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Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice

Yuka Kobayashi, Shizuka Watanabe, Manabu Shirai, Chiemi Yamashiro, Tadahiko Ogata, Fumiaki Higashijima, Takuya Yoshimoto, Takahide Hayano, Yoshiyuki Asai, View ORCID ProfileNoriaki Sasai, Kazuhiro Kimura
doi: https://doi.org/10.1101/2020.12.07.405308
Yuka Kobayashi
1Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Shizuka Watanabe
2Developmental Biomedical Science, Division of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma 630-0192, Japan
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Manabu Shirai
3Omics Research Center (ORC), National Cerebral and Cardiovascular Center, 6-1 Kishibe Shinmachi, Suita, Osaka 564-8565, Japan
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Chiemi Yamashiro
1Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Tadahiko Ogata
1Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Fumiaki Higashijima
1Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Takuya Yoshimoto
1Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Takahide Hayano
4Department of Systems Bioinformatics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Yoshiyuki Asai
4Department of Systems Bioinformatics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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Noriaki Sasai
2Developmental Biomedical Science, Division of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma 630-0192, Japan
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  • ORCID record for Noriaki Sasai
  • For correspondence: k.kimura@yamaguchi-u.ac.jp noriakisasai@bs.naist.jp
Kazuhiro Kimura
1Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan
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  • For correspondence: k.kimura@yamaguchi-u.ac.jp noriakisasai@bs.naist.jp
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Abstract

Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵5 Co-senior authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 07, 2020.
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Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice
Yuka Kobayashi, Shizuka Watanabe, Manabu Shirai, Chiemi Yamashiro, Tadahiko Ogata, Fumiaki Higashijima, Takuya Yoshimoto, Takahide Hayano, Yoshiyuki Asai, Noriaki Sasai, Kazuhiro Kimura
bioRxiv 2020.12.07.405308; doi: https://doi.org/10.1101/2020.12.07.405308
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Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice
Yuka Kobayashi, Shizuka Watanabe, Manabu Shirai, Chiemi Yamashiro, Tadahiko Ogata, Fumiaki Higashijima, Takuya Yoshimoto, Takahide Hayano, Yoshiyuki Asai, Noriaki Sasai, Kazuhiro Kimura
bioRxiv 2020.12.07.405308; doi: https://doi.org/10.1101/2020.12.07.405308

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