Ishii H, Tada H, Isogai S
Second Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
Diabetologia. 1998 Mar;41(3):362-4. doi: 10.1007/s001250050916.
We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-beta (TGF-beta) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGFbeta production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-beta was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10(-6) mol/l. Moreover, the glucose-induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-beta production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-beta and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.
我们研究了抑制多元醇途径对葡萄糖诱导的人肾小球系膜细胞（MCs）中转化生长因子-β（TGF-β）产生增加以及蛋白激酶C（PKC）活性的影响。与5 mmol/l葡萄糖相比，将MCs暴露于33 mmol/l葡萄糖会导致通过ELISA测量的TGF-β产生增加。通过与醛糖还原酶抑制剂（ARI）依帕司他同时孵育，以大于10(-6) mol/l的浓度呈剂量依赖性地阻止了葡萄糖诱导的TGF-β增加。此外，依帕司他也消除了葡萄糖诱导的MCs膜部分中PKC活性增强。向用5 mmol/l葡萄糖培养的MCs中添加依帕司他对TGF-β产生和PKC活性没有明显影响。这些结果为多元醇途径紊乱与葡萄糖诱导的MCs中TGF-β过度产生和PKC活性增强之间的联系提供了直接证据。因此，ARI对MCs中这些代谢异常的作用可能证明其在糖尿病肾病治疗中的临床应用是合理的。
