Diabetic patients frequently suffer contrast media-induced nephropathy. Hyperglycemia in diabetes mellitus causes gradual deterioration of glomerular mesangial cells (MCs) in the kidney. In this study, the authors investigated the response of rat MCs cultured in high-glucose medium to diatrizoate and iohexol, high- and low-osmolar contrast media, respectively.Isolated rat MCs were precultured under basal-glucose (5.5 mmol/L) and high-glucose (30 and 55 mmol/L) conditions for 24 hours to mimic hyperglycemia in diabetes mellitus and then were exposed to diatrizoate (40 and 80 mg I/mL) and iohexol (80, 120, 160 mg I/mL) for 2 hours. The cytotoxic effects of diatrizoate and iohexol were monitored by neutral red uptake in MCs. The protective effects of an antioxidant, d-alpha-tocopherol (Toc), on cytotoxicity of the contrast media were determined when MCs were precultured with Toc under high-glucose conditions or were exposed to the contrast media together with Toc. Peroxide levels in the cells exposed to the contrast media were analyzed by flow cytometry using dichlorofluorescin diacetate.Exposure to both contrast media (diatrizoate and iohexol) induced a concentration-dependent decrease in viability of the cells precultured under basal-glucose conditions (5.5 mmol/L). Preculture under high-glucose conditions (30 and 55 mmol/L) augmented the cytotoxic effects of both contrast media. An increase in the intracellular peroxide level was detected after exposure to both contrast media. Preculture with Toc prevented augmentation of the cytotoxic effects of diatrizoate by the higher glucose concentration (55 mmol/L). The exposure to diatrizoate together with Toc also attenuated its cytotoxic effects. Toc showed no such protective effects against iohexol exposure.These findings suggest that high-glucose conditions enhance the susceptibility of MCs to the cytotoxic effects of both contrast media; the enhanced susceptibility was in part attributable to oxidative stress caused by high-glucose conditions; diatrizoate exerted the cytotoxic effects by means of oxidative stress; and iohexol appeared to exert its cytotoxicity in a manner different from diatrizoate.