Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2372, USA.
Blood. 2010 Oct 21;116(16):3039-48. doi: 10.1182/blood-2010-02-270322. Epub 2010 Jul 13.
The kidney is the main physiologic source of erythropoietin (EPO) in the adult and responds to decreases in tissue oxygenation with increased EPO production. Although studies in mice with liver-specific or global gene inactivation have shown that hypoxia-inducible factor 2 (Hif-2) plays a major role in the regulation of Epo during infancy and in the adult, respectively, the contribution of renal HIF-2 signaling to systemic EPO homeostasis and the role of extrarenal HIF-2 in erythropoiesis, in the absence of kidney EPO, have not been examined directly. Here, we used Cre-loxP recombination to ablate Hif-2α in the kidney, whereas Hif-2-mediated hypoxia responses in the liver and other Epo-producing tissues remained intact. We found that the hypoxic induction of renal Epo is completely Hif-2 dependent and that, in the absence of renal Hif-2, hepatic Hif-2 takes over as the main regulator of serum Epo levels. Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis.
肾脏是成人中促红细胞生成素（EPO）的主要生理来源，它会通过增加 EPO 的产生来应对组织氧合的减少。虽然在肝脏特异性或全局基因失活的小鼠研究中表明，缺氧诱导因子 2（Hif-2）分别在婴儿期和成人期的 Epo 调节中发挥主要作用，但肾脏 HIF-2 信号对全身 EPO 平衡的贡献以及在没有肾脏 EPO 的情况下肾脏外 HIF-2 在红细胞生成中的作用尚未直接研究。在这里，我们使用 Cre-loxP 重组来敲除肾脏中的 Hif-2α，而肝脏和其他产生 Epo 的组织中的 Hif-2 介导的缺氧反应仍然完整。我们发现，肾脏 Epo 的缺氧诱导完全依赖于 Hif-2，并且在没有肾脏 Hif-2 的情况下，肝脏 Hif-2 成为血清 Epo 水平的主要调节剂。此外，我们提供了证据表明，肝细胞来源的 Hif-2 参与了铁代谢基因的调节，支持 HIF-2 在 EPO 合成与铁稳态协调中的作用。
