Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness
Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness
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DOI：
10.1152/jappl.1998.84.4.1242
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发表时间：
1998-04-01
影响因子：
3.3
通讯作者：
Leiter, JC
中科院分区：
文献类型：
--
作者：
Ou, LC;Salceda, S;Leiter, JC
我们检测了两种对缺氧有不同多红细胞反应的Sprague-Dawley大鼠品系在缺氧时的促红细胞生成素（EPO）基因表达和促红细胞生成素的产生。Hilltop (H)大鼠出现严重红细胞增多症、严重低氧血症和肺动脉高压。大鼠经常死于一种与人类慢性高原病（CMS）难以区分的综合征。麦迪逊(M)大鼠会出现红细胞增多症和肺动脉高压，这是适度的，没有额外的死亡率。我们测试了假设，即这些大鼠菌株具有不同的刺激反应特征来控制EPO的产生。各组大鼠缺氧（0.5 atm, 73 Torr Po）(2)，在30 d的缺氧暴露中，定时测定肾组织EPO mRNA和EPO水平、血浆EPO、通气量、动脉和肾静脉血气及肾功能指标。在长时间缺氧暴露期间，与M大鼠相比，H大鼠肾EPO mRNA、肾EPO和血浆EPO水平显著升高。在低氧环境下，各菌株的通气反应和肾功能指标相似。H大鼠在缺氧开始时动脉低氧血症加重，缺氧暴露14天后肾组织低氧血症加重，红细胞增多症加重。当EPO反应作为肾静脉Po的函数表达时(2)，两种菌株似乎处于相同的剂量-反应曲线上，但H大鼠的反应沿着曲线向更低氧的值移动。我们得出结论，H大鼠继发于肾组织氧合较差的红细胞增多症显著增加，但控制EPO基因表达和EPO产生的刺激反应特征在M和H大鼠之间似乎没有差异。最后，缺氧时EPO水平的调节主要发生在转录水平。
We examined erythropoietin (EPO) gene expression and EPO production during hypoxia in two Sprague-Dawley rat strains with divergent polycythemic responses to hypoxia. Hilltop (H) rats develop severe polycythemia, severe hypoxemia, and pulmonary artery hypertension. The H rats often die from a syndrome indistinguishable from chronic mountain sickness (CMS) in humans. Madison (M) rats develop polycythemia and pulmonary artery hypertension that is modest and suffer no excess mortality. We tested the hypothesis that these rat strains have different stimulus-response characteristics governing EPO production. Rats of each strain were exposed to hypoxia (0.5 atm, 73 Torr inspired Po(2)), and renal tissue EPO mRNA and EPO levels, plasma EPO, ventilation, arterial and renal venous blood gases, and indexes of renal function were measured at fixed times during a 30-day hypoxic exposure. During extended hypoxic exposure, H rats had significantly elevated renal EPO mRNA, renal EPO, and plasma EPO levels compared with M rats. Ventilatory responses and indexes of renal function were similar in the strains during the hypoxic exposure. H rats had greater arterial hypoxemia from the onset of hypoxia and more severe renal tissue hypoxemia and greater polycythemia after 14 days of hypoxic exposure. When EPO responses were expressed as functions of renal venous Po(2), the two strains appeared to lie on the same dose-response curves, but the responses of H rats were shifted along the curve toward more hypoxic values. We conclude that H rats have significantly greater polycythemia secondary to poorer renal tissue oxygenation, but the stimulus-response characteristics governing EPO gene expression and EPO production do not seem to differ between M and H rats. Finally, the regulation of EPO levels during hypoxia occurs primarily at the transcriptional level.