Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Student Lab, Tokushima University Faculty of Medicine, Tokushima, Japan.
Lab Invest. 2017 May;97(5):555-566. doi: 10.1038/labinvest.2017.11. Epub 2017 Mar 6.
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 renal EPO and HIF-2α expression was 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 antioxidant 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.
肾性贫血是慢性肾脏病（CKD）的主要并发症。铁补充剂和促红细胞生成素刺激剂被广泛用于治疗肾性贫血。然而，过量的铁通过 Fenton 反应引起氧化应激，铁补充可能会损害包括 CKD 中促红细胞生成素（EPO）产生在内的残余肾功能。直接铁处理后，EPO 基因在小鼠中表达受到抑制。铁处理后，肾脏中的缺氧诱导因子-2α（HIF-2α），EPO 基因的正调节剂，也减少了。铁处理抑制了贫血诱导的肾 EPO 和 HIF-2α 表达的增加。在使用产生 EPO 的 HepG2 细胞的体外实验中，铁刺激降低了 EPO 基因以及 HIF-2α 的表达。此外，铁处理增加了氧化应激，抗氧化化合物 tempol 恢复了铁诱导的 EPO 和 HIF-2α 表达的减少。铁处理抑制了 HIF-2α 与 Epo 启动子的相互作用，而 tempol 则恢复了这种相互作用。这些发现表明，铁补充剂通过氧化应激-HIF-2α 依赖的信号通路降低了 EPO 基因的表达。
