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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia.
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Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia.

机译：Nrf2的靶向破坏会导致再生免疫介导的溶血性贫血。

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摘要

A basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in the cellular defense mechanism by mediating a coordinate up-regulation of antioxidant responsive element-driven detoxification and antioxidant genes. Here, we report that targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes. Splenomegaly and spleen toxicity in Nrf2(-/-) mice raised a possibility of hemolytic anemia and splenic extramedullary hematopoiesis in Nrf2(-/-) mice. In support of this, hematology analysis revealed that Nrf2(-/-) mice suffer from anemia with abnormal red cell morphologies (i.e., Howell-Jolly bodies, acantocytes, and schistocytes). In addition, Nrf2(-/-) erythrocytes were more sensitive to H(2)O(2)-induced hemolysis, and erythrocyte-bound IgG levels were markedly increased in Nrf2(-/-) mice compared with Nrf2(+/+) mice. Because IgG bound to erythrocytes in the presence of oxidative damage in erythrocytes (regardless of Nrf2 genotype), these data support that Nrf2(-/-) erythrocytes have higher levels of damage compared with Nrf2(+/+) cells. Finally, Nrf2(-/-) mice showed increased levels of erythrocyte-bound IgG compared with Nrf2(+/+) mice after H(2)O(2) injection in vivo, suggesting that the decreased glutathione and increased H(2)O(2) render the Nrf2(-/-) mice more susceptible to toxicity. Taken together, these observations indicate that a chronic increase in oxidative stress due to decreased antioxidant capacity sensitizes erythrocytes and causes hemolytic anemia in Nrf2(-/-) mice, suggesting a pivotal role of Nrf2-antioxidant responsive element pathway in the cellular antioxidant defense system.
机译：基本的亮氨酸拉链转录因子，NF-E2相关因子2（Nrf2），通过介导抗氧化剂响应元件驱动的排毒和抗氧化剂基因的协同上调，在细胞防御机制中发挥关键作用。在这里，我们报告针对性的Nrf2破坏会导致再生的免疫介导的溶血性贫血，这是由于增加了对受损红细胞的隔离所致。 Nrf2（-/-）小鼠脾肿大和脾毒性增加了Nrf2（-/-）小鼠溶血性贫血和脾髓外造血的可能性。为此，血液学分析表明Nrf2（-/-）小鼠患有贫血，其红细胞形态异常（即Howell-Jolly体，单核细胞和血细胞）。此外，Nrf2（-/-）红细胞对H（2）O（2）诱导的溶血更敏感，并且与Nrf2（+ / +）相比，Nrf2（-/-）小鼠中红细胞结合的IgG水平明显升高） 老鼠。因为IgG在红细胞中存在氧化性损伤（无论Nrf2基因型如何）时都与红细胞结合，所以这些数据支持Nrf2（-/-）红细胞比Nrf2（+ / +）细胞具有更高的损伤水平。最后，在体内注射H（2）O（2）后，Nrf2（-/-）小鼠与Nrf2（+ / +）小鼠相比显示出增加的红细胞结合IgG水平，表明谷胱甘肽减少和H（2）增加O（2）使Nrf2（-/-）小鼠更容易受到毒性的影响。综上所述，这些观察结果表明，由于抗氧化能力下降导致的氧化应激的慢性增加使Nrf2（-/-）小鼠的红细胞敏感并引起溶血性贫血，这表明Nrf2-抗氧化剂响应元件途径在细胞抗氧化剂防御系统中起着关键作用。 。

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