Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease

KLF6 在糖尿病肾病中对线粒体功能的转录控制

• 批准号: 9286505
• 负责人: Sandeep K Mallipattu
• 金额: $ 36.11万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-12 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286505
• 关键词: Activities of Daily Living; Address; Adult; Albuminuria; American; Apoptosis; Attenuated; Binding; Biogenesis; Biopsy; Catalytic Domain; Cellular Stress; Centers for Disease Control and Prevention (U.S.); Chronic Kidney Failure; Complex; DNA Damage; Data; Diabetes Mellitus; Diabetic Nephropathy; Disease Progression; Embryo; End stage renal failure; Epithelial Cells; Exhibits; Filtration; Gene Chips; Gene Expression; Genes; Genetic Transcription; Glucose; Goals; Human; Individual; Injury; Insulin-Dependent Diabetes Mellitus; Kidney; Kinetics; Knock-in Mouse; Knockout Mice; Laboratories; Light; Mediating; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mus; Mutation; NPHS2 protein; Non-Insulin-Dependent Diabetes Mellitus; Outcomes Research; PPAR gamma; Pathway interactions; Physiologic pulse; Post-Translational Protein Processing; Proteinuria; Proteomics; Reporting; Research; Research Proposals; Risk Factors; Role; Severities; Streptozocin; Structure; System; Tamoxifen; Tetanus Helper Peptide; Transcript; Transcriptional Regulation; United States; Zinc Fingers; base; complex IV; cytochrome c; cytochrome c oxidase; diabetic; disorder prevention; glomerular filtration; glycemic control; improved; inducible gene expression; knock-down; mitochondrial dysfunction; mouse model; novel; overexpression; podocyte; prevent; promoter; protein expression; respiratory; response to injury; transcription factor

Project Summary/Abstract The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans have chronic kidney disease. Diabetes Mellitus is the leading risk factor for chronic kidney disease in the United States. Despite improved glycemic control, individuals with Diabetes Mellitus continue to develop and progress to diabetic kidney disease (DKD). In DKD, along with endothelial injury and mesangial expansion, podocyte loss directly contributes to the functional capacity to maintain the renal filtration barrier. Mitochondrial injury is also uniformly observed in DKD and is accompanied by mitochondrial DNA damage as well as altered expression of genes involved in mitochondrial biogenesis, function, and fragmentation. We recently reported the essential role for the zinc-finger transcription factor, Krüppel-like factor 6 (KLF6), in podocyte injury. Specifically, we demonstrated that KLF6 is an early inducible injury response gene that enhances mitochondrial respiratory complex IV (cytochrome c oxidase, COX) expression, thereby abrogating the release of cytochrome c and activation of apoptosis in the setting of cell stress. KLF6 maintains COX assembly by regulating the expression of key transcripts involved in mitochondrial replication, transcription, and function under cell stress. To date, this is the first study demonstrating a direct regulatory effect of a zinc-finger transcription factor on mitochondrial function in the podocyte. Our preliminary data also suggests that podocyte-specific loss of Klf6 (Klf6-/-) accelerated DKD in mice. In addition, we observed a significant increase in mitochondrial injury with podocyte loss in the diabetic Klf6-/- mice as compared to diabetic wildtype mice. Furthermore, we observed that modulating the level of KLF6 expression in the podocyte directly regulated mitochondrial structure, function, genes involved in COX assembly, and apoptosis. Finally, KLF6 expression was reduced in DKD as compared to healthy control subjects in three independent gene expression arrays from human kidney biopsies. The objective of this research proposal is to demonstrate that KLF6 is required to prevent mitochondrial dysfunction and podocyte injury in DKD. The long-term goal of our project is to identify “druggable” targets in restoring mitochondrial function in podocytes of diabetic kidney. This proposal will address a current gap in the field by demonstrating that COX assembly is critical to preventing mitochondrial dysfunction in podocytes of diabetic kidney. The potential impact of this proposed research is that it will shed new light on the critical role of respiratory complex assembly in improving mitochondrial function in the podocyte and slowing the rate of DKD progression in the kidney. Finally, deciphering the mechanism by which KLF6 regulates COX assembly will provide us with a novel pathway to target in DKD.

项目摘要/摘要 疾病控制与预防中心估计美国超过10％的成年人 2000万美国人患有慢性肾脏疾病。糖尿病是慢性的主要危险因素 美国的肾脏疾病。尽管血糖控制得到改善，但糖尿病患者 继续发展并发展为糖尿病肾脏疾病（DKD）。在DKD中，以及内皮受伤和 肾小球扩张，足细胞损失直接有助于维持肾脏过滤器的功能能力 障碍。线粒体损伤在DKD中也均匀观察到，并伴有线粒体DNA 损害以及参与线粒体生物发生，功能和 分散。我们最近报道了锌指转录因子Krüppel样因子的重要作用 6（klf6），在足细胞损伤中。具体而言，我们证明了KLF6是早期诱导的损伤反应 增强线粒体呼吸复合物IV（细胞色素C氧化酶，COX）表达的基因，从而 在细胞应激的情况下，细胞色素C的释放和凋亡的激活。 KLF6坚持 通过调节与线粒体复制有关的关键转录本的表达，Cox组装， 转录和在细胞应力下的功能。迄今为止，这是第一个展示直接调节的研究 锌指转录因子对足细胞中线粒体功能的影响。我们的初步数据 表明小鼠中KLF6（KLF6 - / - ）的足细胞特异性损失。此外，我们观察到了 与糖尿病KLF6 - / - 小鼠相比 糖尿病野生型小鼠。此外，我们观察到调节足细胞中KLF6表达的水平 直接调节的线粒体结构，功能，涉及Cox组装的基因和凋亡。最后， 与三个独立基因的健康对照受试者相比，DKD中的KLF6表达降低 来自人类肾脏活检的表达阵列。该研究建议的目的是证明 需要KLF6来防止DKD中的线粒体功能障碍和足细胞损伤。长期目标 我们的项目是确定在恢复糖尿病肾足细胞中线粒体功能的“可药物”靶标。 该提案将通过证明考克斯集会对现场的当前差距解决至关重要 防止糖尿病肾足细胞中线粒体功能障碍。该提议的潜在影响 研究是，它将对呼吸复合体组装的关键作用进行新的启示 足细胞中的线粒体功能，并降低了肾脏中DKD进展的速度。最后， 破译KLF6调节Cox组装的机制将为我们提供新的途径 DKD中的目标。