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All-Trans Retinoic Acid Attenuates Blue Light-Induced Apoptosis of Retinal Photoreceptors by Upregulating MKP-1 Expression

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Abstract

The study investigated the antiapoptotic effects of all-trans retinoic acid (RA) on retinal degeneration caused by exposure to blue light. Sprague-Dawley rats received intraperitoneal injections of RA and, if necessary, the mitogen-activated protein kinase phosphotase-1(MKP-1) inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2, 3-dihydro-1H-inden-1-one (BCI), or the retinoic acid receptor (RAR) antagonist, AGN 193109. Retinal damage was induced by 24 h of continuous exposure to blue light. Haematoxylin and eosin staining and electroretinography were performed to measure retinal thickness and retinal function before and at 3 days and 7 days after light exposure. The retinal protein expression levels of phosphorylated c-Jun N-terminal kinase (JNK), phosphorylated nuclear factor-κB, MKP-1, Bim, Bax, and cleaved caspase-3 were also measured. Terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) staining and immunofluorescent staining of cleaved caspase-3 were also performed to evaluate photoreceptor apoptosis. The administration of RA significantly mitigated retinal dysfunction and the decrease in the outer nuclear layer (ONL) thickness at 3 days and 7 days after light exposure. RA also reduced the percentage of TUNEL-positive nuclei in the ONL and cleaved caspase-3 immunofluorescence intensity at 3 days after light exposure. Light exposure increased the retinal expression of proapoptotic proteins (Bim, Bax, and cleaved caspase-3), which was attenuated by RA. Moreover, RA enhanced the expression of MKP-1 and inhibited the phosphorylation of JNK, which were attenuated by the inhibition of RAR. The inhibitory effects of RA on blue light-induced photoreceptor apoptosis were abrogated by the MKP-1inhibitor. Our results indicate that RA alleviates photoreceptor loss following blue light exposure, at least partly, by the MKP-1/JNK pathway, which may serve as a therapeutic target for relieving retinal degeneration.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by research grants from the National Key Basic Research Program of China (2013CB967503) and the Youth Project of the National Natural Science Fund (81700851).

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  1. Xiaonan Zhuang and Jun Ma contributed equally to the work and should be regarded as equivalent authors.

Authors and Affiliations

  1. Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China

    Xiaonan Zhuang, Sisi Xu, Meng Zhang, Gezhi Xu & Zhongcui Sun

  2. Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China

    Xiaonan Zhuang, Jun Ma, Sisi Xu, Meng Zhang, Gezhi Xu & Zhongcui Sun

  3. NHC Key Laboratory of Myopia, Fudan University, Shanghai, China

    Xiaonan Zhuang, Jun Ma, Sisi Xu, Meng Zhang, Gezhi Xu & Zhongcui Sun

  4. Eye Institute, Eye & ENT Hospital, Fudan University, Shanghai, China

    Jun Ma

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  1. Xiaonan Zhuang
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  2. Jun Ma
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  3. Sisi Xu
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  4. Meng Zhang
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Contributions

XZ and JM conceived and designed the experiments. XZ, SX, and MZ performed the experiments. XZ, JM, and ZS analysed the data, wrote, and revised the manuscript. GZ and ZS obtained funding and supervised the experiments. All authors contributed to the article and approved the submitted version.

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Correspondence to Zhongcui Sun.

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All protocols conformed to the ARVO Statement on the Use of Animals in Research and were authorised by the Animal Ethics Committee of the Eye and Ear Nose Throat Hospital of Fudan University, Shanghai, China.

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Zhuang, X., Ma, J., Xu, S. et al. All-Trans Retinoic Acid Attenuates Blue Light-Induced Apoptosis of Retinal Photoreceptors by Upregulating MKP-1 Expression. Mol Neurobiol 58, 4157–4168 (2021). https://doi.org/10.1007/s12035-021-02380-3

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