Unveiling Drivers of Retinal Degeneration in RCS Rats: Functional, Morphological, and Molecular Insights
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Published:2024-03-28
Issue:7
Volume:25
Page:3749
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Ahluwalia Kabir1ORCID, Du Zhaodong2ORCID, Martinez-Camarillo Juan Carlos23, Naik Aditya1, Thomas Biju B.23ORCID, Pollalis Dimitrios23ORCID, Lee Sun Young234, Dave Priyal1, Zhou Eugene1, Li Zeyang1, Chester Catherine1, Humayun Mark S.23, Louie Stan G.12ORCID
Affiliation:
1. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA 2. USC Ginsburg Institute of for Biomedical Therapeutics, University of Southern California, Los Angeles, CA 90033, USA 3. Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA 4. Department of Physiology & Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
Abstract
Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, significantly contribute to adult blindness. The Royal College of Surgeons (RCS) rat is a well-established disease model for studying these dystrophies; however, molecular investigations remain limited. We conducted a comprehensive analysis of retinal degeneration in RCS rats, including an immunodeficient RCS (iRCS) sub-strain, using ocular coherence tomography, electroretinography, histology, and molecular dissection using transcriptomics and immunofluorescence. No significant differences in retinal degeneration progression were observed between the iRCS and immunocompetent RCS rats, suggesting a minimal role of adaptive immune responses in disease. Transcriptomic alterations were primarily in inflammatory signaling pathways, characterized by the strong upregulation of Tnfa, an inflammatory signaling molecule, and Nox1, a contributor to reactive oxygen species (ROS) generation. Additionally, a notable decrease in Alox15 expression was observed, pointing to a possible reduction in anti-inflammatory and pro-resolving lipid mediators. These findings were corroborated by immunostaining, which demonstrated increased photoreceptor lipid peroxidation (4HNE) and photoreceptor citrullination (CitH3) during retinal degeneration. Our work enhances the understanding of molecular changes associated with retinal degeneration in RCS rats and offers potential therapeutic targets within inflammatory and oxidative stress pathways for confirmatory research and development.
Funder
California Institute for Regenerative Medicine National Science Foundation USC Center for Neuronal Longevity Research to Prevent Blindness National Eye Institute Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics Dennis and Michele Slivinski Dr. Ramani Nathan The Retina Research Foundation’s Gertrude D. Pyron Award Department of Defense
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