Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage
Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage
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DOI：
10.2337/db05-1497
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发表时间：
2006-07-01
期刊：
影响因子：
7.7
通讯作者：
Chung, Sookja K.
中科院分区：
文献类型：
--
作者：
Ho, Eric C. M.;Lam, Karen S. L.;Chung, Sookja K.
糖尿病期间通过多元醇途径的过度流量被认为是周围神经病变的主要原因。在这里，我们使用醛糖还原酶（AR）缺陷（AR（-/-））和AR抑制剂（ARI）治疗的小鼠，以进一步了解体内多元醇途径在糖尿病神经病变的发病机制中的作用。在正常条件下，野生型AR（AR（+/+））和AR（-/-）小鼠的神经支配模式无明显差异。在短期糖尿病条件下，AR（-/-）小鼠可免受糖尿病AR（+/+）小鼠中观察到的运动和感觉神经传导速度降低的影响。糖尿病AR（+/+）小鼠坐骨神经中的山梨醇水平显著增加，而糖尿病AR（-/-）小鼠中的山梨醇水平显著低于糖尿病AR（+/+）小鼠。此外，在糖尿病AR（-/-）小鼠中未观察到在糖尿病AR（+/+）小鼠的坐骨神经中观察到的氧化应激的迹象，例如c-Jun NH 2-末端激酶（JNK）的活化增加、还原型谷胱甘肽的消耗、超氧化物形成的增加和DNA损伤，表明糖尿病AR（-/-）小鼠在坐骨神经中受到氧化应激的保护。糖尿病AR（-/-）小鼠尿中排泄的8-羟基-2 '-脱氧鸟苷也少于糖尿病AR（+/+）小鼠。在糖尿病AR（+/+）小鼠的腓肠神经中观察到的结构异常在糖尿病AR（-/-）小鼠中不太严重，尽管在短期糖尿病条件下，AR缺乏仅对腓肠神经产生轻度保护。ARI fidarestat还抑制了糖尿病AR（+/+）神经中的氧化应激和功能及结构异常体征，与糖尿病AR（-/-）小鼠中的情况相似。总之，通过AR的多元醇途径通量增加是糖尿病神经病变早期体征的主要促成因素，可能通过谷胱甘肽耗竭、超氧化物积累增加、JNK活化增加和DNA损伤。
The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR(-/-)) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR(+/+)) and AR(-/-) mice. Under short-term diabetic conditions, AR(-/-) mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR(+/+) mice. Sorbitol levels in the sciatic nerves of diabetic AR(+/+) mice were increased significantly, whereas sorbitol levels in the diabetic AR(-/-) mice were significantly lower than those in diabetic AR(+/+) mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH2-terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR(+/+) mice were not observed in the diabetic AR(-/-) mice, indicating that the diabetic AR(-/-) mice were protected from oxidative stress in the sciatic nerve. The diabetic AR(-/-) mice also excreted less 8-hydroxy-2'-deoxyguanosine in urine than diabetic AR(+/+) mice. The structural abnormalities observed in the sural nerve of diabetic AR(+/+) mice were less severe in the diabetic AR(-/-) mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR(+/+) nerves, similar to those in diabetic AR(-/-) mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.