Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose
Reactive oxygen species as glucose signaling molecules in mesangial cells cultured under high glucose
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DOI：
10.1046/j.1523-1755.2000.07704.x
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发表时间：
2000-09-01
影响因子：
19.6
通讯作者：
Lee, HB
中科院分区：
文献类型：
--
作者：
Ha, HJ;Lee, HB
背景氧化应激是糖尿病血管并发症（包括肾病）的重要介质之一。高糖（HG）会产生活性氧（ROS），这是葡萄糖自氧化、代谢和晚期糖基化终产物形成的结果。ROS诱导的组织损伤的概念最近已被修订的新角色ROS的信号通路和基因的升值：expression.Methods和结果高葡萄糖迅速产生二氯荧光素敏感的细胞溶质ROS在大鼠和小鼠系膜细胞。无论是L-葡萄糖还是3-O-甲基-D-葡萄糖都不能增加细胞内ROS的产生，而细胞松弛素B（一种葡萄糖转运蛋白抑制剂）能有效地抑制HG诱导的ROS产生，这表明在HG诱导的细胞内ROS产生中需要葡萄糖的摄取和随后的代谢。过氧化氢上调纤连蛋白mRNA的表达和蛋白质的合成，这种上调被有效地抑制蛋白激酶C（PKC）抑制剂或通过消耗PKC。HG诱导的ROS产生与PKC和转录因子核因子-κ B的激活有关（NF-κ B）和激活蛋白-1（AP-1）以及转化生长因子-β 1的上调（TGF-β 1）、纤连蛋白mRNA表达和蛋白质合成，因为抗氧化剂有效地抑制了NG诱导的PKC、NF-κ B、AP-1活化，高糖对肾小球系膜细胞TGF-β 1和FN表达的影响。虽然信号转导通路连接HG，活性氧，蛋白激酶C，转录因子和细胞外基质（ECM）蛋白的合成在系膜细胞尚未完全阐明，目前的数据提供的证据表明，由葡萄糖代谢产生的活性氧可能作为一个整体的信号分子下HG在其他膜受体信号。
Background Oxidative stress is one of the important mediators of vascular complications in diabetes including nephropathy. High glucose (HG) generates reactive oxygen species (ROS) as a result of glucose auto-oxidation, metabolism, and formation of advanced glycosylation end products. Thc concept of ROS-induced tissue injury has recently been revised with the appreciation of new roles for ROS in signaling pathways and gene: expression.Methods and Results High glucose rapidly generated dichlorofluorescein-sensitive cytosolic ROS in rat and mouse mesangial cells. Neither L-glucose nor 3-O-methyl-D-glucose increased cytosolic ROS and cytochalasin B, an inhibitor of glucose transporter, effectively inhibited HG-induced ROS generation, suggesting that glucose uptake and subsequent metabolism are required in HG-induced cytosolic ROS generation. H2O2 up-regulated fibronectin mRNA expression and protein synthesis; this up-regulation was effectively inhibited by protein kinase C (PKC) inhibitor or by depletion of PKC. The HG-induced generation of ROS was, in turn, related to activation of PKC and transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) as well as to the up-regulation of transforming growth factor-beta 1 (TGF-beta 1), fibronectin mRNA expression and protein synthesis, because antioxidants effectively inhibited NG-induced PKC, NF-kappa B, AP-I activation, and TGF-beta 1 and fibronectin expression in mesangial cells cultured under HG.Conclusions. Although signal transduction pathways linking HG, ROS, PKC, transcription factors, and extracellular matrix (ECM) protein synthesis in mesangial cells have not been fully elucidated, the current data provide evidence that ROS generated by glucose metabolism may act as integral signaling molecules under HG as in other membrane receptor signaling.