Glucocorticoid activates glomerular antioxidant enzymes and protects glomeruli from oxidant injuries. We examined the effect of glucocorticoid on intrinsic glomerular antioxidant enzyme (AOE) activities. Munich-Wistar rats were treated with daily i.p. injection of vehicle or methylprednisolone [MP, 15 mg/kg body wt, (MP 15)] either for three days or nine days. Glomeruli isolated from rats given MP 15 had significantly higher activities of total (T-) and manganese (Mn-) superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase than vehicle-treated rats P < 0.05). MP15-treated rats were subjected to intrarenal arterial infusion of hydrogen peroxide (35 µmol; over 1 hr). Values for urinary protein excretion rate (U_prV) after hydrogen peroxide infusion were markedly lower in rats pretreated with MP 15 for both three days and nine days than in untreated rats (109 ± 18 and 55 ± 24 vs. 416 ± 73 µg/min, respectively, both P < 0.005). To test whether the same therapeutic intervention attenuates reactive oxygen species (ROS)-mediated glomerular injury in another model, rats given a single i.v. dose of puromycin aminonucleoside (PAN) (50 mg/kg body wt) were treated with daily i.p. injection of vehicle or MP15. Two days after PAN administration, when compared to vehicle-treated controls, PAN rats given MP15 had significantly higher activities of Mn-SOD, GSH-Px and catalase. After eight days of PAN injection, T- and Mn-SOD activities were, likewise, significantly higher in MP 15- than vehicle-treated PAN rats. PAN rats given MP 15 also had substantially less proteinuria, compared to PAN rats given vehicle alone, U_prV averaging 32.3 ± 9.4 versus 159.0 ± 13.8 mg/24 hr (P < 0.05). Elevated glomerular malondialdehyde (MDA) level characteristic of PAN rats was absent in rats treated with MP15. Moreover, epithelial foot process fusion and cell vacuolization seen in vehicle-treated PAN rats were markedly attenuated in MP15-treated PAN rats. These data indicate that the mechanism for therapeutic effect of glucocorticoids on ROS-mediated renal injuries includes an enhancement of endogenous glomerular AOE activities, which attenuates lipid peroxidation of glomerular tissue.