Department of Inflammation, Pfizer Global Research and Development, 700 West Chesterfield Parkway, St Louis, MO 63017, USA.
Dis Model Mech. 2010 Nov-Dec;3(11-12):763-72. doi: 10.1242/dmm.004788. Epub 2010 Oct 19.
In mammals, the production of red blood cells is tightly regulated by the growth factor erythropoietin (EPO). Mice lacking a functional Epo gene are embryonic lethal, and studying erythropoiesis in EPO-deficient adult animals has therefore been limited. In order to obtain a preclinical model for an EPO-deficient anemia, we developed a mouse in which Epo can be silenced by Cre recombinase. After induction of Cre activity, Epo(KO/flox) mice experience a significant reduction of serum EPO levels and consequently develop a chronic, normocytic and normochromic anemia. Furthermore, compared with wild-type mice, Epo expression in Epo(KO/flox) mice is dramatically reduced in the kidney, and expression of a well-known target gene of EPO signaling, Bcl2l1, is reduced in the bone marrow. These observations are similar to the clinical display of anemia in patients with chronic kidney disease. In addition, during stress-induced erythropoiesis these mice display the same recovery rate as their heterozygous counterparts. Taken together, these results demonstrate that this model can serve as a valuable preclinical model for the anemia of EPO deficiency, as well as a tool for the study of stress-induced erythropoiesis during limiting conditions of EPO.
在哺乳动物中，红细胞的生成受到生长因子促红细胞生成素（EPO）的严格调节。缺乏功能性 Epo 基因的小鼠在胚胎期就会死亡，因此，研究 EPO 缺乏的成年动物中的红细胞生成受到限制。为了获得 EPO 缺乏性贫血的临床前模型，我们开发了一种可以通过 Cre 重组酶沉默 Epo 的小鼠。在 Cre 活性诱导后，Epo(KO/flox) 小鼠的血清 EPO 水平显著降低，随后发生慢性、正细胞正色素性贫血。此外，与野生型小鼠相比，Epo(KO/flox) 小鼠肾脏中的 Epo 表达显著降低，EPO 信号的一个已知靶基因 Bcl2l1 的表达在骨髓中降低。这些观察结果与慢性肾脏病患者贫血的临床表现相似。此外，在应激诱导的红细胞生成过程中，这些小鼠的恢复率与杂合子小鼠相同。总之，这些结果表明，该模型可作为 EPO 缺乏性贫血的有价值的临床前模型，以及在 EPO 有限条件下研究应激诱导的红细胞生成的工具。
