PDF(Pubmed)
Abstract：
In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.
摘要：
在诊所,铁调素水平在各种贫血相关疾病中升高，特别是在铁难治性贫血和抑制铁吸收的高炎症状态，这仍然是一个紧迫的未满足的医疗需求。确定各种类型的铁难治性贫血的有效治疗方案，评估了缺氧和药理学模拟药物FG-4592（Roxadustat）的潜在作用，缺氧诱导因子（HIF）-脯氨酸酰羟化酶（PHD）抑制剂，在铁难治性缺铁性贫血（IRIDA）小鼠模型上，炎症性贫血和5-氟尿嘧啶诱导的化疗相关贫血。发现了缺氧和FG-4592对IRIDA以及其他2个测试小鼠队列的有效保护作用。机械上,证明缺氧或FG-4592可以稳定十二指肠Hif2α，无论铁调素水平如何，都会导致Fpn转录的激活，这反过来又导致肠道铁吸收增加和铁调素激活的贫血的改善。此外，十二指肠Hif2α过表达完全挽救了Tmprss6基因敲除小鼠的表型，和Hif2α基因敲除在肠道显著延迟从5-氟尿嘧啶诱导的贫血的恢复，FG-4592治疗无法挽救。一起来看,这项研究的结果提供了令人信服的证据，即靶向肠道缺氧相关途径可以作为治疗广谱贫血的潜在治疗策略。尤其是铁难治性贫血。
