Abstract
Iron is the indispensable element for an animal, but has the toxicity of strong oxidative stress. Erythropoietin (EPO) is a hematopoietic cytokine and has several non-hematopoietic tissue effects such as protection of cell. EPO production is regulated by hypoxia inducible factor (HIF) of the transcriptional factor. HIF-α, subunit of HIF, level is controlled by proline hydroxylase (PHD) dependent on iron. The effect of iron-induced oxidative stress on EPO production is not clear. We examined a relation between EPO production regulated by iron and oxidative stress of iron. EPO-producing HepG2 cells in normoxia were added several concentrations of iron. Whole cells collected after 24 hours and measured protein and mRNA level and content of malondialdehyde (MDA) of index of peroxidation. The addition of FeCl3 to HepG2 cell decreased EPO mRNA level to 100 µM, but more than 200 μM was restored EPO mRNA levels. The content of MDA increased by FeCl3 addition more than 200 μM. Additon of hemin, an iron-containing porphyrin, hardly increased MDA content, and there was not the recovery of EPO mRNA level in the high concentration of hemin. High concentration of FeCl3 increased HIF-α content and mRNA level. The recovery of the EPO mRNA level with high concentration of FeCl3 was restrained by tempol of the antioxidant. These results suggested that oxidative stress of high concentration of iron promoted EPO production, and offseted a HIF-α breakdown through iron-induced PHD activation.
