Tada H, Ishii H, Isogai S
Second Department of Medicine, Toho University School of Medicine, Tokyo, Japan.
Metabolism. 1997 Jul;46(7):779-84. doi: 10.1016/s0026-0495(97)90122-0.
Altered functions of mesangial cells (MCs) induced by high glucose levels are thought to play an important role in the pathogenesis of diabetic nephropathy. We investigate whether D-alpha-tocopherol (Toc), an antioxidant, can prevent malfunction of cultured human MCs induced by high-glucose media. Incubating MCs with 33 mmol/L glucose caused increased lipid peroxide (LPO) levels, disturbed cell replication, enhanced cytotoxicity, enhanced activity of the diacylglycerol (DAG)-protein kinase C (PKC) pathway, and overproduction of fibronectin and eicosanoids (6-keto prostaglandin F1 alpha [PGF1 alpha] and thromboxane B2 [TXB2]). The amount of LPO in MCs grown in 5 mmol/L glucose was reduced by the addition of Toc in a dose-dependent manner. Since the maximum effect of Toc on decreasing LPO was achieved at a concentration of 100 mumol/L, this dose was selected for the following experiments. Addition of Toc prevented increased LPO levels and [51Cr]-release from MCs induced by high-glucose media without affecting cell number. Toc decreased the total DAG level and PKC activity in membrane fractions in MCs cultured at both 5 and 33 mmol/L glucose. Furthermore, glucose-induced overproduction of fibronectin and eicosanoids from MCs was completely abolished by Toc. These results strongly suggest that Toc ameliorates glucose-induced malfunctions of MCs in vitro.
高糖水平诱导的系膜细胞（MCs）功能改变被认为在糖尿病肾病的发病机制中起重要作用。我们研究了抗氧化剂D-α-生育酚（Toc）是否能预防高糖培养基诱导的培养人MCs功能障碍。用33 mmol/L葡萄糖孵育MCs会导致脂质过氧化物（LPO）水平升高、细胞复制紊乱、细胞毒性增强、二酰甘油（DAG）-蛋白激酶C（PKC）途径活性增强以及纤连蛋白和类花生酸（6-酮前列腺素F1α[PGF1α]和血栓素B2[TXB2]）过度产生。在5 mmol/L葡萄糖中生长的MCs中，添加Toc可使LPO量呈剂量依赖性降低。由于Toc在浓度为100 μmol/L时对降低LPO的效果最佳，因此该剂量被选用于以下实验。添加Toc可预防高糖培养基诱导的MCs中LPO水平升高和[51Cr]释放，而不影响细胞数量。Toc降低了在5和33 mmol/L葡萄糖培养的MCs膜组分中的总DAG水平和PKC活性。此外，Toc完全消除了葡萄糖诱导的MCs中纤连蛋白和类花生酸的过度产生。这些结果强烈表明，Toc可改善体外葡萄糖诱导的MCs功能障碍。
