A novel Role for endogenous fructose production and metabolism in the pathogenesis of contrast-induced nephropathy

 描述（由申请方提供）：造影剂肾病（CIN）是院内急性肾损伤（阿基）的最常见原因之一。尽管对阿基发病机制的理解取得了所有进展，但CIN治疗非常有限，对总体管理没有共识。因此，需要进一步表征CIN的发病机制，以建立可以加速损伤后肾脏恢复的更有效的可用治疗。高葡萄糖水平（糖尿病）、高渗造影剂和缺氧环境是显著促成CIN的常见风险因素。多元醇途径是由两种酶（醛糖还原酶和山梨醇脱氢酶）构成的代谢途径。醛糖还原酶将葡萄糖转化为山梨糖醇，而山梨糖醇脱氢酶将山梨糖醇代谢为果糖。感兴趣的是，以及对于CIN，高血糖、高渗和缺氧是醛糖还原酶表达和多元醇途径活化的主要刺激物。本提案的PI获得的数据表明，肾脏中多元醇途径的激活、内源性果糖的产生及其通过果糖激酶的代谢是缺血性阿基发病机制中的重要事件。此外，我们在经历CIN的小鼠中的初步数据显示：1）在CIN中存在多元醇途径和果糖激酶的显著活化。2)不能在肾脏中代谢果糖的小鼠通过减少尿酸、氧化剂和肾小管间质损伤的产生而免受CIN的影响。这些观察结果使PI得出了他对该应用的总体假设，即在造影剂诱导的肾病中，存在醛糖还原酶和多元醇途径以及果糖激酶的激活，这有助于近端小管细胞死亡。这一假设是PI从K奖向前迈出的自然一步，以了解内源性果糖代谢在阿基发病机制中的具体作用。这一建议的意义在于，由于可获得依帕司他（epalrestat，ranirestat），因此在急性肾损伤患者中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造影剂肾病中的作用从未被考虑过。这项工作旨在使PI能够通过以下方式建立独立性和R 01资金：在与PI正在研究的模型不同但平行的急性肾损伤（对比剂诱导的肾病）模型中彻底表征多元醇途径和果激酶。他当前的K奖（缺血性阿基）将拓宽PI研究的知识和相关性。如果本申请中提出的假设是正确的，PI在过去3年中开发的工作以及将通过本RO 3扩展的工作将对伴有阿基和/或CIN风险因素（高血糖症）的患者产生直接的临床影响。

 DESCRIPTION (provided by applicant): Contrast-induced nephropathy (CIN) is one of the most common causes of in-hospital acute kidney injury (AKI). Despite all the advances in the understanding of the pathogenesis of AKI, CIN treatment is very limited with no consensus on overall management. Therefore, there is a need for further characterization of the pathogenesis of CIN in order to establish a more efficient available treatment that can accelerate kidney recovery post-injury. High glucose levels (diabetes), hypertonic contrast agents and a hypoxic environment are common risk factors that significantly contribute to CIN 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. Of interest, as well as for CIN, hyperglycemia, hypertonicity and hypoxia are the main stimulants of aldose reductase expression and the activation of the polyol pathway. Data obtained by the PI of this proposal demonstrate that the activation of the polyol pathway in the kidney, the production of endogenous fructose and its metabolism through fructokinase are important events in the pathogenesis of ischemic AKI. Furthermore, our preliminary data in mice undergoing CIN show that 1) there is a significant activation of the polyol pathway and fructokinase in CIN. 2) Mice who cannot metabolize fructose in the kidney are protected against CIN with reduced generation of uric acid, oxidants and tubulointerstitial injury. These observations have lead the PI to his overall hypothesis of this application in that in contrast-induced nephropathy there is an activation ofaldose reductase and the polyol pathway and fructokinase which contributes to proximal tubule cell death. This hypothesis is a natural step forward from the K award for the PI to understand the specific role of endogenous fructose metabolism in the pathogenesis of AKI. The significance of this proposal is that inhibition of the polyol pathway is feasible in patients with acute kidney injury due to the availability of inhibitos (epalrestat, ranirestat). The innovation of this proposal is that a role for endogenous fructose and renal fructokinase has never been considered in contrast-induced nephropathy. This work is designed to enable the PI to establish independence and R01 funding in the following ways: Thorough characterization of the polyol pathway and fructokinase in a different but parallel model of acute kidney injury (contrast-induced nephropathy) than the one the PI is working on his current K award (ischemic AKI) will broaden the knowledge and the relevance of the PI's studies. If the hypothesis proposed in this application are correct, the work that the PI has been developing in the last 3 years and that will be expanded with this RO3 will have an immediate clinical impact in patients with concomitant risk factors (hyperglycemia) for AKI and/or CIN.