An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-β and protein kinase C activity in cultured human mesangial cells

Abstract

We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-β (TGF-β) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGF-β production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-β was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10-6 mol/l. Moreover, the glucose- induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-β production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-β and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.