Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells
Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells
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DOI：
10.1681/asn.2008060576
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发表时间：
2009-03-01
影响因子：
13.6
通讯作者：
Sautin, Yuri Y.
中科院分区：
文献类型：
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作者：
Cirillo, Pietro;Gersch, Michael S.;Sautin, Yuri Y.
果糖摄入量的增加可能在代谢综合征的流行中起重要作用，并可能预示糖尿病、心血管疾病和慢性肾脏疾病的发展。一旦进入细胞，果糖被己酮糖激酶（KHK）磷酸化，导致ATP消耗，AMP形成，并通过黄嘌呤氧化还原酶（XOR）产生尿酸。本研究旨在研究果糖对人肾近曲小管上皮细胞（HK-2）的直接影响，以及这些影响是否通过KHK介导的果糖代谢。在与餐后外周血中观察到的浓度相似的浓度下，果糖诱导HK-2细胞中单核细胞趋化蛋白1（MCP-1）和活性氧簇的产生。通过用小发夹RNA稳定转染KHK的敲低证明这些过程是KHK依赖性的。几种抗氧化剂，包括NADPH氧化酶和XOR的特异性抑制剂，阻止了MCP-1的分泌。我们在HK-2细胞中检测到XOR mRNA，并通过质谱鉴定尿酸证实其活性。果糖增加细胞内尿酸，尿酸也诱导MCP-1的产生。总之，餐后果糖浓度刺激近端肾小管细胞氧化还原和尿酸盐依赖性炎症介质。
Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.