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Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration.

Authors
  • Jadeja, Ravirajsinh N1
  • Jones, Malita A2
  • Abdelrahman, Ammar A3
  • Powell, Folami L2
  • Thounaojam, Menaka C4
  • Gutsaeva, Diana4
  • Bartoli, Manuela5
  • Martin, Pamela M6
  • 1 Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. Electronic address: [email protected] , (Georgia)
  • 2 Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. , (Georgia)
  • 3 Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. , (Egypt)
  • 4 Departments of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. , (Georgia)
  • 5 Departments of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA; Department of Culver Vision Discovery Institute and Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. , (Georgia)
  • 6 Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA; Departments of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA; Department of Culver Vision Discovery Institute and Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA; Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. Electronic address: [email protected] , (Georgia)
Type
Published Article
Journal
Redox Biology
Publisher
Elsevier
Publication Date
Sep 29, 2019
Volume
28
Pages
101336–101336
Identifiers
DOI: 10.1016/j.redox.2019.101336
PMID: 31590045
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The retinal pigment epithelium (RPE) is consistently exposed to high levels of pro-oxidant and inflammatory stimuli. As such, under normal conditions the antioxidant machinery in the RPE cell is one of the most efficient in the entire body. However, antioxidant defense mechanisms are often impacted negatively by the process of aging and/or degenerative disease leaving RPE susceptible to damage which contributes to retinal dysfunction. Thus, understanding better the mechanisms governing antioxidant responses in RPE is critically important. Here, we evaluated the role of the redox sensitive microRNA miR-144 in regulation of antioxidant signaling in human and mouse RPE. In cultured human RPE, miR-144-3p and miR-144-5p expression was upregulated in response to pro-oxidant stimuli. Likewise, overexpression of miR-144-3p and -5p using targeted miR mimics was associated with reduced expression of Nrf2 and downstream antioxidant target genes (NQO1 and GCLC), reduced levels of glutathione and increased RPE cell death. Alternately, some protection was conferred against the above when miR-144-3p and miR-144-5p expression was suppressed using antagomirs. Expression analyses revealed a higher conservation of miR-144-3p expression across species and additionally, the presence of two potential Nrf2 binding sites in the 3p sequence compared to only one in the 5p sequence. Thus, we evaluated the impact of miR-144-3p expression in the retinas of mice in which a robust pro-oxidant environment was generated using sodium iodate (SI). Subretinal injection of miR-144-3p antagomir in SI mice preserved retinal integrity and function, decreased oxidative stress, limited apoptosis and enhanced antioxidant gene expression. Collectively, the present work establishes miR-144 as a potential target for preventing and treating degenerative retinal diseases in which oxidative stress is paramount and RPE is prominently affected (e.g., age-related macular degeneration and diabetic retinopathy). Copyright © 2019. Published by Elsevier B.V.

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