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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1446521
This article is part of the Research Topic Targeting Mitochondrial Dysfunction for the Discovery and Development of Novel CNS Therapies in Rare and Neurodegenerative Diseases View all 3 articles

YAP activation in Müller cells protects against NMDA-induced retinal ganglion cell injury by regulating Bcl-xL expression

Provisionally accepted
Toshihide Kashihara Toshihide Kashihara *Yui Morita Yui Morita Misaki Hatta Misaki Hatta Akane Morita Akane Morita Tsutomu Nakahara Tsutomu Nakahara *
  • Kitasato University, Minato-ku, Japan

The final, formatted version of the article will be published soon.

    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 N-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 Yap 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.

    Keywords: Retina, Müller cell, retinal ganglion cell, YAP, Bcl-XL, NMDA, Mitochondrial dysfunction

    Received: 10 Jun 2024; Accepted: 23 Jul 2024.

    Copyright: © 2024 Kashihara, Morita, Hatta, Morita and Nakahara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Toshihide Kashihara, Kitasato University, Minato-ku, Japan
    Tsutomu Nakahara, Kitasato University, Minato-ku, Japan

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