Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

  1. Toshihide Kurihara
  2. Peter D Westenskow
  3. Marin L Gantner
  4. Yoshihiko Usui
  5. Andrew Schultz
  6. Stephen Bravo
  7. Edith Aguilar
  8. Carli Wittgrove
  9. Mollie SH Friedlander
  10. Liliana P Paris
  11. Emily Chew
  12. Gary Siuzdak
  13. Martin Friedlander  Is a corresponding author
  1. Keio University School of Medicine, Japan
  2. The Scripps Research Institute, United States
  3. The Lowy Medical Research Institute, United States
  4. Tokyo Medical University Hospital, Japan
  5. National Institutes of Health, United States
  6. The Scripps Research institute, United States

Abstract

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

Article and author information

Author details

  1. Toshihide Kurihara

    Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Peter D Westenskow

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Marin L Gantner

    The Lowy Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yoshihiko Usui

    Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrew Schultz

    Center for Metabolomics, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephen Bravo

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Edith Aguilar

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Carli Wittgrove

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mollie SH Friedlander

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Liliana P Paris

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Emily Chew

    National Eye Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Gary Siuzdak

    Center for Metabolomics, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Martin Friedlander

    Department of Cell and Molecular Biology, The Scripps Research institute, La Jolla, United States
    For correspondence
    friedlan@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-0045-3) of the Scripps Research Institute. All surgery was performed under isofluorane and/or ketamine/xylazine anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Jeremy Nathans, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: January 9, 2016
  2. Accepted: March 11, 2016
  3. Accepted Manuscript published: March 15, 2016 (version 1)
  4. Accepted Manuscript updated: March 21, 2016 (version 2)
  5. Version of Record published: April 27, 2016 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Toshihide Kurihara
  2. Peter D Westenskow
  3. Marin L Gantner
  4. Yoshihiko Usui
  5. Andrew Schultz
  6. Stephen Bravo
  7. Edith Aguilar
  8. Carli Wittgrove
  9. Mollie SH Friedlander
  10. Liliana P Paris
  11. Emily Chew
  12. Gary Siuzdak
  13. Martin Friedlander
(2016)
Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration
eLife 5:e14319.
https://doi.org/10.7554/eLife.14319

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