Yagihashi S, Yamagishi S, Wada R, Sugimoto K, Baba M, Wong H G, Fujimoto J, Nishimura C, Kokai Y
Department of Pathology, Hirosaki University School of Medicine, Japan.
Diabetes. 1996 Jan;45(1):56-9. doi: 10.2337/diab.45.1.56.
We studied the functional consequences of an enhanced polyol pathway activity, elicited with galactose feeding, on the peripheral nerve of transgenic mice expressing human aldose reductase. Nontransgenic littermate mice were used as controls. With a quantitative immunoassay, the expression level of human aldose reductase in the sciatic nerve was 791 +/- 44 ng/mg protein (mean +/- SE), about 25% of that in human sural nerve. When the transgenic mice were fed food containing 30% galactose, significant levels of galactitol accumulated in the sciatic nerve. Galactose feeding of nontransgenic littermate mice led to a 10-fold lower accumulation of galactitol. Galactose feeding for 16 weeks caused a significant and progressive decrease in motor nerve conduction velocity in transgenic mice to 80% of the level of galactose-fed littermate mice, which was not significantly different from that of galactose-free littermate mice. A morphometric analysis of sciatic nerve detected > 10% reduction of mean myelinated fiber size but no alterations of myelinated fiber density in galactose-fed transgenic mice compared with other groups. The functional and structural changes that develop in galactose-fed transgenic mice are similar to those previously reported in diabetic animals. The results of these studies suggest that transgenic mice expressing human aldose reductase may be a useful model not only for defining the role of the polyol pathway in diabetic neuropathy but also for identifying and characterizing effective inhibitors specific for human aldose reductase.
我们研究了通过喂食半乳糖引发的多元醇途径活性增强对表达人醛糖还原酶的转基因小鼠周围神经的功能影响。非转基因同窝小鼠用作对照。通过定量免疫测定，坐骨神经中人醛糖还原酶的表达水平为791±44 ng/mg蛋白质（平均值±标准误），约为人类腓肠神经中表达水平的25%。当给转基因小鼠喂食含30%半乳糖的食物时，坐骨神经中积累了大量的半乳糖醇。给非转基因同窝小鼠喂食半乳糖导致半乳糖醇的积累量降低10倍。喂食半乳糖16周导致转基因小鼠运动神经传导速度显著且逐渐下降，降至喂食半乳糖的同窝小鼠水平的80%，这与未喂食半乳糖的同窝小鼠无显著差异。与其他组相比，对喂食半乳糖的转基因小鼠坐骨神经进行形态计量分析发现，有髓纤维平均大小减少>10%，但有髓纤维密度无变化。喂食半乳糖的转基因小鼠出现的功能和结构变化与先前在糖尿病动物中报道的相似。这些研究结果表明，表达人醛糖还原酶的转基因小鼠不仅可能是用于确定多元醇途径在糖尿病神经病变中作用的有用模型，而且还可用于鉴定和表征对人醛糖还原酶具有特异性的有效抑制剂。
