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DHA Inhibited AGEs-Induced Retinal Microglia Activation Via Suppression of the PPARγ/NFκB Pathway and Reduction of Signal Transducers in the AGEs/RAGE Axis Recruitment into Lipid Rafts

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Abstract

Recent studies revealed that dietary intake of docosahexaenoic acid (DHA) prevented diabetic retinopathy (DR), but the underlying mechanism was not fully understood. Retinal microglia are a specialized population of macrophages in retina. Considerable evidence has shown that microglia activation may trigger neuronal death and vascular dysfunction in DR. The aim of this study was to investigate the effects of DHA on advanced glycation end products (AGEs)-induced microglia activation using an in vitro microglia culture system, and concurrently to explore the mediating mechanisms. DHA inhibited AGEs-induced microglia activation and tumor necrosis factor α (TNFα) secretion. These effects of DHA were directly linked with suppression of nuclear factor-kappa B (NFκB) activity, as evident by the reduction of p-IκBα expression, p-NFκB p65 nucleus translocation, NFκB DNA binding activity, and the regulation of gene transcription (TNFα, IL-1β, ICAM-1, and RAGE mRNA). Furthermore, DHA significantly increased phosphorylation of peroxisome proliferator-activated receptor-gamma (PPARγ), and combined with PPARγ stealth RNAi oligonucleotide, we confirmed that DHA inhibition of AGEs-induced microglia activation was partially through the PPARγ/NFκB pathway. Moreover, although AGEs incubation dramatically elevated expression of the cell surface receptor for AGEs (RAGE), DHA significantly inhibited RAGE and Src recruitment into lipid rafts. The AGEs–RAGE axis downstream signal transducers increased mitogen-activated protein kinase (p38 and JNK) phosphorylation. Taken together, DHA might inhibit AGEs-induced microglia activation via suppression of the PPARγ/NFκB pathway, and reduction of RAGE and AGEs/RAGE transducer recruitment into lipid rafts. These results provide a novel potential mechanism for the anti-inflammatory effects of DHA in DR prevention.

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Acknowledgments

This work was funded by a research Grant from the Foundation of Chongqing Science and Technology Commission (CSTC2010BB5167).

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The authors declare that there are no conflict of interest.

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    Authors and Affiliations

    1. Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Shapingba District, Chongqing, 400038, People’s Republic of China

      Li Wang, Ka Chen, Kai Liu, Yong Zhou, Ting Zhang, Bin Wang & Mantian Mi

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    1. Li Wang
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    2. Ka Chen
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    3. Kai Liu
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    Correspondence to Ka Chen or Mantian Mi.

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    Li Wang and Ka Chen have contributed equally in this paper.

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    Wang, L., Chen, K., Liu, K. et al. DHA Inhibited AGEs-Induced Retinal Microglia Activation Via Suppression of the PPARγ/NFκB Pathway and Reduction of Signal Transducers in the AGEs/RAGE Axis Recruitment into Lipid Rafts. Neurochem Res 40, 713–722 (2015). https://doi.org/10.1007/s11064-015-1517-1

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