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 NH 2 -Terminal Kinase Activation, Depletion of Reduced Glutathione, Increased Superoxide Accumulation, and DNA Damage Eric C.M. Ho 1 2 , Karen S.L. Lam 2 3 , Yuk Shan Chen 1 4 , Johnny C.W. Yip 1 , Meena Arvindakshan 1 , Shin-Ichiro Yamagishi 5 , Soroku Yagihashi 5 , Peter J. Oates 6 , Craig A. Ellery 6 , Stephen S.M. Chung 1 3 7 and Sookja K. Chung 1 3 4 1 Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China 2 Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China 3 Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, SAR, China 4 Department of Anatomy, The University of Hong Kong, Hong Kong, SAR, China 5 Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan 6 Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut 7 Department of Physiology, The University of Hong Kong, Hong Kong, SAR, China Address correspondence and reprint requests to Dr. S.K. Chung, Department of Anatomy, The University of Hong Kong, Hong Kong, SAR, China. E-mail: skchung{at}hkucc.hku.hk Abstract 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 NH 2 -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 str