Neurotrophic function of erythropoietin

促红细胞生成素（EPO）是一种糖蛋白，由成人肾脏产生。长期以来，人们一直认为促红细胞生成是EPO唯一的生理功能，但我们已经证明，EPO是在脑中产生的，并保护神经元免受缺血性损伤。这一发现得到了随后发表的大量论文的支持，重组人EPO将被用作多种脑疾病的治疗剂。EPO基因在肾和脑中的表达均为缺氧诱导型，但表达模式有很大差异。当动物暴露于缺氧（7%氧）时，暴露后4小时两个器官中的EPO mRNA增加40-80倍。EPO mRNA保持在高水平，只要动物暴露于缺氧。虽然其机制尚不清楚，但这一发现暗示了以下生理重要性：（1）肾脏EPO mRNA的持续高水平导致红细胞增多，导致各种血管疾病，因此尽管缺氧，肾脏中的EPO mRNA必须降低，并且（2）脑中的EPO是低氧下神经保护所必需的，因此在低氧期间持续高水平。在子宫，EPO作为血管生成因子，促进子宫内膜层的周期性生长。子宫中的EPO产生也是低氧诱导的，但EPO的低氧诱导需要雌激素。

Erythropoietin (EPO) is a glycoprotein that is produced by the kidney in adults. It has been belived for long time that stimulation of erythropoiesis is a sole physiological function of EPO but we have demonstrated that EPO is produced in brain and protects neurons from ischemic damage. This finding has been supported by a number of papers subsequently publised and recombinant human EPO is going to be examined as a therapeutic of various brain diseases.Expression of EPO gene is markedly enhanced by hypoxia. Expression of EPO gene in both kidney and brain is hypoxia-inducible but the expression patterns are quite different. When animals are exposed to hypoxia (7 % oxygen), EPO mRNA in both organs increases 40-80-fold at 4 hr after exposure. EPO mRNA is kept at a high level as far as animals are exposed to hypoxia. Although the mechanism remains unknown, this finding implicates the physiological importance that (1) the continuous high level of the kidney EPO mRNA causes erthrocytosis, leading to various vascular disorders and therefore EPO mRNA in the kidney must be decreased despite of hypoxia and that (2) EPO in the brain is required for neuroprotection under hyoxia and therefore a high level continues during hypoxia.We have shown that EPO is also produced in the uterus where EPO acts as an angiogenic factor for periodical growth of uterine endometrial layer. EPO production in the uterus is also hypoxia-inducible but estrogen is required for hypoxic induction of EPO.