High glucose directly promotes lipid peroxidation and stimulates collagen production by cultured mesangial cells. We conducted the following experiments to ascertain whether vitamin E, a lipophilic antioxidant agent, could reverse these effects in vitro. Rat mesangial cells were grown to confluence and then maintained for 7 additional days in control media (DME) containing 5.6 mM glucose or experimental media containing 33.3 mM glucose. The test condition resulted in a near doubling of mesangial cell lipid peroxidation, assessed by measuring the content of conjugated dienes. High-glucose media also enhanced collagen production by 28% above the basal level in control media. Addition of vitamin E (100 microM) reversed both effects of the elevated ambient glucose level and prevented lipid peroxidation and normalized collagen production in cultured mesangial cells. These findings suggest that vitamin E functions as an endogenous antioxidant agent in the kidney to limit the development of glomerulosclerosis in diabetic nephropathy.