LRG1 promotes epithelial-mesenchymal transition of retinal pigment epithelium cells by activating NOX4
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Hai-Feng Xu and Ling-Ling Yang. Shandong Eye Institute, 5 Yanerdao Road, Qingdao 266071, Shandong Province, China. chxhf@126.com; lingling6008@126.com

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Supported by the National Natural Science Foundation of China (No.81670828); the Shandong Provincial Key Research and Development Program (No.2017GSF18141); the Innovation Project of Shandong Academy of Medical Sciences and the National Science and Technology Major Project of China (No.2017ZX09304-010). Yang LL is partially supported by the Taishan Scholar Youth Professional Program (No.tspd20150215; No.tsgn20161059).

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    Abstract:

    AIM: To investigate the effect of leucine-rich-alpha-2-glycoprotein 1 (LRG1) on epithelial-mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells, and to explore the role of NADPH oxidase 4 (NOX4). METHODS: RPE cells (ARPE-19 cell line) were treated with transforming growth factor-β1 (TGF-β1) to induce EMT. Changes of the mRNA and protein expression levels of LRG1 were tested in the TGF-β1 treated cells. The recombinant human LRG1 protein (rLRG1) and siRNA of LRG1 were used to establish accumulation of exogenous LRG1 model and the down-regulation of LRG1 model in ARPE-19 cells respectively, and to detect EMT-related markers including fibronectin, α-smooth muscle actin (α-SMA) and zonula occludens-1 (ZO-1). The mRNA and protein expression level of NOX4 were measured according to the above treatments. VAS2870 was used as a NOX4 inhibitor in rLRG1-treated cells. EMT-related markers were detected to verify the effect of NOX4 in the process of EMT. RESULTS: TGF-β1 promoted the expression of LRG1 at both the mRNA and protein levels during the process of EMT which showed the up-regulation of fibronectin and α-SMA, as well as the down-regulation of ZO-1. Furthermore, the rLRG1 promoted EMT of ARPE-19 cells, which manifested high levels of fibronectin and α-SMA and low level of ZO-1, whereas knockdown of LRG1 prevented EMT by decreasing the expressions of fibronectin and α-SMA and increasing the expression of ZO-1 in ARPE-19 cells. Besides, the rLRG1 activated and LRG1 siRNA suppressed NOX4 expression. EMT was inhibited when VAS2870 was used in the rLRG1-treated cells. CONCLUSION: These results for the first time demonstrate that LRG1 promotes EMT of RPE cells by activating NOX4, which may provide a novel direction to explore the mechanisms of subretinal fibrosis.

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Li Zhou, De-Peng Shi, Wen-Juan Chu, et al. LRG1 promotes epithelial-mesenchymal transition of retinal pigment epithelium cells by activating NOX4. Int J Ophthalmol, 2021,14(3):349-355

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Publication History
  • Received:April 15,2020
  • Revised:October 14,2020
  • Adopted:
  • Online: February 24,2021
  • Published: