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The Involvement of Iron on Erythropoietin Expression
Author(s) -
Ikeda Yasumasa,
Oshima Keisuke,
Horinouchi Yuya,
IzawaIshizawa Yuki,
Kihira Yoshitaka,
Ishizawa Keisuke,
Tsuchiya Koichiro,
Tamaki Toshiaki
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1217.19
Subject(s) - erythropoietin , erythropoiesis , oxidative stress , hypoxia inducible factors , endocrinology , anemia , medicine , hypoxia (environmental) , kidney , stimulation , downregulation and upregulation , hepcidin , gene expression , chemistry , gene , oxygen , biochemistry , organic chemistry
Background Renal anemia is often seen in the development of chronic renal failure (CRF). Therefore, Iron supplementation, as well as erythropoiesis‐stimulating agents, are used for treatment of renal anemia. Meanwhile, iron is shown to cause oxidative stress through toxic hydroxyl radical production via iron catalyzed‐Fenton reaction. Therefore, iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CRF. In the present study, we studied iron action on erythropoietin expression. Methods and Results In mice with unilateral ureter obstruction (UUO), EPO gene was reduced, and renal iron content was elevated in kidney of UUO side. Similarly, EPO gene was suppressed in mice with iron treatment. The expression of hypoxia‐inducible factor‐2 alpha (HIF‐2a), a positive regulator of EPO gene, was also diminished in both UUO‐ and iron‐treated kidney. In in vitro experiments using HepG2 cells, iron stimulation reduced the expression of EPO gene, as well as HIF‐2a, in a dose‐dependent manner. Iron also suppressed CoCl 2 ‐induced EPO gene upregulation under hypoxia‐mimicked condition. Moreover, iron treatment augmented oxidative stress production, and iron‐induced reduction of EPO and HIF‐2a expression was restored by an anti‐oxidant agent treatment. Conclusion These findings suggested that Iron supplementation reduced EPO gene expression through oxidative stress‐HIF‐2a‐dependent manner.