several indicators of senescence increase progressively in the order wildtype < bradykinin receptor B2 null < Akita diabetic < B2 receptor null Akita diabetic. 8-OHdG content, point mutations and deletions in mitochondrial (mt) DNA increased in the same progression, as did indicators of oxidative stress. We now propose three specific aims and the generation of two new mouse models to determine the interplay between genetic factors that influence BK action, the production of NO, and diabetes-related increases in mutations in mtDNA. Specific aim 1 will determine the effect on diabetic complications of eliminating both BK receptors throughout the body, or in a tissue or cell specific manner; the effects of reducing oxidative stress in these mice will also be determined. Specific aim 2 will investigate the relationship between glomerular damage and mtDNA mutations in eNOS -/- diabetic mice in which we have found that oxidative stress is paradoxically less than in eNOS +/+ diabetic mice. Specific aim 3 will test the hypothesis that increasing the frequency of mtDNA mutations by introducing a proof reading defect into mitochondrial DNA polymerase gamma will exacerbate the complications in Akita diabetic mice even though oxidative stress is not further increased over that due to the diabetes alone.

描述（由申请人提供）：在我们以前的工作中，我们已经证明，控制缓激肽（BK）和一氧化氮（NO）的生产的遗传因素，大大影响糖尿病小鼠肾脏并发症的发展与链脲佐菌素（STZ）或秋田糖尿病基因C86 Y突变的Ins 2。我们还发现，糖尿病肾病和衰老的几个指标以野生型<缓激肽受体B2缺失型<秋田糖尿病< B2受体缺失型秋田糖尿病的顺序进行性增加。8-OHdG含量，线粒体（mt）DNA的点突变和缺失在同一进程中增加，氧化应激指标也是如此。我们现在提出了三个具体的目标和两个新的小鼠模型的产生，以确定影响BK作用，NO的产生和糖尿病相关的mtDNA突变增加的遗传因素之间的相互作用。具体目标1将确定消除全身或以组织或细胞特异性方式消除两种BK受体对糖尿病并发症的影响;还将确定减少这些小鼠中氧化应激的影响。具体目标2将研究eNOS -/-糖尿病小鼠中肾小球损伤与mtDNA突变之间的关系，我们发现在eNOS -/-糖尿病小鼠中氧化应激矛盾地低于eNOS +/+糖尿病小鼠。具体目标3将检验以下假设：通过将校对阅读缺陷引入线粒体DNA聚合酶γ中来增加线粒体DNA突变的频率将加剧秋田糖尿病小鼠的并发症，即使氧化应激没有进一步增加超过单独的糖尿病所致的氧化应激。