July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
NRF-2/PGC-1α deficiency induces retinal degeneration in mice
Author Affiliations & Notes
  • Niko Kivinen
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
    Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
  • Szabolcs Felszeghy
    Institute of Dentistry, University of Eastern Finland, Kuopio, Finland
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
  • Jussi Paterno
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
    Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
  • Johanna Viiri
    Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
  • Mei Chen
    Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
  • Debasish Sinha
    The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Deborah A. Ferrington
    Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States
  • Ram Kannan
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California, United States
  • Anu Kauppinen
    School of Pharmacy, University of Eastern Finland, Kuopio, Finland
  • Kai Kaarniranta
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
    Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
  • Footnotes
    Commercial Relationships   Niko Kivinen, None; Szabolcs Felszeghy, None; Jussi Paterno, None; Johanna Viiri, None; Mei Chen, None; Debasish Sinha, None; Deborah Ferrington, None; Ram Kannan, None; Anu Kauppinen, None; Kai Kaarniranta, None
  • Footnotes
    Support  Kuopio University Hospital Grant number 5503743, the Finnish Eye Foundation, the Finnish Funding Agency for Technology and Innovation, the Health Research Council of the Academy of Finland Grant Numbers 218050 and 296840, the Päivikki and Sakari Sohlberg Foundation, the Evald and Hilda Nissi Foundation and the Finnish Cultural Foundation-North-Savo
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2455. doi:
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    • Get Citation

      Niko Kivinen, Szabolcs Felszeghy, Jussi Paterno, Johanna Viiri, Mei Chen, Debasish Sinha, Deborah A. Ferrington, Ram Kannan, Anu Kauppinen, Kai Kaarniranta; NRF-2/PGC-1α deficiency induces retinal degeneration in mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2455.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The pathogenesis of dry AMD includes degeneration of the retinal pigment epithelium (RPE), that secondarily leads to loss of rods and cones (photoreceptors). RPE cells are constantly exposed to oxidative stress that could cause damage to cellular proteins, DNA, and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome and the lysosomal/autophagosomal pathways are the two major proteolytic systems that are responsible for removing damaged molecules. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of proteins involved in cellular detoxification. In this study, we examined the role of NRF-2 and PGC-1α in the regulation of RPE cell structure and function by using global double knockout (dKO) mice.

Methods : Light, confocal, and electron microscopy were used to examine microscopic anatomy and age-related RPE degeneration. . Immunohistochemical methods were used to study markers of oxidative stress (4-HNE (4-hydroxynonenal)), endoplasmic reticulum stress (GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4)), proteasome(ubiquitin), autophagy (p62/SQSTM1(sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta)) and macrophages (Iba-1) . Micro-MRI imaging was performed to find possible macroscopic differences between the dKO and WT mice.

Results : The NRF-2/PGC-1α dKO mice showed significant age-related RPE degeneration, accumulation of the oxidative stress marker (4-HNE) as well as endoplasmic reticulum stress markers GRP78 and ATF4. Furthermore, levels of protein ubiquitination and autophagy markers p62/SQSTM1, Beclin-1 and LC3B were significantly increased together with Iba-1 (ionized calcium binding adaptor molecule 1) macrophage marker staining. RPE cell size was also increased, suggesting more cell death occurred in the dKO mouse.

Conclusions : The RPE degeneration/phenotype in the NRF-2/PGC-1α dKO mouse replicates key features of dry AMD and thus, may be a valuable model for investigating the mechanism behind development of dry AMD.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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