Metabolic Reprogramming in Acute Kidney Injury

急性肾损伤中的代谢重编程

• 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
• 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

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)：由缺血再灌注损伤(IRI)引起的急性肾损伤(AKI)是一个常见的临床问题，在重症监护环境中具有很高的死亡率。此外，它也是慢性肾脏疾病(CKD)进展的重要因素。调节肾脏缺氧/缺血反应的一个中心途径是脯氨酰羟基酶(PhD)/缺氧诱导因子(HIF)氧感应通路。PHD蛋白是铁和2-氧戊二酸依赖的加氧酶，其功能是作为氧感受器，通过催化其α-亚基的氧依赖降解区域内特定的脯氨酸残基的羟化来调节HIF的活性。HIF是多效性异源二聚体转录因子，在细胞适应和缺氧/缺血条件下的存活中发挥关键作用。三种主要的HIF-PhD，PhD1，-2和-3都在肾脏中表达。虽然PHD2调节肾上皮细胞中HIF-1的活性，并被证明控制肾间质细胞中促红细胞生成素的产生，但PhD1和PHD3在肾脏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研究小组已经在临床前动物模型中证明，短期药物灭活肾脏PHD在预防急性缺血性损伤及其长期后遗症方面具有巨大的治疗潜力。为了了解单个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学和药理学方法来剖析特定细胞类型的PHD功能及其在调节肾脏代谢中的作用。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起着核心作用。在这项资助下，我们使用基因工程小鼠来研究肾脏中急性PHD失活的代谢后果。提出了三个具体目标。AIMS 1研究PHD2在肾脏能量代谢中的作用，AIM 2研究肾小管上皮细胞PhD1和PHD3在肾脏生理学和IRI中的功能作用，AIM 3研究IRI中与细胞保护相关的特定代谢途径。