Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231719308687 |
| _version_ | 1819014475449106432 |
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| author | Ravirajsinh N. Jadeja Malita A. Jones Ammar A. Abdelrahman Folami L. Powell Menaka C. Thounaojam Diana Gutsaeva Manuela Bartoli Pamela M. Martin |
| author_facet | Ravirajsinh N. Jadeja Malita A. Jones Ammar A. Abdelrahman Folami L. Powell Menaka C. Thounaojam Diana Gutsaeva Manuela Bartoli Pamela M. Martin |
| author_sort | Ravirajsinh N. Jadeja |
| collection | DOAJ |
| description | 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). Keywords: Nrf2, Oxidative stress, microRNA, miR-144, Retinal pigment epithelium, RPE |
| first_indexed | 2024-12-21T02:16:26Z |
| format | Article |
| id | doaj.art-ec994286402a463f82b458cbbb257d5d |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-21T02:16:26Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-ec994286402a463f82b458cbbb257d5d2022-12-21T19:19:16ZengElsevierRedox Biology2213-23172020-01-0128Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degenerationRavirajsinh N. Jadeja0Malita A. Jones1Ammar A. Abdelrahman2Folami L. Powell3Menaka C. Thounaojam4Diana Gutsaeva5Manuela Bartoli6Pamela M. Martin7Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA; Corresponding author.Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USADepartments 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, EgyptDepartments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USADepartments of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USADepartments of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USADepartments 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, USADepartments 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; Corresponding author. Departments of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.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). Keywords: Nrf2, Oxidative stress, microRNA, miR-144, Retinal pigment epithelium, RPEhttp://www.sciencedirect.com/science/article/pii/S2213231719308687 |
| spellingShingle | Ravirajsinh N. Jadeja Malita A. Jones Ammar A. Abdelrahman Folami L. Powell Menaka C. Thounaojam Diana Gutsaeva Manuela Bartoli Pamela M. Martin Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration Redox Biology |
| title | Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration |
| title_full | Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration |
| title_fullStr | Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration |
| title_full_unstemmed | Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration |
| title_short | Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration |
| title_sort | inhibiting microrna 144 potentiates nrf2 dependent antioxidant signaling in rpe and protects against oxidative stress induced outer retinal degeneration |
| url | http://www.sciencedirect.com/science/article/pii/S2213231719308687 |
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