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

 描述(申请人提供)：造影剂肾病(CIN)是院内急性肾损伤(AKI)最常见的原因之一。尽管对AKI的发病机制有了很大的了解，但CIN的治疗非常有限，在整体治疗上还没有达成共识。因此，有必要对CIN的发病机制进行进一步的研究，以便建立一种更有效的治疗方法，以促进损伤后肾脏的恢复。高血糖水平(糖尿病)、高渗造影剂和低氧环境是导致CIN的常见危险因素。多元醇途径是由两种酶组成的代谢途径，即醛糖还原酶和山梨醇脱氢酶。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。值得注意的是，与CIN一样，高血糖、高张和低氧是醛糖还原酶表达和多元醇途径激活的主要刺激因素。这一建议的PI所获得的数据表明，肾脏多元醇途径的激活、内源性果糖的产生及其通过果糖激酶的代谢是缺血性AKI发病机制中的重要事件。此外，我们在接受CIN的小鼠中的初步数据显示：1)在CIN中存在显著的多元醇途径和果糖激酶的激活。2)不能在肾脏代谢果糖的小鼠可通过减少尿酸、氧化剂的生成和肾小管间质损伤来保护CIN。这些观察结果使PI得出了他关于这一应用的总体假设，即在造影剂诱导的肾病中，存在醛糖还原酶、多元醇途径和果糖激酶的激活，这有助于近端肾小管细胞的死亡。这一假说在K奖的基础上自然向前迈进了一步，让PI了解内源性果糖代谢在AKI发病机制中的具体作用。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造影剂诱导的肾病中的作用。这项工作旨在通过以下方式使PI能够建立独立性和R01资助：在一个不同但平行的急性肾损伤(造影剂肾病)模型中彻底表征多元醇途径和果糖激酶，而不是PI目前正在研究的K奖(缺血性AKI)将拓宽PI的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年中一直在发展的工作，并将扩大该R03将对伴有AKI和/或CIN的危险因素(高血糖)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.