Targeting Keap1 by miR-626 protects retinal pigment epithelium cells from oxidative injury by activating Nrf2 signaling
| Autor: | Yun-fang Zhen, Xiang-zhong Xu, Ke-ran Li, Jin Yao, Yu Tang, Li-bo Cheng, Qin Jiang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Survival NF-E2-Related Factor 2 Apoptosis Retinal Pigment Epithelium Protective Agents medicine.disease_cause Biochemistry Retinal ganglion Macular Degeneration Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Physiology (medical) microRNA medicine Animals Humans Mice Knockout Kelch-Like ECH-Associated Protein 1 Retinal pigment epithelium Chemistry KEAP1 Cell biology MicroRNAs Oxidative Stress 030104 developmental biology medicine.anatomical_structure GCLC Gene Expression Regulation Case-Control Studies sense organs Protein stabilization Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Free Radical Biology and Medicine. 143:387-396 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2019.08.024 |
| Popis: | 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-19 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. |
| Databáze: | OpenAIRE |
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