June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Expression and Regulation of Humanin Nuclear Isoform Genes in the RPE and Age-related Macular Degeneration
Author Affiliations & Notes
  • Sarah Xin Zhang
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
    Department of Biochemistry and Neuroscience Program, University at Buffalo, Buffalo, New York, United States
  • Brian Unruh
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
  • Kathyrn Arthur
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
  • Joshua Wang
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
  • Ivana K Kim
    Retina Service, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Leah Owen
    Department of Ophthalmology and Visual Sciences, The University of Utah School of Medicine, Salt Lake City, Utah, United States
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
  • Michael H Farkas
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
    Veterans Administration Western New York Healthcare System, Buffalo, New York, United States
  • Margaret M DeAngelis
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, New York, United States
    Veterans Administration Western New York Healthcare System, Buffalo, New York, United States
  • Footnotes
    Commercial Relationships   Sarah Zhang None; Brian Unruh None; Kathyrn Arthur None; Joshua Wang None; Ivana Kim None; Leah Owen None; Michael Farkas None; Margaret DeAngelis None
  • Footnotes
    Support  NIH/NEI Grants EY019949, EY025061, EY030970, and an Unrestricted Grant to the Department of Ophthalmology, the State University of New York at Buffalo, from Research to Prevent Blindness, Macular Degeneration Foundation Inc., Carl Marshall Reeves Foundation
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2740. doi:
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    • Get Citation

      Sarah Xin Zhang, Brian Unruh, Kathyrn Arthur, Joshua Wang, Ivana K Kim, Leah Owen, Michael H Farkas, Margaret M DeAngelis; Expression and Regulation of Humanin Nuclear Isoform Genes in the RPE and Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2740.

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

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Abstract

Purpose : The intrinsic mechanisms and genetic factors that govern the RPE homeostasis and function play a vital role in the pathogenesis of age-related macular degeneration (AMD). Recent studies show that humanin (MTRNR2), a mitochondrial-derived peptide, protects against oxidative damage of the RPE. Herein, we investigate the expression and regulation of humanin and its 13 nuclear-encoded isoform genes (MTRNR2L), in human donor eyes with AMD and in the RPE.

Methods : RNA-sequencing was performed on macular RPE/choroid and macular neural retina from 27 well-characterized donor eyes with various clinical stages of AMD or normal controls. All donor eyes were recovered within 6 hours post-mortem interval, phenotyped, and processed using a standardized published protocol. Bioinformatic and statistical analyses including DESeq2, followed by PCA, Benjamini Hockberg Analysis, and Bonferonni correction were applied to resultant data. Human RPE (ARPE-19 and iPSC-derived RPE) cells were cultured and challenged with AMD-pertinent stress conditions induced by 4-hydroxynonenal (4-HNE) and hypoxia. Gene expression levels were evaluated by quantitative real-time PCR.

Results : RNA-seq analysis identified 1204 differential gene expression (DEG) genes in neovascular AMD (n=5) and 40 DEG genes in intermediate AMD (AREDS3, n=10) compared to normal eyes (n=12). Among all DEG genes, MTRNR2L1 was found to have the highest upregulation in the RPE/choroid as well as in the retina in both stages of AMD. A significant decrease in MTRNR2L12 expression was observed in the RPE of AREDS3 eyes vs neovascular AMD. There was no change in humanin-encoded MTRNR2 gene in AMD eyes. Intriguingly, the levels of MTRNR2L2, MTRNR2L3, MTRNR2L6, MTRNR2L8, MTRNR2L10, and MTRNR2L12 in the RPE/choroid are significantly higher than in the retina in normal donor eyes. In cultured RPE cells, both 4-HNE (50 μM) and hypoxia (1% oxygen) treatments, pertinent to AREDS3 and neovascular AMD respectively, for 24 - 72 hrs significantly increased MTRNR2L1 and MTRNR2L12 expression (n=3, p<0.05).

Conclusions : Our results show significant changes in the expression of humanin nuclear isoform genes in the RPE, regulated by oxidative stress and hypoxia, during AMD progression. Studies to characterize the functional implications of these genes, in particular MTRNR2L1 and MTRNR2L12, may identify new mechanisms and therapeutic targets for RPE protection in AMD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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