Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.
Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.
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星形胶质细胞N-myc下游调节基因2保护大脑免受中风引起的脑水肿
作者：
Guo H;Yin A;Ma Y;Fan Z;Tao L;Tang W;Ma Y;Hou W;Cai G;Zhuo L;Zhang J;Li Y;Xiong L
脑水肿是脑缺血的严重并发症，是脑疝形成和死亡的主要原因。虽然星形胶质细胞肿胀是细胞毒性水肿的主要贡献者，但参与该过程的分子机制仍然难以捉摸。N-myc下游调节基因2（NDRG 2）是一种研究广泛的肿瘤抑制基因，主要表达于哺乳动物脑中的星形胶质细胞。在这里，我们发现NDRG 2缺乏导致缺血后脑水肿恶化、Na+转移失衡和星形胶质细胞肿胀。我们还发现，星形胶质细胞中的NDRG 2缺失显著改变了缺血脑中与细胞极性密切相关的水通道蛋白-4和Na+-K+-ATP酶β1的表达和分布。在NDRG 2敲除小鼠脑中，通过挽救星形胶质细胞Na+-K+-ATP酶β1的表达，脑水肿和星形胶质细胞肿胀显著减轻。此外，通过慢病毒构建体上调星形胶质细胞NDRG 2显著减轻脑水肿、星形胶质细胞肿胀和血脑屏障破坏。我们的研究结果表明，NDRG 2在维持星形胶质细胞极化，促进Na+和水的转移平衡，并保护脑缺血性水肿的特殊作用。这些发现为NDRG 2作为脑水肿的治疗靶点提供了见解。NDRG 2-KO小鼠易发生卒中诱导的脑水肿和星形胶质细胞肿胀。NDRG 2缺陷显着改变星形胶质细胞的形态和极性。NDRG 2可能作为缺血性脑水肿干预的潜在靶点。
Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N‐myc downstream‐regulated gene 2 (NDRG2), a well‐studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na+ transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin‐4 and Na+‐K+‐ATPase β1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na+‐K+‐ATPase β1 in NDRG2‐knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood–brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na+ and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema. NDRG2‐KO mice were susceptible to stroke‐induced brain edema and astrocytic swelling. NDRG2 deficiency dramatically changed astrocytic morphology and polarity. NDRG2 may serve as a potential target for ischemic brain edema intervention.
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DOI：
10.1073/pnas.1110655108
发表时间：
2011-10-25
影响因子：
11.1
作者：
Haj-Yasein, Nadia Nabil;Vindedal, Gry Fluge;Nagelhus, Erlend Arnulf
通讯作者：
Nagelhus, Erlend Arnulf
影响因子：
2.2
作者：
Alvestad, Silje;Hammer, Janniche;Ottersen, Ole Petter
通讯作者：
Ottersen, Ole Petter
DOI：
10.1073/pnas.0409308102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Eid, T;Lee, TSW;de Lanerolle, NC
通讯作者：
de Lanerolle, NC
脑出血大鼠模型脑组织中NDRG2的时空表达：初步研究
影响因子：
2.5
作者：
Gao, Lingfeng;Li, Xiang;Chen, Gang
通讯作者：
Chen, Gang
局灶性脑缺血再灌注后大鼠脑内NDRG2的时空表达
影响因子：
2.9
作者：
Li, Yan;Shen, Lan;Xiong, Lize
通讯作者：
Xiong, Lize