RESEACH FOR THE PATHOGENIC MECHANISM OF DIABETIC NEUROPATHY

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Aims : Polyol pathway hyperactivity and altered PKC activity have been proposed as the pathogenic mechanism of diabetic neuropathy. However, the relationship between polyol pathway and PKC activity has not been precisely investigated. The present study was conducted to investigate the effects of high glucose and polyol pathway on the PKC-MAPK cascade and cell growth using.cultured rat Schwannoma cells (JS-1 cells).Methods : JS-1 cells were cultured in 5.5 or 20 mM glucose (HG) with or without epalrestat (Ep ; 1μM) for 14 days, or treated with an antisense against PKC-α (AS) or a p38 MAPK specific inhibitor, SB-203580 (SB). The proliferation activity by assay of [^3H]-thyraidine uptake (% of control), PKCα activity by its protein expression in membrane fraction, and p38 activity by the ratio of phosphorylated to total p38 protein expression were measured.Results : 1) PKC-a and p38 activityies were decreased under the HG condition, which were ameliorated by Ep. 2) With AS treatment, the protein expression of PKC-α and p3S activity were decreased in a time- and dose-dependent fashion. 3) Proliferation activity was decreased by both AS and SB in a dose-dependent fashion. Conclusions: These results suggest that PKC-α and p38 MAPK activities are decreased by high glucose through the alclose reductase-sensit.ive pathway, and that PKC-α-p38 cascade would play an important- role in proliferation of neural cells, indicating,that glucose-induced polyol. Pathway hyperactivity would deteriorate the proI.ifernIion of Sdiwmm cells through' the decreased activities of PKC-α and p38 MAPK, leading t.o diabetic neuropathy.