Metabolic Reprogramming in Acute Kidney Injury

急性肾损伤中的代谢重编程

基本信息

批准号：
9100699
负责人：
Volker Hans Haase
金额：
$ 35.55万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100699
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Animal Model Antioxidants Biochemical Biogenesis Biological Biological Assay Biological Process Brain Hypoxia-Ischemia Chronic Chronic Kidney Failure Clinical Cre-LoxP Critical Care Critiques Cytoprotection Energy Metabolism Epithelial Epithelial Cells Epithelium Erythropoiesis Erythropoietin Event Functional disorder Genetic Genetically Engineered Mouse Glutamine Grant Health Homologous Gene Hydroxylation Hypoxia Hypoxia Inducible Factor Image In Vitro Individual Inflammatory Injury Intensive Care Iron Kidney Laboratories Lead Mass Spectrum Analysis Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Molecular Genetics Natural regeneration Outcome Oxygen Oxygenases Pathway interactions Physiology Play Prevention Procollagen-Proline Dioxygenase Production Proline Proteins Regulation Renal Interstitial Cell Reperfusion Injury Resolution Respiration Role Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization System Tetracyclines Therapeutic Therapeutic Intervention Tubular formation Work alpha ketoglutarate angiogenesis bHLH-PAS factor HLF base cell type clinical care glucose metabolism hypoxia inducible factor 1 improved in vivo inhibitor/antagonist injured insight macromolecule metabolic abnormality assessment mortality pre-clinical programs renal epithelium renal hypoxia renal ischemia renal ischemia/hypoxia repaired response sensor targeted treatment therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a frequently encountered clinical problem and associates with high mortality in a critical care setting. It is furthermore an important contributor to the progressionof chronic kidney disease (CKD). A central pathway in the regulation of renal hypoxia/ischemia responses is the prolyl-hydroxylase (PHD)/hypoxia-inducible factor (HIF) oxygen-sensing pathway. PHD proteins are iron- and 2-oxoglutarate-dependent oxygenases that function as oxygen sensors and regulate HIF activity by catalyzing the hydroxylation of specific proline residues within the oxygen-dependent degradation domain of it's alpha-subunit. HIFs are pleiotropic heterodimeric transcription factors that play key roles in cellular adaptation and survival under hypoxic/ischemic conditions. All three main HIF-PHDs, PHD1, -2 and -3, are expressed in the kidney. While PHD2 regulates HIF-1 activity in renal epithelial cells and has been shown to control erythropoietin production in renal interstitial cells, the role of PHD1 and PHD3 in renal hypoxia responses and pathophysiology is unknown. Our laboratory and other groups have demonstrated in preclinical animal models that short-term pharmacologic inactivation of renal PHDs has great therapeutic potential for the prevention of acute ischemic injuries and their long-term sequelae. In order to understand the functional role of individual PHDs in renal physiology and to gain insight into the molecular and cellular basis of PHD/HIF-mediated renoprotection, we have begun to use genetic and pharmacologic approaches to dissect cell type-specific PHD functions and their role in the regulation of renal metabolism. Here we hypothesize that PHD/HIF-controlled re-programming of metabolism in renal epithelial cells plays a central role in determining the biological outcome of ischemic kidney injuries. Under this grant we use genetically engineered mice to investigate the metabolic consequences of acute PHD inactivation in the kidney. Three specific aims are proposed. Aims 1 investigates the role of PHD2 in renal energy metabolism, aim 2 examines the functional role of tubular epithelial PHD1 and PHD3 in renal physiology and IRI, and aim 3 examines specific metabolic pathways that associate with cytoprotection in IRI.

描述（由申请人提供）：缺血再灌注损伤（IRI）引起的急性肾损伤（AKI）是一个经常遇到的临床问题，并且与重症监护环境中的高死亡率相关。此外，它还是慢性肾病（CKD）进展的重要因素。调节肾脏缺氧/缺血反应的中心途径是脯氨酰羟化酶（PHD）/缺氧诱导因子（HIF）氧敏感途径。 PHD 蛋白是铁和 2-酮戊二酸依赖性加氧酶，充当氧传感器，并通过催化其 α 亚基的氧依赖性降解域内特定脯氨酸残基的羟基化来调节 HIF 活性。 HIF 是多效性异二聚体转录因子，在缺氧/缺血条件下的细胞适应和生存中发挥关键作用。所有三种主要的 HIF-PHD，PHD1、-2 和 -3，均在肾脏中表达。虽然 PHD2 调节肾上皮细胞中的 HIF-1 活性，并已被证明可以控制肾间质细胞中促红细胞生成素的产生，但 PHD1 和 PHD3 在肾缺氧反应和病理生理学中的作用尚不清楚。我们的实验室和其他小组已经在临床前动物模型中证明，短期药物灭活肾脏 PHD 对于预防急性缺血性损伤及其长期后遗症具有巨大的治疗潜力。为了了解个体 PHD 在肾脏生理学中的功能作用，并深入了解 PHD/HIF 介导的肾脏保护的分子和细胞基础，我们已经开始使用遗传和药理学方法来剖析细胞类型特异性 PHD 功能及其肾代谢的调节作用。在这里，我们假设 PHD/HIF 控制的肾上皮细胞代谢重编程在决定缺血性肾损伤的生物学结果中发挥着核心作用。在这笔资助下，我们使用基因工程小鼠来研究肾脏急性 PHD 失活的代谢后果。提出了三个具体目标。目标 1 研究 PHD2 在肾脏能量代谢中的作用，目标 2 检查肾小管上皮 PHD1 和 PHD3 在肾脏生理和 IRI 中的功能作用，目标 3 检查与 IRI 细胞保护相关的特定代谢途径。