Batsuuri Khulan, Toychiev Abduqodir H, Viswanathan Suresh, Wohl Stefanie G, Srinivas Miduturu
Department of Biological and Vision Sciences, SUNY College of Optometry, New York, New York, USA.
Indiana University School of Optometry, Bloomington, Indiana, USA.
Glia. 2025 Jul;73(7):1398-1419. doi: 10.1002/glia.70013. Epub 2025 Mar 28.
Astrocytes in the retina and optic nerve head play an important role in the pathogenesis of glaucoma. Astrocytes extensively express connexin 43 (Cx43), a protein that forms gap junction (GJ) channels and transmembrane unopposed hemichannels. While it is well documented that Cx43 expression is augmented in retinal injuries, the role of astrocytic Cx43 channels in glaucomatous injury is not fully understood. Here, we used a mouse model of ocular hypertension caused by intracameral microbead injections and a more severe model, optic nerve crush (ONC) injury, and assessed changes in Cx43 expression and GJ channel function. The effect of astrocyte-specific deletion of Cx43 (Cx43KO) on retinal ganglion cell (RGC) loss and visual function was also assessed. We show that the Cx43 expression is increased in retinal astrocytes at early time points and remained elevated even after sustained elevation of intraocular pressure (IOP) (~8 weeks), which paralleled an increase in astrocytic GJ coupling. Deletion of astrocytic Cx43 markedly improved the survival of RGCs by ~93% and preserved visual function as assessed by ERG and reduced numbers of activated microglial/macrophages in the glaucomatous retina. Cx43 expression was also substantially increased after ONC injury, and the absence of Cx43 in this model increased RGC survival by ~48%. These results reveal a deleterious role for Cx43 in glaucoma progression. Intravitreal injections of Gap19, a peptide that reportedly inhibits Cx43 hemichannels but not GJ channels, markedly increased RGC survival and visual function. Further studies are required to assess whether targeting Cx43 hemichannels might be useful for glaucoma treatment.
视网膜和视神经头中的星形胶质细胞在青光眼的发病机制中起重要作用。星形胶质细胞广泛表达连接蛋白43（Cx43），该蛋白形成缝隙连接（GJ）通道和跨膜无对抗半通道。虽然有充分的文献记载视网膜损伤时Cx43表达会增加，但星形胶质细胞Cx43通道在青光眼性损伤中的作用尚未完全了解。在此，我们使用前房内注射微珠引起的高眼压小鼠模型以及更严重的模型——视神经挤压（ONC）损伤，并评估Cx43表达和GJ通道功能的变化。还评估了星形胶质细胞特异性缺失Cx43（Cx43KO）对视网膜神经节细胞（RGC）丢失和视觉功能的影响。我们发现，在早期时间点视网膜星形胶质细胞中Cx43表达增加，即使在眼压持续升高（约8周）后仍保持升高，这与星形胶质细胞GJ耦合的增加平行。删除星形胶质细胞Cx43可使RGC的存活率显著提高约93%，并保留视觉功能，这通过视网膜电图评估，且青光眼视网膜中活化的小胶质细胞/巨噬细胞数量减少。ONC损伤后Cx43表达也大幅增加，在该模型中缺失Cx43可使RGC存活率提高约48%。这些结果揭示了Cx43在青光眼进展中的有害作用。玻璃体内注射Gap19，一种据报道可抑制Cx43半通道但不抑制GJ通道的肽，可显著提高RGC存活率和视觉功能。需要进一步研究以评估靶向Cx43半通道是否对青光眼治疗有用。
