GEP100/ARF6 regulates VEGFR2 signaling to facilitate high-glucose-induced epithelial-mesenchymal transition and cell permeability in retinal pigment epithelial cells

Author:

You Zhi-Peng1,Chen Shan-Shan1,Yang Zhong-Yi1,Li Shu-Rong1,Xiong Fan1,Liu Ting1,Fu Shu-Hua1ORCID

Affiliation:

1. Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China

Abstract

Cell permeability and epithelial-mesenchymal transition (EMT) were found to be enhanced in diabetic retinopathy, and the aim of this study was to investigate the underlying mechanism. ARPE-19 cell line or primary retinal pigment epithelial (RPE) cells were cultured under high or normal glucose conditions. Specific shRNAs were employed to knock down ADP-ribosylation factor 6 (ARF6), GEP100, or VEGF receptor 2 (VEGFR2) in ARPE-19 or primary RPE cells. Cell migration ability was measured using Transwell assay. Western blotting was used to measure indicated protein levels. RPE cells treated with high glucose showed increased cell migration, paracellular permeability, EMT, and expression of VEGF. Knockdown of VEGFR2 inhibited the high-glucose-induced effects on RPE cells via inactivation of ARF6 and MAPK pathways. Knockdown ARF6 or GEP100 led to inhibition of high-glucose-induced effects via inactivation of VEGFR2 pathway. Knockdown of ARF6, but not GEP100, decreased high-glucose-induced internalization of VEGFR2. High-glucose enhances EMT and cell permeability of RPE cells through activation of VEGFR2 and ARF6/GEP100 pathways, which form a positive feedback loop to maximize the activation of VEGF/VEGFR2 signaling.

Funder

National Natural Science Foundation of China (NSFC)

The Natural Science Foundation Key Program of Jiangxi Province

The Natural Science Foundation of Jiangxi Province

The Scientific Research Program of the Second Affiliated Hospital of Nanchang University

The Scientific Research Program of Jiangxi Health and Family Planning Commission

Doctor Start-up Fund of the Second Affiliated Hospital of Nanchang University

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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