Interaction between the polyol pathway and non-enzymatic glycation on mesangial cell gene expression
Interaction between the polyol pathway and non-enzymatic glycation on mesangial cell gene expression
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DOI：
10.1159/000080684
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发表时间：
2004-01-01
影响因子：
--
通讯作者：
Lam, KSL
中科院分区：
文献类型：
--
作者：
Dan, QH;Wong, RLC;Lam, KSL
背景/目标：多元醇途径的激活和非酶糖基化的增强都与糖尿病性肾小球病的发病机制有关。我们使用正常系膜细胞（MCs）和转基因（TG）MCs与升高的醛糖还原酶（AR）活性研究这两种途径之间的相互作用。方法：建立人AR基因（hAR）在肾系膜细胞中表达的TG小鼠模型。研究了小鼠肾小球和来自hAR TG和野生型（WT）小鼠的MC的原代培养物中AR活性、转化生长因子-β（1）（TGF-β（1））和IV型胶原mRNA和蛋白水平的变化，以响应由晚期糖基化终产物修饰的BSA（AGE-BSA）。结果如下：体外添加AGE-BSA可增加WT和TG肾小球中AR活性、TGF-β 1和IV型胶原mRNA水平，其中TG肾小球中升高幅度更大。这些增量被AR抑制剂zopolrestat减弱。在培养的MCs中，AGE-BSA增强WT和TG MCs的AR活性、TGF-β 1和IV型胶原mRNA和蛋白水平，TG MCs的增加幅度更大。AGE诱导的TGF-β 1和IV型胶原表达的增强被zopolrestat或AR反义寡核苷酸转染抑制。结论：这些数据表明，AGEs对多元醇通路的激活，在AR活性增加的遗传条件下更为明显，可能通过增强系膜细胞TGF-β（1）和IV型胶原蛋白的表达，促进糖尿病肾小球病变的发病机制。版权所有（C）2004 S. Karger AG，巴塞尔。
Background/Aims: Both activation of the polyol pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the interaction between these two pathways using normal mesangial cells (MCs) and transgenic (TG) MCs with elevated aldose reductase (AR) activity. Methods: TG mice with expression of the human AR (hAR) gene in kidney MCs were established. Mouse glomeruli and primary cultures of MCs from hAR TG and wild-type (WT) mice were studied regarding the changes in AR activity, transforming growth factor-beta(1) (TGF-beta(1)) and type IV collagen mRNA and protein levels, in response to BSA modified by advanced glycation endproducts (AGE-BSA). Results: Ex vivo addition of AGE-BSA increased AR activity, TGF-beta(1) and type IV collagen mRNA levels in both WT and TG glomeruli, with greater rise in TG glomeruli. These increments were attenuated by zopolrestat, an AR inhibitor. In cultured MCs, AGE-BSA enhanced AR activity, TGF-beta(1) and type IV collagen mRNA and protein levels both in WT and TG MCs, again with greater increases in TG MCs. The AGE-induced enhancement in TGF-beta(1) and type IV collagen expression were suppressed by either zopolrestat or transfection with an AR antisense oligonucleotide. Conclusion: These data suggest that the activation of the polyol pathway by AGEs, more marked in genetic conditions with increased AR activity, may contribute to the pathogenesis of diabetic glomerulopathy, through enhancing mesangial cell expression of TGF-beta(1) and type IV collagen. Copyright (C) 2004 S. Karger AG, Basel.