Oxidative stress has been implicated in the pathogenesis of both acquired and hereditary polycystic kidney disease. Mechanisms of oxidant injury in C57BL/6J-cpk mice and Han:SPRD-Cy rats with rapidly or slowly progressive polycystic kidney disease were explored. Expression of heme oxygenase-1 mRNA, an inducible marker of oxidative stress, was shown to be increased in cystic kidneys of mice and rats in a pattern that reflected disease severity. By contrast, there was a decrease in mRNA expression of the antioxidant enzymes extracellular glutathione peroxidase, superoxide dismutase, catalase, and glutathione S-transferase during disease progression. Renal mRNA levels of these enzymes were strikingly reduced in rapidly progressive disease in homozygous cystic mice and rats. In slowly progressive disease in heterozygous rats, renal antioxidant mRNA levels were decreased to a greater extent in cystic males than in the less severely affected females. Protein levels for extracellular glutathione peroxidase were also reduced in plasma and in cystic kidneys of mice and rats. Plasma extracellular glutathione peroxidase enzymatic activity was also decreased, whereas the lipid peroxidation products malondialdehyde and 4-hydroxy-2(E)-nonenal were increased in kidneys and blood plasma of cystic mice. Reduced antioxidant enzyme protection and increased oxidative damage represent general mechanisms in the pathogenesis of polycystic kidney disease.