Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes.

OBJECTIVE: Activation of the cyclooxygenase (COX) pathway with secondary neurovascular deficits are implicated in the pathogenesis of experimental diabetic peripheral neuropathy (DPN). The aim of this study was to explore the interrelationships between hyperglycemia, activation of the COX-2 pathway, and oxidative stress and inflammation in mediating peripheral nerve dysfunction and whether COX-2 gene inactivation attenuates nerve fiber loss in long-term experimental diabetes. RESEARCH DESIGN AND METHODS: Motor and sensory digital nerve conduction velocities, sciatic nerve indexes of oxidative stress, prostaglandin content, markers of inflammation, and intraepidermal nerve fiber (IENF) density were measured after 6 months in control and diabetic COX-2-deficient (COX-2(-/-)) and littermate wild-type (COX-2(+/+)) mice. The effects of a selective COX-2 inhibitor, celecoxib, on these markers were also investigated in diabetic rats. RESULTS: Under normal conditions, there were no differences in blood glucose, peripheral nerve electrophysiology, markers of oxidative stress, inflammation, and IENF density between COX-2(+/+) and COX-2(-/-) mice. After 6 months, diabetic COX-2(+/+) mice experienced significant deterioration in nerve conduction velocities and IENF density and developed important signs of increased oxidative stress and inflammation compared with nondiabetic mice. Diabetic COX-2(-/-) mice were protected against functional and biochemical deficits of experimental DPN and against nerve fiber loss. In diabetic rats, selective COX-2 inhibition replicated this protection. CONCLUSIONS: These data suggest that selective COX-2 inhibition may be useful for preventing or delaying DPN.

Regulation of the human taurine transporter by oxidative stress in retinal pigment epithelial cells stably transformed to overexpress aldose reductase.

In diabetes, overexpression of aldose reductase (AR) and consequent glucose-induced impairment of antioxidant defense systems may predispose to oxidative stress and the development of diabetic complications, but the mechanisms are poorly understood. Taurine (2-aminoethanesulfonic acid) functions as an antioxidant, osmolyte, and calcium modulator such that its intracellular depletion could promote cytotoxicity in diabetes. The relationships of oxidative stress and basal AR gene expression to Na+-taurine cotransporter (TT) gene expression, protein abundance, and TT activity were therefore explored in low AR-expressing human retinal pigment epithelial (RPE) 47 cells and RPE 47 cells stably transformed to overexpress AR (RPE 75). Changes in TT gene expression were determined using a 4.6-kb TT promoter-luciferase fusion gene. Compared with RPE 47 cells, in high AR-expressing RPE 75 cells, TT promoter activity was decreased by 46%, which was prevented by an AR inhibitor. TT promoter activity increased up to 900% by prooxidant exposure, which was associated with increased TT peptide abundance and taurine transport. However, induction of TT promoter activity by oxidative stress was attenuated in high AR-expressing cells and partially corrected by AR inhibitor. Finally, exposure of RPE 75 cells to high glucose increased oxidative stress, but down-regulated TT expression. These studies demonstrate for the first time that the TT is regulated by oxidative stress and that overexpression of AR and high glucose impair this response. Abnormal expression of AR may therefore impair antioxidant defense, which may determine tissue susceptibility to chronic diabetic complications.