Gap Junctional Coupling Between Retinal Astrocytes Exacerbates Neuronal Damage in Ischemia-Reperfusion Injury.
Gap Junctional Coupling Between Retinal Astrocytes Exacerbates Neuronal Damage in Ischemia-Reperfusion Injury.
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视网膜星形胶质细胞之间的间隙连接耦合加剧了缺血再灌注损伤中的神经元损伤。
DOI：
10.1167/iovs.62.14.27
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发表时间：
2021-11-01
影响因子：
4.4
通讯作者：
Srinivas M
中科院分区：
文献类型：
--
作者：
Toychiev AH;Batsuuri K;Srinivas M
视网膜星形胶质细胞大量表达连接蛋白43（Cx43），一种形成间隙连接（GJ）通道和非反向半通道的跨膜蛋白。虽然已经确定Cx43在视网膜损伤中上调，但尚不清楚星形胶质细胞Cx43是否在与损伤相关的视网膜神经节细胞（RGC）损失中起作用。在这里，我们研究了星形胶质细胞特异性Cx43缺失（Cx43 KO）和通道抑制剂对视网膜缺血/再灌注（I/R）损伤中RGC损失的影响，并评估了I/R损伤中表达和GJ通道和半通道功能的变化。还评估了Cx43缺失对未损伤视网膜中神经功能的影响。采用免疫组化和Western印迹法测定I/R损伤后野生型和Cx43 KO小鼠中Cx43表达、星形胶质细胞密度和形态以及RGC死亡。使用ERG记录评估视功能。GJ耦合和半通道活性进行了评估，分别使用示踪剂耦合和摄取研究。I/R损伤中RGCs的丢失伴随着星形胶质细胞中Cx43表达的增加。功能研究表明，I/R损伤增强星形胶质细胞GJ偶联，但不Cx43半通道活性。重要的是，星形胶质细胞Cx43的缺失改善了急性缺血中神经元的存活，但在没有损伤的情况下并不影响RGC功能。在支持，药理学抑制GJ耦合提供了I/R损伤的神经保护。在急性I/R损伤期间Cx43表达和GJ偶联的增加加剧了RGC的丢失。抑制星形胶质细胞Cx43通道可能是一个有用的策略，以促进RGC在病理条件下的生存。
Retinal astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and unopposed hemichannels. While it is well established that Cx43 is upregulated in retinal injuries, it is unclear whether astrocytic Cx43 plays a role in retinal ganglion cell (RGC) loss associated with injury. Here, we investigated the effect of astrocyte-specific deletion of Cx43 (Cx43KO) and channel inhibitors on RGC loss in retinal ischemia/reperfusion (I/R) injury and assessed changes in expression and GJ channel and hemichannel function that occur in I/R injury. The effect of Cx43 deletion on neural function in the uninjured retina was also assessed. Cx43 expression, astrocyte density and morphology, and RGC death in wild-type and Cx43KO mice after I/R injury were determined using immunohistochemistry and Western blotting. Visual function was assessed using ERG recordings. GJ coupling and hemichannel activity were evaluated using tracer coupling and uptake studies, respectively. Loss of RGCs in I/R injury was accompanied by an increase of Cx43 expression in astrocytes. Functional studies indicated that I/R injury augmented astrocytic GJ coupling but not Cx43 hemichannel activity. Importantly, deletion of astrocytic Cx43 improved neuronal survival in acute ischemia but did not affect RGC function in the absence of injury. In support, pharmacologic inhibition of GJ coupling provided neuroprotection in I/R injury. The increase in Cx43 expression and GJ coupling during acute I/R injury exacerbates RGC loss. Inhibition of astrocytic Cx43 channels might represent a useful strategy to promote RGC survival in pathologic conditions.
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DOI：
10.1073/pnas.95.26.15735
发表时间：
1998-12-22
影响因子：
11.1
作者：
Cotrina, ML;Lin, JHC;Nedergaard, M
通讯作者：
Nedergaard, M
影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
3.4
作者：
Alqawlaq, Samih;Flanagan, John G.;Sivak, Jeremy M.
通讯作者：
Sivak, Jeremy M.
影响因子：
2.5
作者：
Ivanova, Elena;Kovacs-Oller, Tamas;Sagdullaev, Botir T.
通讯作者：
Sagdullaev, Botir T.
DOI：
10.1073/pnas.012589799
发表时间：
2002-01-08
影响因子：
11.1
作者：
Contreras, JE;Sánchez, HA;Sáez, JC
通讯作者：
Sáez, JC