MiRNA-141 attenuates UV-induced oxidative stress via activating Keap1-Nrf2 signaling in human retinal pigment epithelium cells and retinal ganglion cells.

Li-Bo Cheng,Feng Wang,Xiu-Miao Li,Nan Yi,Jin Yao,Bo Xue,Qin Jiang,Zhi-Feng Wu,Ying-Shun Pan,Ke-Ran Li

doi:10.18632/oncotarget.14489

Abstract

Activation of NF-E2-related factor 2 (Nrf2) signaling could protect cells from ultra violet (UV) radiation. We aim to provoke Nrf2 activation via downregulating its inhibitor Keap1 by microRNA-141 (“miR-141”). In both human retinal pigment epithelium cells (RPEs) and retinal ganglion cells (RGCs), forced-expression of miR-141 downregulated Keap1, causing Nrf2 stabilization, accumulation and nuclear translocation, which led to transcription of multiple antioxidant-responsive element (ARE) genes (HO1, NOQ1 and GCLC). Further, UV-induced reactive oxygen species (ROS) production and cell death were significantly attenuated in miR-141-expressing RPEs and RGCs. On the other hand, depletion of miR-141 via expressing its inhibitor antagomiR-141 led to Keap1 upregulation and Nrf2 degradation, which aggravated UV-induced death of RPEs and RGCs. Significantly, Nrf2 shRNA knockdown almost abolished miR-141-mediated cytoprotection against UV in RPEs. These results demonstrate that miR-141 targets Keap1 to activate Nrf2 signaling, which protects RPEs and RGCs from UV radiation.

Highlights

Existing evidences have shown that excessive ultra violet (UV) radiation may induce direct damages to resident retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs) [1, 2], which is the major contributor of retinal degeneration [3,4,5]
Two stable RGC cell lines expressing miR-141 were established: miR-141-L1/ L2 RGCs. These RGCs again expressed high level of miR141 (Figure 1C), but depleted Keap1 (Figure 1D). These results clearly show that forced-expression of miR-141 downregulated Keap1 in both human RPEs and RGCs
We showed that miR-141 expression activated NF-E2-related factor 2 (Nrf2) signaling in both RPEs and RGCs

Summary

Introduction

Existing evidences have shown that excessive ultra violet (UV) radiation may induce direct damages to resident retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs) [1, 2], which is the major contributor of retinal degeneration [3,4,5]. Growth evidences have demonstrated that UV radiation in RPEs and RGCs promotes reactive oxygen species (ROS) production, which leads to cell apoptosis [1, 2, 6,7,8,9,10]. NF-E2-related factor 2 (Nrf2) transcriptionally controls the expression of several key anti-oxidative enzymes [11,12,13]. Expression of these enzymes, i.e. heme oxygenase-1 (HO1), NAD(P)H quinone oxidoreductase 1. Activated Nrf, for example via phosphorylation at Ser, disassociates with Keap, causing Nrf stabilization and accumulation [11,12,13]. Nrf will translocate to nuclei and binds to antioxidant-responsive element (ARE), dictating transcription of the above enzymes [11,12,13]

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