Applied Oxygen Physiology Project, New Industry Creation Hatchery Center, Tohoku University, Sendai, Miyagi, Japan.
Division of Oxygen Biology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Blood Adv. 2023 Aug 8;7(15):3793-3805. doi: 10.1182/bloodadvances.2023009798.
The erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients with kidney disease. However, the roles of the liver in the HIF-PHI-mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Furthermore, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.
促红细胞生成素（erythropoietin，EPO）是一种主要由成年哺乳动物肾脏产生的红细胞生长因子，可诱导红细胞的扩张和铁的利用以合成血红蛋白。肝脏也以低于肾脏的水平产生 EPO。肾脏和肝脏的 EPO 产生受缺氧诱导转录因子（hypoxia-inducible transcription factors，HIFs）以缺氧/贫血诱导的方式进行基本调节。最近，已经推出了一些通过抑制 HIF-脯氨酰羟化酶（HIF-prolyl hydroxylases，HIF-PHIs）来激活肾脏中的 HIF 并增加 EPO 产生的小分子化合物，用于治疗肾病患者的 EPO 缺乏性贫血。然而，肝脏在 HIF-PHI 介导的红细胞生成和铁动员中的作用仍存在争议。在这里，为了阐明肝脏在 HIF-PHI 介导的促红细胞生成和铁动员中的作用，分析了缺乏肾脏 EPO 产生能力的基因修饰小鼠系。在突变小鼠中，HIF-PHI 给药通过诱导肝脏 EPO 产生，仅轻微增加了血浆 EPO 浓度和外周红细胞。突变小鼠中未观察到 HIF-PHIs 对储存铁的动员作用以及对肝脏 hepcidin（一种抑制铁储存细胞中铁释放的抑制分子）的抑制作用。这些发现表明，肾脏中 EPO 的充分诱导对于实现 HIF-PHIs 的全部治疗效果（包括抑制 hepcidin）是必不可少的。这些数据还表明，HIF-PHIs 可直接诱导与膳食铁摄入相关的十二指肠基因表达。此外，肝脏 EPO 诱导被认为部分有助于 HIF-PHIs 的促红细胞生成作用，但不足以补偿肾脏大量的 EPO 诱导。
