A novel role for endogenous fructose in ischemic acute kidney injury

描述(申请人提供)：急性肾损伤是住院的常见原因，死亡率高，30%的重症监护病房患者受到影响。在有关其病理生理学的几十年的重要发现之后，还没有临床适用的治疗方法来加速急性肾损伤的肾脏恢复。多元醇途径是由醛糖还原酶和山梨醇脱氢酶两种酶组成的代谢途径。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。我们在缺血性急性肾损伤小鼠中的初步数据表明，肾脏皮质中存在显著的多元醇途径的激活，以高水平的醛糖还原酶和果糖积累(内源性果糖)为标志。我们已发表的数据表明，在肾脏中，果糖被果糖激酶酶代谢导致ATP耗竭，尿酸和氧化剂的产生导致急性肾小管间质损伤。这些观察结果导致了这一应用的总体假设，即缺血性急性肾损伤激活了多元醇途径和果糖激酶，从而导致近端肾小管细胞死亡。这一建议的意义在于，由于抑制剂(依帕司他、雷尼司他)的可用性，在急性肾损伤患者中抑制多元醇途径是可行的。这一建议的创新之处在于，从未考虑过内源性果糖和肾脏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 这些研究包括：1)利用野生型和果糖还原酶缺陷小鼠造成的急性缺血性肾损伤；2)利用野生型和果糖激酶全域和近端小管缺陷小鼠激活果糖激酶和内源性果糖代谢及其在缺血性急性肾损伤中的有害作用；3)利用人近端小管细胞(HK-2)揭示果糖下游导致近端小管功能障碍、损伤和细胞死亡的机制。申请者将依靠理查德·约翰逊博士作为他的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所起作用的主要研究人员之一。他目前是科罗拉多大学丹佛大学肾脏疾病和高血压学部的科长和医学教授。此外，科罗拉多大学丹佛分校医学副教授Sarah Faubel博士是他的二级导师，也是缺血性急性肾损伤的主要研究人员，在动物模型、肾脏损伤的特征和多器官功能障碍方面具有专长。申请者还将依赖肾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博士是醛糖还原酶的世界专家，Scott Lucia博士(肾脏和泌尿生殖系统病理主管)也将担任肾脏损伤评估的合作者，Bruce Molitoris博士也将担任合作者，印第安纳大学医学教授将协助Lanaspa博士开发近端小管果糖激酶缺陷小鼠该奖项将允许申请者发展成为独立科学家所需的技能，并将通过教学计划和讲座以及通过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。

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.