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To elucidate the molecular mechanisms underlying the development of diabetic neuropathy, we isolated the Schwann cells from the sciatic nerves of adult rats and characterized the polyol pathway activity. Despite the presence of aldose reductase (AR) activity, no accumulation of sorbitol was observed in the cells cultured under 30 mM glucose conditions. Increased levels of sorbitol were detected in the medium conditioned by these cells. SNK-860 (fidarestat), an inhibitor of AR, decreased the sorbitol levels at 10(-6)M, while addition of SDI-158, an inhibitor of sorbitol dehydrogenase, did not affect the level in the cells grown in high glucose. These observations suggested that sorbitol produced by AR in the isolated Schwann cells may be predominantly excreted. In contrast, a significant increase in sorbitol level was observed in cells cultured under hyperosmotic conditions with 30 mM glucose. A significant correlation was observed between sorbitol level and AR activity (r = 0.998). The increase was suppressed by addition of SNK-860, while SDI-158 augmented sorbitol accumulation in a dose-dependent manner. These results suggested that the isolated Schwann cells may not accumulate sorbitol unless the activity of AR is augmented by some as yet undetermined mechanism under high glucose conditions, such as the hyperosmotic stress induced in this study.

No abstract

To elucidate the molecular mechanisms underlying the development of diabetic neuropathy, we isolated the Schwann cells from the sciatic nerves of adult rats and characterized the polyol pathway activity. Despite the presence of aldose reductase (AR) activity, no accumulation of sorbitol was observed in the cells cultured under 30 mM glucose conditions. Increased levels of sorbitol were detected in the medium conditioned by these cells. SNK-860 (fidarestat), an inhibitor of AR, decreased the sorbitol levels at 10(-6)M, while addition of SDI-158, an inhibitor of sorbitol dehydrogenase, did not affect the level in the cells grown in high glucose. These observations suggested that sorbitol produced by AR in the isolated Schwann cells may be predominantly excreted. In contrast, a significant increase in sorbitol level was observed in cells cultured under hyperosmotic conditions with 30 mM glucose. A significant correlation was observed between sorbitol level and AR activity (r = 0.998). The increase was suppressed by addition of SNK-860, while SDI-158 augmented sorbitol accumulation in a dose-dependent manner. These results suggested that the isolated Schwann cells may not accumulate sorbitol unless the activity of AR is augmented by some as yet undetermined mechanism under high glucose conditions, such as the hyperosmotic stress induced in this study.