Neurotrophin-3 (NT-3), a neurotrophic factor that mainly binds to the tyrosine kinase C (trkC) receptor, has been shown to play a crucial role in proliferation, differentiation, and survival. However, the role of NT-3 in the hypoxia-induced retinopathy has not been investigated extensively. Here, we created a model of hypoxia (1% O2) in vitro and found that hypoxia promoted the apoptosis of mouse cone photoreceptor-derived 661W cells, increased the expression of TrkC and cleaved caspase-3. In contrast, the hypoxia-mediated 661W cell apoptosis was markedly alleviated by co-culturing with primary mouse Müller cells. Further mechanism studies revealed that hypoxia increased the synthesis and secretion of NT-3 by Müller cells, and exogenous NT-3 stimulation increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 by binding to TrkC in 661W cells. Besides, both siRNA knockdown of TrkC expression and incubation with an ERK-specific inhibitor PD98059 triggered apoptosis in hypoxic 661W cells. Altogether, these data suggest that NT-3 originating from Müller cells protects photoreceptors from hypoxia-induced apoptosis through a TrkC/ERK-dependent pathway. Our findings may facilitate future studies on the therapeutic implications of NT-3 in the treatment of hypoxia-relevant retinal diseases.

中文翻译：

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Müller细胞来源的Neurotrophin-3通过TrkC / ERK途径抑制缺氧诱导的感光细胞凋亡。

Neurotrophin-3（NT-3）是一种主要与酪氨酸激酶C（trkC）受体结合的神经营养因子，已显示在增殖，分化和存活中起关键作用。然而，尚未广泛研究NT-3在缺氧引起的视网膜病变中的作用。在这里，我们创建了体外缺氧（1％O2）模型，发现缺氧促进了小鼠视锥光感受器衍生的661W细胞的凋亡，增加了TrkC的表达并切割了caspase-3。相反，通过与原代小鼠Müller细胞共培养，缺氧介导的661W细胞凋亡得到明显缓解。进一步的机理研究表明，缺氧增加了Müller细胞对NT-3的合成和分泌，NT-3刺激通过与661W细胞中的TrkC结合而增加了细胞外信号调节激酶（ERK）1/2的磷酸化。此外，敲低TrkC表达的siRNA和与ERK特异性抑制剂PD98059的孵育均会触发低氧661W细胞的凋亡。总之，这些数据表明，源自Müller细胞的NT-3通过TrkC / ERK依赖性途径保护光感受器免受低氧诱导的细胞凋亡。我们的发现可能有助于NT-3在与低氧相关的视网膜疾病的治疗中的治疗意义的未来研究。这些数据表明，源自Müller细胞的NT-3通过TrkC / ERK依赖性途径保护光感受器免受缺氧诱导的细胞凋亡。我们的发现可能有助于NT-3在与低氧相关的视网膜疾病的治疗中的治疗意义的未来研究。这些数据表明，源自Müller细胞的NT-3通过TrkC / ERK依赖性途径保护光感受器免受缺氧诱导的细胞凋亡。我们的发现可能有助于NT-3在与低氧相关的视网膜疾病的治疗中的治疗意义的未来研究。