Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice.
Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice.
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DOI：
10.1038/ncomms14181
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发表时间：
2017-02-13
影响因子：
16.6
通讯作者：
Lanaspa MA
中科院分区：
文献类型：
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作者：
Andres-Hernando A;Li N;Cicerchi C;Inaba S;Chen W;Roncal-Jimenez C;Le MT;Wempe MF;Milagres T;Ishimoto T;Fini M;Nakagawa T;Johnson RJ;Lanaspa MA
急性肾损伤与高死亡率相关，特别是在重症监护病房患者中。多元醇途径是能够将葡萄糖转化为果糖的代谢途径。在这里，我们显示了有害的作用，内源性果糖生产的多元醇途径和代谢，通过果糖激酶在缺血性急性肾损伤（iAKI）的发病机制。与阿基患者中升高的尿果糖一致，经历iAKI的小鼠在肾皮质中显示出显著的多元醇途径活化，其特征在于高水平的醛糖还原酶、山梨醇和内源性果糖。野生型而非果糖激酶敲除动物表现出与ATP耗竭、尿酸升高、氧化应激和炎症相关的严重肾损伤。有趣的是，当暴露于最近发现的果糖激酶抑制剂木樨草素时，经历iAKI的野生型小鼠的肾损伤和功能障碍均显著改善。本研究证实了果糖激酶和内源性果糖作为急性肾脏疾病介质的作用。将葡萄糖转化为山梨糖醇和果糖的多元醇途径在慢性疾病如肝脂肪变性和慢性肾病中是活跃的。Andres-Hernando等人的研究表明，在缺血性急性肾病期间，果糖的产生促进肾损伤，而果糖激酶抑制剂可保护肾免受损伤。
Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease. The polyol pathway, which converts glucose into sorbitol and fructose, is active in chronic conditions like hepatic steatosis and chronic kidney disease. Here, Andres-Hernando et al. show that fructose production promotes renal injury and fructokinase inhibition protects against kidney damage during ischaemic acute kidney disease.