Diabetic nephropathy is a leading cause of morbidity and mortality in diabetes mellitus. Since diabetic glomerulopathy is characterized by an expansion of glomerular mesangium that eventually progresses to obliterate the capillary lumen, mesangial cells (MCs) are thought to play a central role in the pathogenesis of diabetic nephropathy. Elevated glucose levels appear to initiate MC dysfunction, probably via metabolic abnormalities such as derangements in polyol pathway [1], increased activity of protein kinase C (PKC) [2,3], and increased production of transforming growth factor-b (TGF-b) [4]. However, the interaction between these metabolic abnormalities is unclear. To clarify this, we investigated whether inhibition of the polyol pathway by an aldose reductase inhibitor (ARI) could prevent the glucose-induced increase in the production of TGF-b and the activity of PKC in cultured human MCs. Materials and methodsHuman MCs were cultured as previously reported [5]. A single cell line between the third and eighth passages was employed in this study. RPMI-1640 medium (GIBCO BRL, Gaithersburg, Md., USA) containing 20 % fetal calf serum (FCS) was supplemented with either 5 or 33 mmol/l glucose in the presence (10 ±8~5 10 ±5 mol/l) or absence of epalrestat. Medium supplemented with 5 mmol/l glucose + 28 mmol/l mannitol was used as an osmotic control. Since our preliminary experiments showed that incubating MCs with 33 mmol/l glucose for 6 days resulted in a greater increase in TGF-b proDiabetologia (1998) 41: 362±364 Rapid communicationAn aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-b and protein kinase C activity in cultured human mesangial cells Summary We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-b (TGF-b) 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-b production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-b 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-b production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-b 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.[ Diabetologia (1998) 41: 362±364]

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