Astrocyte-specific deletion of Kir6.1/K-ATP channel aggravates cerebral ischemia/reperfusion injury through endoplasmic reticulum stress in mice
Astrocyte-specific deletion of Kir6.1/K-ATP channel aggravates cerebral ischemia/reperfusion injury through endoplasmic reticulum stress in mice
复制标题
星形胶质细胞特异性缺失 Kir6.1/K-ATP 通道通过内质网应激加重小鼠脑缺血/再灌注损伤
DOI：
10.1016/j.expneurol.2018.10.005
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发表时间：
2019
影响因子：
5.3
通讯作者：
Hu Gang
中科院分区：
文献类型：
--
作者：
Zhong Chong-Jin;Chen Miao-Miao;Lu Ming;Ding Jian-Hua;Du Ren-Hong;Hu Gang
ATP敏感性钾离子通道（K-ATP）是一种将细胞代谢与细胞膜电位耦合的通道，与脑卒中等脑疾病有关。越来越多的证据表明星形胶质细胞在脑缺血的病理生理过程中起重要作用。Kir6.1是K-ATP通道的成孔亚基，在星形胶质细胞中表达显著，参与调节其功能。然而，星形胶质细胞Kir6.1/K-ATP通道在缺血性脑卒中中的确切作用尚不清楚。在此，我们发现星形胶质细胞Kir6.1基因敲除（KO）小鼠在大脑中动脉闭塞中风模型中表现出更大的梗死面积和更严重的脑水肿和神经功能缺损。星形胶质细胞Kir6.1基因敲除小鼠的活化胶质增生和神经元丢失均加重。此外，星形胶质细胞Kir6.1基因敲除小鼠的促凋亡蛋白Bcl-2相关X（Bax）和活性caspase-3的蛋白水平上调，抗凋亡蛋白Bcl-2的表达下调。在缺血/再灌注（I/R）损伤期间，这伴随着脑组织和星形胶质细胞中增强的内质网应激（ER应激）反应。最后，抑制ER应激挽救了I/R损伤过程中Kir6.1缺失诱导的星形胶质细胞凋亡。总之，我们的研究结果表明星形胶质细胞Kir6.1/K-ATP通道通过抑制内质网应激对脑缺血/再灌注损伤具有保护作用，提示星形胶质细胞Kir6.1/K-ATP通道是一个有希望的缺血性脑卒中治疗靶点。
ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases including stroke. Emerging evidence shows that astrocytes play important roles in the pathophysiology of cerebral ischemia. Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the exact role of astrocytic Kir6.1-containg K-ATP channel (Kir6.1/K-ATP) in ischemic stroke remains unclear. Here, we found that astrocytic Kir6.1 knockout (KO) mice exhibited larger infarct areas and more severe brain edema and neurological deficits in middle cerebral artery occlusion stroke model. Both activated gliosis and neuronal loss were aggravated in astrocytic Kir6.1 KO mice. Furthermore, the protein levels of pro-apoptotic protein Bcl-2 associated X (Bax) and active caspase-3 were up-regulated and the expression of anti-apoptotic protein Bcl-2 was down-regulated in astrocytic Kir6.1 KO mice. This is accompanied by enhanced endoplasmic reticulum stress (ER stress) responses in brain tissues and in astrocytes during ischemia/reperfusion (I/R) injury. Finally, inhibition of ER stress rescued astrocyte apoptosis induced by Kir6.1 deletion during I/R injury. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects brain from cerebral ischemia/reperfusion injury through inhibiting ER stress and suggest that astrocytic Kir6.1/K-ATP channel is a promising therapeutic target for ischemic stroke.