Previously, we have demonstrated that leptin increases blood pressure (BP) in the rats through two oxidative stress-dependent mechanisms: stimulation of extracellular signal-regulated kinases (ERK) by H₂O₂ and scavenging of nitric oxide (NO) by superoxide ( \textO₂ ^{- ·} ) \left( {{\text{O}}_{2} ^{ - \bullet } } \right) . Herein, we examined if renal glutathione system and antioxidant enzymes determine the mechanism of prohypertensive effect of leptin. Leptin administered at 0.5 mg/kg/day for 4 or 8 days increased BP and renal Na⁺,K⁺-ATPase activity and reduced fractional sodium excretion; these effects were prevented by NADPH oxidase inhibitor, apocynin. Superoxide scavenger, tempol, abolished the effect of leptin on BP and renal Na⁺ pump in rats receiving leptin for 8 days, whereas ERK inhibitor, PD98059, was effective in animals treated with leptin for 4 days. Leptin administered for 4 days decreased glutathione (GSH) and increased glutathione disulfide (GSSG) in the kidney. In animals receiving leptin for 8 days GSH returned to normal level, which was accompanied by up-regulation of γ-glutamylcysteine synthetase (γ-GCS), a rate-limiting enzyme of the GSH biosynthetic pathway. In addition, superoxide dismutase (SOD) activity was decreased, whereas glutathione peroxidase (GPx) was increased in rats receiving leptin for 8 days. Cotreatment with γ-GCS inhibitor, buthionine sulfoximine (BSO), accelerated, whereas GSH precursor, N-acetylcysteine (NAC), attenuated leptin-induced changes in γ-GCS, SOD, and GPx. In addition, coadministration of BSO changed the mechanism of BP elevation from H₂O₂-ERK to ( \textO₂ ^{- ·} ) \left( {{\text{O}}_{2} ^{ - \bullet } } \right) –NO dependent in animals receiving leptin for 4 days, whereas NAC had the opposite effect in rats treated with leptin for 8 days. These results suggest that initial change in GSH redox status induces decrease in SOD/GPx ratio, which results in greater amount of ( \textO₂ ^{- ·} ) \left( {{\text{O}}_{2} ^{ - \bullet } } \right) versus H₂O₂ in later phase of leptin treatment, thus shifting the mechanism of BP elevation from H₂O₂-ERK to ( \textO₂ ^{- ·} ) \left( {{\text{O}}_{2} ^{ - \bullet } } \right) –NO dependent.