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Effects of Pro- and Antioxidative Compounds on Renal Production of Erythropoietin¹

Institute of Physiology, Medical University, Luebeck, Germany

Address all correspondence and requests for reprints to: Horst Pagel, Ph.D., Institute of Physiology, Medical University, Ratzeburger Allee 160, 23538 Luebeck, Germany. E-mail: pagel{at}physio.mu-luebeck.de

The most important stimulus for the enhanced synthesis of erythropoietin (Epo) is a lowered O₂ tension in the tissue. However, the mechanism by which an impaired O₂ supply is transduced into appropriate Epo production is still not fully understood. Recently, studies in human hepatoma cells (line HepG2) indicate that reactive O₂ species are involved in the signal transduction from the cellular O₂ sensor to the Epo gene. To clarify the role of reactive O₂ species in the regulation of Epo synthesis in the kidney, the principal Epo-producing organ in vivo, we investigated the influence of potent pro- and antioxidants on Epo production in isolated perfused rat kidneys. Under normoxic conditions, the iron chelator desferrioxamine and the antioxidant vitamin A increased renal Epo production, mimicking hypoxic induction. In contrast, supplementation of the perfusion medium of hypoxically perfused kidneys with the prooxidant compounds H₂O₂ or pyrogallol caused a significant reduction of Epo synthesis. The inhibition of Epo formation by reactive O₂ species could be completely antagonized by desferrioxamine and the hydroxyl radical-(OH^.)-scavenger tetramethylthiourea. Vitamin A also antagonized the H₂O₂-dependent inhibition of hypoxically induced Epo synthesis. Interestingly, the addition of the antioxidant vitamin A to hypoxically perfused kidneys also induced Epo production significantly. Our data strongly support the idea that reactive O₂ species, especially H₂O₂, are part of the signaling chain of the cellular O₂-sensing mechanism regulating the renal synthesis of Epo.

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