A novel role for endogenous fructose in ischemic acute kidney injury

内源性果糖在缺血性急性肾损伤中的新作用

基本信息

批准号：
8511623
负责人：
Miguel Angel Lanaspa Garcia
金额：
$ 15.24万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511623
关键词：
Accounting Acute Acute Kidney Tubular Necrosis Acute Renal Failure with Renal Papillary Necrosis Admission activity Affect Aldehyde Reductase Animal Model Apoptosis Award Cell Death Cells Cessation of life Clinical Colorado Complication Creatinine Data Development Diet Environment Enzymes Fructokinases Fructose Functional disorder Generations Genitourinary system Glucose Head Hospitalization Hour Human Hypoxia In Vitro Indiana Injury Institution Intensive Care Units Kidney Kidney Diseases L-Iditol 2-Dehydrogenase Lead Medicine Mentors Mentorship Metabolic Metabolic syndrome Metabolism Molecular Mus Operative Surgical Procedures Ophthalmology Oxidants Oxidative Stress Pathology Pathway interactions Patients Play Production Protocols documentation Publishing Recovery Renal Hypertension Renal function Research Research Design Research Personnel Research Proposals Role Route Scientist Serum Small Interfering RNA Sorbitol Technology Tubular formation Universities Up-Regulation Uric Acid Wild Type Mouse Xanthine Oxidase acid stress clinically relevant in vivo inhibitor/antagonist innovation kidney cortex kidney metabolism lectures mortality multiorgan injury novel polyol prevent professor programs response to injury skills urinary

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury is a common cause of hospitalization with high mortality affecting 30% of patients admitted to the intensive care unit. After decades of important discoveries regarding its pathophysiology, no clinically applicable treatment to accelerate kidney recovery in acute kidney injury has emerged. The polyol pathway is a metabolic route constituted by two enzymes, aldose reductase and sorbitol dehydrogenase. Aldose reductase converts glucose to sorbitol while sorbitol dehydrogenase metabolizes sorbitol to fructose. Our preliminary data in mice with ischemic acute kidney injury demonstrate that there is a significant activation of the polyol pathway in the kidney cortex as noted by high level of aldose reductase, and fructose accumulation (endogenous fructose). Our published data demonstrate that in the kidney the metabolism of fructose by the enzyme fructokinase results in ATP depletion and the generation of uric acid and oxidants causing acute tubulointerstitial injury. These observations lead to the overall hypothesis of this application that ischemic acute kidney injury activates the polyol pathway and fructokinase which contributes to proximal tubule cell death. The significance of this proposal is that inhibition of the polyol pathway is feasible n patients with acute kidney injury due to the availability of inhibitors (epalrestat, ranirestat). Te innovation of this proposal is that a role for endogenous fructose and renal fructokinase has never been considered in ischemic acute kidney injury. The research design to study the deleterious role of the polyol pathway and endogenous fructose production and metabolism will involve the characterization of 1) the activation of the polyol pathway and its deleterious role in ischemic acute kidney injury by using wild type and aldose reductase deficient mice, 2) the activation of fructokinase and endogenous fructose metabolism and its deleterious role in ischemic acute kidney injury by utilizing wild type and fructokinase global and proximal tubule deficient mice and 3) the fructose downstream mechanisms that leads to proximal tubule dysfunction, injury and cell death by employing human proximal tubular cells, (HK-2). The applicant will rely on an excellent mentorship program with Dr. Richard Johnson as his primary Mentor. Dr Johnson is one of the leading researchers in fructose, uric acid and the role they play in endothelial dysfunction, metabolic syndrome and kidney disease. He is currently the Division Head and Professor of Medicine at the University of Colorado Denver, Division of Renal Diseases and Hypertension. In addition, Dr. Sarah Faubel, Associate Professor of Medicine, at University of Colorado Denver, is his secondary Mentor and a leading investigator in ischemic acute kidney injury with expertise in animal models, characterization of kidney injury and multiorgan dysfunction. The applicant will also rely on the expertise and technology from several consultants outside the Renal Division, Dr Mark Petrash, Professor and Vice Chair for Research, Department of Ophthalmology, who is a world expert on aldose reductase is serving as a collaborator, Dr Scott Lucia (Chief of Renal and genitourinary pathology) awill also act as collaborator in the assessment of kidney injury and Dr Bruce Molitoris, Professor of Medicine at Indiana University will assist Dr Lanaspa in the development of proximal tubule fructokinase deficient mice This award will allow the applicant to develop the skills necessary to become an independent scientist and will provide for intellectual development through both didactic programs and lectures and by facilitating interactions with a variety of researchers in different departments and institutions.

描述（由申请人提供）：急性肾损伤是住院的常见原因，死亡率很高，影响了重症监护病房 30% 的患者。经过数十年关于其病理生理学的重要发现，尚未出现临床适用的加速急性肾损伤肾脏恢复的治疗方法。多元醇途径是由醛糖还原酶和山梨糖醇脱氢酶两种酶构成的代谢途径。醛糖还原酶将葡萄糖转化为山梨醇，而山梨醇脱氢酶将山梨醇代谢为果糖。我们在患有缺血性急性肾损伤的小鼠中的初步数据表明，肾皮质中的多元醇途径显着激活，如高水平的醛糖还原酶和果糖积累（内源性果糖）所示。我们发表的数据表明，在肾脏中，果糖激酶对果糖的代谢会导致 ATP 消耗，并产生尿酸和氧化剂，从而导致急性肾小管间质损伤。这些观察结果得出本申请的总体假设，即缺血性急性肾损伤激活多元醇途径和果糖激酶，从而导致近端肾小管细胞死亡。该提议的意义在于，由于抑制剂（依帕司他、雷尼司他）的可用性，多元醇途径的抑制在急性肾损伤患者中是可行的。该提案的创新之处在于，从未考虑过内源性果糖和肾果糖激酶在缺血性急性肾损伤中的作用。研究多元醇途径和内源性果糖产生和代谢的有害作用的研究设计将涉及以下特征：1) 多元醇途径的激活及其在以下方面的有害作用：使用野生型和醛糖还原酶缺陷型小鼠进行缺血性急性肾损伤，2) 果糖激酶和内源性果糖代谢的激活及其在缺血性急性肾损伤中的有害作用，使用野生型和果糖激酶整体和近端小管缺陷型小鼠进行，3) 果糖通过使用人近端肾小管细胞（HK-2），导致近端肾小管功能障碍、损伤和细胞死亡的下游机制。申请人将依赖以理查德·约翰逊博士为主要导师的优秀导师计划。约翰逊博士是果糖、尿酸及其在内皮功能障碍、代谢综合征和肾脏疾病中的作用方面的领先研究人员之一。他目前是科罗拉多大学丹佛分校肾脏疾病和高血压科主任兼医学教授。此外，科罗拉多大学丹佛分校医学副教授 Sarah Faubel 博士是他的第二导师，也是缺血性急性肾损伤领域的首席研究员，在动物模型、肾损伤特征和多器官功能障碍方面拥有专业知识。申请人还将依赖肾脏科以外的几位顾问的专业知识和技术，眼科教授兼研究副主席 Mark Petrash 博士是世界醛糖还原酶专家，Scott Lucia 博士是合作者（肾脏和泌尿生殖病理学主任）a will 还将作为肾损伤评估的合作者，印第安纳大学医学教授 Bruce Molitoris 博士将协助 Lanaspa 博士进行开发该奖项将使申请人能够培养成为独立科学家所需的技能，并通过教学计划和讲座以及促进与不同部门和机构的各种研究人员的互动来促进智力发展。