Mitochondrial-Derived Superoxide in Type 2 Diabetic Kidney Disease

2 型糖尿病肾病中线粒体衍生的超氧化物

• 批准号: 9210544
• 负责人: Kumar Sharma
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210544
• 关键词: 5' -AMP-activated protein kinase; Aerobic; Affect; African American; Age; Albuminuria; Animal Model; Automobile Driving; Belief; Biochemical; Biogenesis; Biological Assay; Biopsy; Cardiovascular Diseases; Cell physiology; Cellular Structures; Chronic Kidney Failure; Clinical Data; Complex; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diagnosis; Disease; Down-Regulation; Electron Spin Resonance Spectroscopy; Electron Transport; End stage renal failure; Enrollment; Enzymes; Fibrosis; Functional disorder; Funding; Generations; Glucose; Health; Healthcare Systems; Heart; High Prevalence; Hormones; Human; Hydrogen Peroxide; Hypertension; Imaging Techniques; Incidence; Individual; Inflammation; Inflammatory; Injury; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Kidney Failure; Lead; Link; Mass Fragmentography; Measurement; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated kidney disease; Organ; Organ failure; Oxidases; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Peptides; Plasma; Play; Population; Production; Protein Kinase; Reactive Oxygen Species; Regulation; Renal function; Research; Resolution; Role; Sampling; Source; Superoxides; Testing; Therapeutic Intervention; Time; Tissues; Transforming Growth Factors; United States; United States Department of Veterans Affairs; Urine; Veterans; Warburg Effect; adiponectin; aerobic glycolysis; base; cytokine; db/db mouse; diabetic; differential expression; fatty acid oxidation; high risk; improved; in vivo imaging; kidney cell; metabolomics; mitochondrial metabolism; mouse model; novel; novel therapeutics; oxidation; patient population; potential biomarker; pre-clinical; public health relevance; restoration; sensor; targeted treatment; transcription factor; type I diabetic

 DESCRIPTION (provided by applicant): Each year in the United States, more than 100,000 people are diagnosed with kidney failure. Diabetes is the most common cause of chronic kidney disease and kidney failure. From the last several years, our research efforts are focused on identifying molecular mechanisms and potential biomarkers involved in the complications of diabetic kidney disease. Our research established a central role for the pro-fibrotic cytokine Transforming Growth Factor- (TGF) in diabetic nephropathy. We also showed that the hormone adiponectin negatively correlates with albuminuria in obese African Americans, a portion of the VA population that has a high incidence of kidney disease. This observation directly led us to the recognition that the master energy sensor, the enzyme AMP activated protein kinase (AMPK), is regulated by adiponectin and plays a major role in kidney disease. Our recent studies, supported by VA Merit funding, further demonstrated that both type 1 diabetic kidney disease and obesity-related kidney disease are characterized by reduced AMPK activity. Restoration of AMPK activity blocked matrix accumulation and TGF- production and activity. In addition, we recently found that AMPK activation reduces inflammation and hydrogen peroxide levels, likely via regulation of NAPDH oxidase. By using GC-MS based metabolomic analysis we recently identified a significant reduction in 13 metabolites, potential biomarkers of kidney function, in patients with diabetes and chronic kidney disease. Twelve of the 13 differentially expressed metabolites are linked to mitochondrial metabolism, suggesting defective mitochondrial activity. Another major recent breakthrough was that by using novel real-time imaging techniques, we found that mitochondrial superoxides are reduced in the kidneys and heart of animal models with type 1 diabetes, which is in contrast to the current belief that increased mitochondrial superoxide is responsible for organ damage. Stimulation with AMPK activators resulted in an increase in mitochondrial content, an increase in mitochondrial complex activity, an increase in mitochondrial superoxide production and resolution of inflammation and fibrosis. Therefore, we hypothesize that alterations in substrate oxidation and mitochondrial activity may play a key role in early diabetic kidney disease and prolonged reduction of mitochondrial content may lead to organ failure. However, similar studies have not been performed in type 2 diabetes. Although we find evidence of reduced mitochondrial function in patients with type 2 diabetes and CKD, we have not established the basis of these findings using animal models. As type 2 diabetes development is very different than pathogenesis of type 1 diabetes, there could be different effects on metabolism and mitochondrial function. However, in preliminary studies we find that mitochondrial superoxide is also reduced in the kidney of the db/db mouse model of type 2 diabetes. The current proposal will be focused to understand the mechanisms and consequences of mitochondrial derived superoxides in type 2 models of diabetic kidney disease. We will analyze specific changes associated with mitochondrial and cellular metabolism and approaches to improve mitochondrial function with the aim of identifying targets for therapeutic intervention.

 描述（由申请人提供）： 在美国，每年有超过 100,000 人被诊断患有肾衰竭，糖尿病是慢性肾病和肾衰竭的最常见原因。过去几年，我们的研究工作重点是确定相关的分子机制和潜在的生物标志物。我们的研究确定了促纤维化细胞因子转化生长因子（TGF）在糖尿病肾病中的核心作用，我们还表明激素脂联素与糖尿病肾病呈负相关。肥胖的非裔美国人中存在白蛋白尿，这是 VA 人群中肾病高发人群的一部分。这一观察结果直接让我们认识到，主要的能量传感器，即 AMP 激活蛋白激酶 (AMPK)，受到脂联素和脂联素的调节。我们最近在 VA Merit 资助下的研究表明，1 型糖尿病肾病和肥胖相关肾病的特点是 AMPK 活性降低，进而阻碍基质积累。此外，我们最近发现 AMPK 激活可能通过 NAPDH 氧化酶的调节降低炎症和过氧化氢水平。通过使用基于 GC-MS 的代谢组学分析，我们最近发现了 13 种代谢物（潜在的生物标志物）的显着减少。糖尿病和慢性肾病患者的肾功能，13 种差异表达的代谢物中有 12 种与线粒体代谢有关，表明线粒体活性存在缺陷，这是通过使用新型实时技术来实现的。通过成像技术，我们发现 1 型糖尿病动物模型的肾脏和心脏中线粒体超氧化物减少，这与目前认为线粒体超氧化物增加导致器官损伤的观点相反。线粒体含量、线粒体复合物活性增加、线粒体超氧化物产生增加以及炎症和纤维化的解决因此，我们认为底物氧化和线粒体活性的改变可能在早期糖尿病中发挥关键作用。 肾脏疾病和线粒体含量长期减少可能导致器官衰竭。然而，虽然我们发现 2 型糖尿病和 CKD 患者线粒体功能减少的证据，但尚未建立基础。使用动物模型得出这些发现。由于 2 型糖尿病的发展与 1 型糖尿病的发病机制有很大不同，因此可能对代谢和线粒体功能产生不同的影响。然而，在初步研究中，我们发现线粒体超氧化物在肾脏中也减少了。这db/db 2 型糖尿病小鼠模型。目前的提案将重点了解 2 型糖尿病肾病模型中线粒体衍生的超氧化物的机制和后果，我们将分析与线粒体和细胞代谢相关的具体变化以及改善方法。线粒体功能，旨在确定治疗干预的目标。