A novel role for endogenous fructose in ischemic acute kidney injury

描述（由申请人提供）：急性肾损伤是住院治疗的常见原因，死亡率高，重症监护病房收治的患者占30%。经过几十年病理生理学方面的重要发现，尚未出现临床适用的加速急性肾损伤肾恢复的治疗方法。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。我们对缺血性急性肾损伤小鼠的初步数据表明，肾皮质多元醇通路明显激活，醛糖还原酶水平升高，果糖积累（内源性果糖）增加。我们发表的数据表明，在肾脏中，果糖激酶代谢果糖导致ATP消耗，尿酸和氧化剂的产生，导致急性肾小管间质损伤。这些观察结果导致本应用的总体假设，即缺血性急性肾损伤激活多元醇途径和果糖激酶，导致近端小管细胞死亡。该建议的意义在于，由于抑制剂（依帕司他、雷尼司他）的可用性，对急性肾损伤患者抑制多元醇途径是可行的。该建议的创新之处在于，内源性果糖和肾果糖激酶在缺血性急性肾损伤中的作用从未被考虑过。研究多元醇途径与内源性果糖产生和代谢的有害作用的研究设计将涉及表征1)多元醇途径的激活及其在

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.