Effects of pro- and antioxidative compounds on renal production of erythropoietin

The most important stimulus for the enhanced synthesis of erythropoietin (E po) is a lowered O-2 tension in the tissue. However, the mechanism by which an impaired O-2 supply is transduced into appropriate Epo production is st ill not fully understood. Recently, studies in human hepatoma cells (line H epG2) indicate that reactive O-2 species are involved in the signal transdu ction from the cellular O-2 sensor to the Epo gene. To clarify the role of reactive O-2 species in the regulation of Epo synthesis in the kidney, the principal Epo-producing organ in vivo, we investigated the influence of pot ent pro- and antioxidants on Epo production in isolated perfused rat kidney s. Under normoxic conditions, the iron chelator desferrioxamine and the ant ioxidant vitamin A increased renal Epo production, mimicking hypoxic induct ion. In contrast, supplementation of the perfusion medium of hypoxically pe rfused kidneys with the prooxidant compounds H2O2 or pyrogallol caused a si gnificant reduction of Epo synthesis. The inhibition of Epo formation by re active O-2 species could be completely antagonized by desferrioxamine and t he hydroxyl radical-(OH.)-scavenger tetramethylthiourea. Vitamin A also ant agonized the H2O2-dependent inhibition of hypoxically induced Epo synthesis . Interestingly, the addition of the antioxidant vitamin A to hypoxically p erfused kidneys also induced Epo production significantly. Our data strongl y support the idea that reactive O-2 species, especially H2O2, are part of the signaling chain of the cellular O-2-sensing mechanism regulating the re nal synthesis of Epo.