Kashihara Toshihide, Morita Yui, Hatta Misaki, Inoue Sae, Suzuki Yume, Morita Akane, Nakahara Tsutomu
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
Front Pharmacol. 2024 Aug 6;15:1446521. doi: 10.3389/fphar.2024.1446521. eCollection 2024.
Retinal neurodegeneration, characterized by retinal ganglion cell (RGC) death, is a leading cause of vision impairment and loss in blind diseases, such as glaucoma. Müller cells play crucial roles in maintaining retinal homeostasis. Thus, dysfunction of Müller cells has been implicated as one of the causes of retinal diseases. Yes-associated protein 1 (YAP), a nuclear effector of the Hippo pathway, regulates mammalian cell survival. In this study, we investigated the role of YAP in Müller cells during -methyl-D-aspartic acid (NMDA)-induced excitotoxic RGC injury in rats. We found that YAP expression increased and was activated in Müller cells after NMDA-induced RGC injury. This YAP response was partly due to an increase in mRNA levels, although it may be independent of the Hippo pathway and β-TrCP-mediated YAP degradation. Morphological analysis revealed that verteporfin, a selective YAP inhibitor, exacerbated NMDA-induced RGC degeneration, suggesting that YAP activation in Müller cells contributes to RGC survival in NMDA-treated retinas. Studies in the rat Müller cell line (rMC-1) demonstrated that overexpression of YAP increased the levels of Bcl-xL, while verteporfin decreased the levels of Bcl-xL and cell viability and increased the levels of cytochrome c released from mitochondria and cleaved caspase-3. Finally, we found that Bcl-xL expression increased slightly in NMDA-treated retinas, whereas intravitreal injection of verteporfin suppressed this increase. Our findings suggest that activated YAP in Müller cells protects against NMDA-induced RGC injury by upregulating Bcl-xL expression.
视网膜神经退行性变以视网膜神经节细胞（RGC）死亡为特征，是青光眼等致盲疾病中视力损害和丧失的主要原因。Müller细胞在维持视网膜内环境稳定中起关键作用。因此，Müller细胞功能障碍被认为是视网膜疾病的病因之一。Yes相关蛋白1（YAP）是Hippo通路的核效应器，调节哺乳动物细胞存活。在本研究中，我们研究了YAP在大鼠N-甲基-D-天冬氨酸（NMDA）诱导的兴奋性毒性RGC损伤过程中在Müller细胞中的作用。我们发现，NMDA诱导RGC损伤后，Müller细胞中YAP表达增加并被激活。这种YAP反应部分归因于mRNA水平的增加，尽管它可能独立于Hippo通路和β-TrCP介导的YAP降解。形态学分析显示，选择性YAP抑制剂维替泊芬加剧了NMDA诱导的RGC变性，这表明Müller细胞中YAP的激活有助于NMDA处理的视网膜中RGC的存活。对大鼠Müller细胞系（rMC-1）的研究表明，YAP的过表达增加了Bcl-xL的水平，而维替泊芬降低了Bcl-xL的水平和细胞活力，并增加了从线粒体释放的细胞色素c和裂解的caspase-3的水平。最后，我们发现NMDA处理的视网膜中Bcl-xL表达略有增加，而玻璃体内注射维替泊芬抑制了这种增加。我们的研究结果表明，Müller细胞中激活的YAP通过上调Bcl-xL表达来保护免受NMDA诱导的RGC损伤。
