Upregulation of CKIP-1 inhibits high-glucose induced inflammation and oxidative stress in HRECs and attenuates diabetic retinopathy by modulating Nrf2/ARE signaling pathway: An in vitro study

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Abstract

Purpose: The aim of this study was to investigate the underlying mechanisms of diabetic retinopathy (DR) development. Methods: Real-Time qPCR was used to detect Casein kinase 2 interacting protein-1 (CKIP-1) and Nuclear factor E2-related factor 2 (Nrf2) mRNA levels. Western Blot was employed to detect protein levels. Malondialdehyde (MDA) assay kit, superoxide dismutase (SOD) kit and glutathione peroxidase (GSH-Px) kit were used to evaluate oxidative stress in high-glucose treated human retinal endothelial cells (HRECs). Calcein-AM/propidium iodide (PI) double stain kit was employed to detect cell apoptosis. Enzyme-linked ImmunoSorbent Assay (ELISA) was used to detect inflammation associated cytokines secretion. Co-immunoprecipitation (CO-IP) was performed to investigate the interactions between CKIP-1 and Nrf2. Luciferase reporter gene system was used to detect the transcriptional activity of Nrf2. Results: CKIP-1 was significantly downregulated in either DR tissues or high-glucose treated HRECs comparing to the Control groups. Besides, high-glucose (25 mM) inhibited HRECs viability and induced oxidative stress, inflammation associated cytokines (TNF-α, IL-6 and IL-1β) secretion and cell apoptosis, which were all reversed by synergistically overexpressing CKIP-1 and aggravated by knocking down CKIP-1. Of note, we found that overexpressed CKIP-1 activated Nrf2/ARE signaling pathway and increased its downstream targets including HO-1, NQO-1, γGCS and SOD in high-glucose treated HRECs. Further results also showed that CKIP-1 regulated cell viability, oxidative stress, inflammation and apoptosis in high-glucose treated HRECs by activating Nrf2/ARE signaling pathway. Conclusion: We concluded that overexpressed CKIP-1 alleviated DR progression by activating Nrf2/ARE signaling pathway.

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Zhang, L., Yu, J., Ye, M., & Zhao, H. (2019). Upregulation of CKIP-1 inhibits high-glucose induced inflammation and oxidative stress in HRECs and attenuates diabetic retinopathy by modulating Nrf2/ARE signaling pathway: An in vitro study. Cell and Bioscience, 9(1). https://doi.org/10.1186/s13578-019-0331-x

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