Sites of erythropoietin production
Sites of erythropoietin production
复制标题
DOI：
10.1038/ki.1997.52
复制
发表时间：
1997-02-01
影响因子：
19.6
通讯作者：
Ratcliffe, PJ
中科院分区：
文献类型：
--
作者：
Maxwell, PH;Ferguson, DJP;Ratcliffe, PJ
促红细胞生成素是一种循环激素，控制红细胞生成速率，从而控制血液的携氧能力。为了应对贫血或低氧血症，促红细胞生成素的循环水平可以增加一千倍；其背后的调节机制为生理和分子水平上的氧传感提供了一个重要的模型系统。距 Jacobson 及其同事证明切除肾脏可以阻止红细胞生成对出血或钴的反应，而消融许多其他器官却不能起到作用，已经过去了近 40 年[11]。大量证据已证实，肾脏是成人产生促红细胞生成素的主要部位，而负责的细胞现已被确定为成纤维细胞样群 [2, 3]。除肾脏外，已确定成人肝脏是促红细胞生成素的重要来源 [4]，所涉及的细胞群已被确定为肝细胞 [5, 6] 和 Ito 细胞 [71]。除肾脏和肝脏外，促红细胞生成素 mRNA 已在一系列其他正常器官中使用敏感且特定的技术（RNase 保护或逆转录酶 PCR）得到证实。这些研究总结于表 1 [2, 8-11]。促红细胞生成素的表达也已在早期植入后小鼠胚胎[12]、人胎盘[13]和多种肿瘤[14-19]中得到记录。回到正常成年动物，尽管培养的星形胶质细胞确实产生免疫反应性促红细胞生成素，但尚不清楚促红细胞生成素 mRNA 在肝脏和肾脏以外的器官中是否被翻译成促红细胞生成素[201。有趣的是，未受刺激的啮齿动物睾丸和大脑中的 mRNA 总量分别约为肾脏中水平的 30% 和 10%。血脑屏障使得大脑促红细胞生成素基因表达的任何作用很可能是局部的而不是全身的。因此，这些组织中促红细胞生成素基因表达的功能意义（如果有的话）仍有待确定。显而易见的是，在肾脏和肝脏以外的组织中，贫血和/或低压缺氧通常会导致促红细胞生成素 mRNA 水平升高（通常为 2 至 3 倍）（表 1）。这是第一个线索，表明基因表达的缺氧调节不仅仅是肝脏和肾脏中专门的促红细胞生成素生成细胞的特征，而且更广泛。我们现在知道，HIF-1 低氧调节系统在组织培养细胞中广泛发挥作用 [21, 22]，并且与多种基因的控制有关，至少在培养的细胞系中如此（参见本卷中的其他文章）。© 1997 年，国际肾病学会
Erythropoietin is a circulating hormone that governs the rate of red blood cell production and hence the oxygen-carrying capacity of the blood. In response to anemia or hypoxemia circulating levels of erythropoietin can increase a thousand-fold; the regulatory mechanisms underlying this offer an important model system for oxygen-sensing at both the physiological and molecular levels. It is now almost 40 years since Jacobson and colleagues showed that removal of the kidneys prevented the erythropoietic response to hemorrhage or cobalt, whereas ablation of a number of other organs did not [11. A wealth of evidence has confirmed that the kidneys are the principal site of erythropoietin production in the adult, and the cells responsible have now been identified as the fibroblast-like population [2, 3]. In addition to the kidneys, it is established that the adult liver is an important source of erythropoietin [4], and the cell populations involved have been identified as the hepatocytes [5, 6] and the Ito cells [71. Apart from kidney and liver, erythropoietin mRNA has been demonstrated in a range of other normal organs using sensitive and specific techniques (RNase protection or reverse transcrip-tase-PCR). These studies are summarized in Table 1 [2, 8—11]. Erythropoietin expression has also been documented in early postimplantation mouse embryos [12], human placenta [13] and a variety of tumors [14—19]. Returning to the normal adult animal, it is not established that erythropoietin mRNA is translated into erythropoietin in organs other than the liver and kidney, although cultured astrocytes do produce immunoreactive erythropoietin [201. Interestingly, the total amount of mRNA in the testis and brain of unstimulated rodents is in the region of 30% and 10%, respectively, of the level in the kidney. The blood-brain barrier makes it likely that any role of brain erythropoietin gene expression is local rather than systemic. Thus the functional significance (if any) of erythropoietin gene expression in these tissues remains to he ascertained. What is clear is that in tissues outside the kidney and liver the level of erythropoietin niRNA is generally increased (usually 2-to 3-fold) by anemia and/or hypobaric hypoxia (Table 1). This was one of the first clues that hypoxic regulation of gene expression was not simply a feature of specialized erythropoietin producing cells in the liver and kidney, hut was more widespread. We now know that the HIF-1 system of hypoxic regulation operates widely in tissue culture cells [21, 22] and has been implicated in the control of a broad range of genes, at least in cultured cell lines (see other other articles in this volume).© 1997 by the International Society of Nephrology