Diabetic neuropathy in mice transgenic for human aldose reductase.

为了探讨多元醇途径与蛋白激酶C(PKC)的关系，我们检测了转人醛糖还原酶(TG)基因的糖尿病小鼠神经内膜和富含蛋白1的神经外膜组织中的PKC活性和PKC亚型的表达。用链脲佐菌素复制8周龄糖尿病小鼠模型，给予醛糖还原酶抑制剂(ARI)或安慰剂治疗12周。与非糖尿病组相比，糖尿病组神经内膜山梨醇含量增加6.4倍，神经外膜山梨醇含量增加5.1倍，而糖尿病组仅神经内膜山梨醇含量增加。糖尿病患者尿内皮细胞PKC活性明显降低。而糖尿病组和糖尿病组神经外膜PKC活性均升高，两组间差异无统计学意义。这些改变均经ARI治疗后得到纠正。与PKC活性变化相一致的是，糖尿病TG组和DM组大鼠神经内膜PKC a表达减少，而神经外膜PKCβII表达增加。这些发现表明，在多元醇-PKC相关的糖尿病神经病变的发病机制中，神经和血管组织之间存在二分性代谢途径。

To explore the relationship between polyol pathway and protein kinase C(PKC), we examined PKC activities and expressions of PKC isoforms separately in endoneurial and vesse1-rich epineurial tissues in diabetic mice transgenic for human aldose reductase(Tg). Tg and littermate control mice(Lm) were made diabetic by streptozotocin at 8 weeks of age and treated with aldose reductase inhibitor(ARI) (fidarestat 4mg/kg/day, per os) or placebo for 12 weeks. At end, compared to non-diabetic state, sorbitol contents were increased 6.4 fold in endoneurium and 5.1 fold in epineurium in diabetic Tg, whereas the increase was detected only in endoneurium in diabetic Lm. Endoneurial PKC activity was significantly reduced in diabetic Tg. By contrast, epineurial PKC activity was increased in both diabetic Lm and diabetic Tg and there was no significant difference between the two groups. These changes were all corrected by ARI treatment. Consistent with the changes of PKC activities, diabetic Tg showed decreased expression of PKC a in endoneurium, whereas there was an increased expression of PKC β II in epineurium in both diabetic Tg and diabetic Lm. These findings suggest the presence of dichotomous metabolic pathway between neural and vascular tissues in the polyol-PKC-related pathogenesis of diabetic neuropathy.