Emmy Noether Research Group, University of Technology, Dresden, Germany.
Blood. 2013 Feb 21;121(8):1436-45. doi: 10.1182/blood-2012-08-449181. Epub 2012 Dec 20.
Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.
红细胞生成必须保持紧密平衡，以保证身体所有组织都能获得足够的氧气供应。这个过程主要依赖于激素促红细胞生成素（EPO）及其转录因子缺氧诱导因子（HIF）。越来越多的证据表明，氧敏感脯氨酰羟化酶（PHD）是整个系统的重要调节因子。在这里，我们描述了一种新型的条件性 PHD2 敲除（cKO P2）小鼠品系，其肾脏产生 EPO 的细胞、神经元和星形胶质细胞中的 PHD2 被条件性敲除，由于 HIF-2α的过度激活，导致 EPO 过度产生，从而引发严重的红细胞增多症。相比之下，HIF-1α 是一种保护因子，可确保 cKO P2 小鼠的存活率，HCT 值高达 86%。通过使用不同的遗传方法，我们发现同时敲除 PHD2 和 HIF-1α 会导致 PHD3 的急剧减少，从而导致 HIF-2α 相关基因的过表达、神经退行性变和死亡。综上所述，我们的研究结果首次表明，条件性敲除小鼠的 PHD2 会导致 HIF-2α依赖性的红细胞增多症，而 HIF-1α 则可以保护这些小鼠，为开发新的 EPO 相关疾病（如贫血）的治疗方法提供了平台。
