Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation

Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor-2 alpha (HIF-2α), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment. Anemia-induced increase in EPO and HIF-2α expression was also inhibited by iron-treatment. In in vitro experiments using EPO-producing HepG2 cells, iron stimulation reduced the expression of the EPO gene, as well as HIF-2α. Moreover, iron treatment augmented oxidative stress, and iron-induced reduction of EPO and HIF-2α expression was restored by tempol, an anti-oxidant compound. HIF-2α interaction with the EPO promoter was inhibited by iron treatment, and was restored by tempol. These findings suggested that iron supplementation reduced EPO gene expression via an oxidative stress-HIF-2α-dependent signaling pathway.

This is the Author's Accepted Manuscript of the following article: Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation, Keisuke Oshima, Yasumasa Ikeda, Yuya Horinouchi, Hiroaki Watanabe, Hirofumi Hamano, Yoshitaka Kihira, Seiji Kishi, Yuki Izawa-Ishizawa, Licht Miyamoto, Tasuku Hirayama, Hideko Nagasawa, Keisuke Ishizawa, Koichiro Tsuchiya & Toshiaki Tamaki, Laboratory Investigation 97, 555–566 (2017), which has been published in final form at https://doi.org/10.1038/labinvest.2017.11.