Targeting Keap1 by miR-626 protects retinal pigment epithelium cells from oxidative injury by activating Nrf2 signaling.
Free Radic Biol Med
; 143: 387-396, 2019 11 01.
Article
em En
| MEDLINE
| ID: mdl-31446056
ABSTRACT
Activation of the NF-E2-related factor 2 (Nrf2) cascade can offer significant protection against oxidative stress in retinal pigment epithelium (RPE) cells. Here, we identified a novel kelch-like ECH-associated protein 1 (Keap1)-targeting microRNA, microRNA-626 (miR-626) that activates Nrf2 signaling. In ARPE-19â¯cells and primary human RPE cells, ectopic overexpression of miR-626 targeting the 3'-UTR (3'-untranslated region) of Keap1 downregulated its expression, promoting Nrf2 protein stabilization and nuclear translocation, leading to expression of ARE-dependent genes (HO1, NOQ1 and GCLC). Functional studies showed that miR-626 protected RPE cells from hydrogen peroxide (H2O2)-induced oxidative injury. Conversely, miR-626 inhibition induced Keap1 upregulation and Nrf2 cascade inhibition, exacerbating oxidative injury in RPE cells. Further studies demonstrated that miR-626 was ineffective in Keap1-knockout or Nrf2-knockout RPE cells. Importantly, miR-626 also activated Keap1-Nrf2 signaling cascade in human lens epithelial cells (HLECs) and primary human retinal ganglion cells (RGCs), providing protection from H2O2. At last, we show that plasma miR-626 levels are significantly downregulated in age-related macular degeneration (AMD) patients than those in the healthy donors. We conclude that targeting Keap1 by miR-626 protects RPE cells and other ophthalmic cells from oxidative injury via activation of Nrf2 signaling cascade.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Oxidativo
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Substâncias Protetoras
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MicroRNAs
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Fator 2 Relacionado a NF-E2
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Epitélio Pigmentado da Retina
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Proteína 1 Associada a ECH Semelhante a Kelch
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Degeneração Macular
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article