Exposure of cultured rat mesangial cells to CdCl2 caused a dose- and time-dependent increase in intracellular glutathione that was significant at 0.5 microM and maximal at 1 microM Cd2+. The effect depended on glutathione synthesis and was masked by inhibiting synthesis with buthionine sulfoximine. The cells responded to slightly higher concentrations of Cd with a marked decrease in DNA synthesis, and reversible depletion of glutathione enhanced this sensitivity. Pre-induction of the thiol-rich protein metallothionein with ZnCl2 afforded a degree of protection to the glutathione-depleted cells. We conclude that the Cd-dependent elevation of glutathione in these cells may be protective at concentrations of Cd that can arise during acute environmental and occupational exposures.