Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor.
Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor.
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DOI：
10.3389/fncel.2018.00292
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发表时间：
2018
影响因子：
5.3
通讯作者：
Nicoletti F
中科院分区：
文献类型：
--
作者：
Busceti CL;Di Menna L;Bianchi F;Mastroiacovo F;Di Pietro P;Traficante A;Bozza G;Niehrs C;Battaglia G;Bruno V;Fornai F;Volpe M;Rubattu S;Nicoletti F
Dickkopf-3 （Dkk3）是Wnt抑制剂Dkk家族的非典型成员，与神经退行性疾病的病理生理有关。然而，Dkk3在细胞退化和保护机制中的作用尚不清楚。我们使用Dkk3敲除小鼠来研究内源性Dkk3如何影响缺血性脑损伤。此外，我们利用星形胶质细胞的原代培养或星形胶质细胞和神经元的混合培养来研究Dkk3对细胞损伤的作用，并解剖其潜在的分子机制。在永久性大脑中动脉（MCA）闭塞（MCAO）引起的局灶性脑缺血模型中，Dkk3 - / -小鼠在MCAO后的所有时间点（1、3和7天）均显示出比野生型小鼠更大的梗死面积。免疫组化分析显示，Dkk3在缺血灶边缘表达增强，主要在星形胶质细胞中检测到。这提出了星形胶质细胞产生的Dkk3作为保护分子的可能性。我们使用皮质星形胶质细胞的原代培养或包含神经元和星形胶质细胞的混合皮质培养来验证这一假设。Dkk3基因缺失对氧化应激或葡萄糖剥夺引起的星形胶质细胞损伤是允许的。此外，应用人重组Dkk3 （hrDkk3）对培养的星形胶质细胞的氧化应激具有高度的保护作用。我们验证了Dkk3的保护活性是由血管内皮生长因子（VEGF）介导的假设。有趣的是，葡萄糖剥夺上调了野生型小鼠培养的星形胶质细胞中的Dkk3和VEGF。在缺乏Dkk3的星形胶质细胞中（即在Dkk3−/−小鼠制备的培养物中）未观察到VEGF诱导。在皮质细胞混合培养中，当星形胶质细胞缺乏Dkk3时，n -甲基- d -天冬氨酸（NMDA）短脉冲诱导的兴奋性毒性神经元死亡显著增强，而在NMDA后添加hrDkk3则具有神经保护作用。hrDkk3的神经保护作用通过药物阻断2型VEGF受体而显著降低，并被hrVEGF模仿。这些数据提供了Dkk3保护神经元和星形胶质细胞免受各种毒性损伤的第一个证据，至少在培养中，保护涉及VEGF诱导。
Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. However, the role of Dkk3 in mechanisms of cell degeneration and protection is unknown. We used Dkk3 knockout mice to examine how endogenous Dkk3 influences ischemic brain damage. In addition, we used primary cultures of astrocytes or mixed cultures of astrocytes and neurons to investigate the action of Dkk3 on cell damage and dissect the underlying molecular mechanisms. In a model of focal brain ischemia induced by permanent middle cerebral artery (MCA) occlusion (MCAO) Dkk3−/− mice showed a significantly greater infarct size with respect to their wild-type counterparts at all time points investigated (1, 3 and 7 days after MCAO). Immunohistochemical analysis showed that Dkk3 expression was enhanced at the borders of the ischemic focus, and was predominantly detected in astrocytes. This raised the possibility that Dkk3 produced by astrocytes acted as a protective molecule. We tested this hypothesis using either primary cultures of cortical astrocytes or mixed cortical cultures containing both neurons and astrocytes. Genetic deletion of Dkk3 was permissive to astrocyte damage induced by either oxidative stress or glucose deprivation. In addition, application of human recombinant Dkk3 (hrDkk3) was highly protective against oxidative stress in cultured astrocytes. We tested the hypothesis that the protective activity of Dkk3 was mediated byvascular endothelial growth factor (VEGF). Interestingly, glucose deprivation up-regulated both Dkk3 and VEGF in cultured astrocytes prepared from wild-type mice. VEGF induction was not observed in astrocytes lacking Dkk3 (i.e., in cultures prepared from Dkk3−/− mice). In mixed cultures of cortical cells, excitotoxic neuronal death induced by a brief pulse with N-methyl-D-aspartate (NMDA) was significantly enhanced when Dkk3 was lacking in astrocytes, whereas post-NMDA addition of hrDkk3 was neuroprotective. Neuroprotection by hrDkk3 was significantly reduced by pharmacological blockade of type-2 VEGF receptors and was mimicked by hrVEGF. These data offer the first evidence that Dkk3 protects both neurons and astrocytes against a variety of toxic insults, and at least in culture, protection involves VEGF induction.
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影响因子：
--
作者：
Nakamura RE;Hunter DD;Yi H;Brunken WJ;Hackam AS
通讯作者：
Hackam AS
影响因子：
5.6
作者：
Shim JW;Madsen JR
通讯作者：
Madsen JR
Wnt/β-catenin 在电针预处理诱发局灶性脑缺血耐受中的作用
影响因子：
4.2
作者：
He, Xin;Mo, Yunchang;Wang, Junlu
通讯作者：
Wang, Junlu
DOI：
10.1007/s00424-017-2018-7
发表时间：
2017-08
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
--
作者：
Gröne EF;Federico G;Nelson PJ;Arnold B;Gröne HJ
通讯作者：
Gröne HJ
影响因子：
8
作者：
Federico, Giuseppina;Meister, Michael;Groene, Hermann-Josef
通讯作者：
Groene, Hermann-Josef