title: 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.
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 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.
authors.affiliation: Department of Anatomy, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Eric C M
authors.initials: EC
authors.lastname: Ho
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Yuk Shan
authors.initials: YS
authors.lastname: Chen
authors.forename: Johnny C W
authors.initials: JC
authors.lastname: Yip
authors.forename: Meena
authors.initials: M
authors.lastname: Arvindakshan
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Soroku
authors.initials: S
authors.lastname: Yagihashi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oates
authors.forename: Craig A
authors.initials: CA
authors.lastname: Ellery
authors.forename: Stephen S M
authors.initials: SS
authors.lastname: Chung
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
mesh_terms: D000449:Aldehyde Reductase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology*; D004789:Enzyme Activation; D005632:Fructose / Q000378:metabolism; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000502:physiology*; D009431:Neural Conduction / Q000502:physiology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D012016:Reference Values; D013012:Sorbitol / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013497:Sural Nerve / Q000503:physiopathology
chemical_list: D013481:Superoxides; D011064:Poly Adenosine Diphosphate Ribose; D005632:Fructose; D007294:Inositol; D013012:Sorbitol; D000449:Aldehyde Reductase; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; D005947:Glucose