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Salutary effect of fenofibrate on type 1 diabetic retinopathy via inhibiting oxidative stress–mediated Wnt/β-catenin pathway activation

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Abstract

Fenofibrate has been shown to have therapeutic effects on diabetic retinopathy (DR). Our previous studies demonstrated that the oxidative stress–activated Wnt/β-catenin pathway plays a pathogenic role in diabetic complications. In the present study, we evaluate the effect and mechanism of fenofibrate on regulating the oxidative stress–activated Wnt/β-catenin pathway by using the genetic type 1 diabetes model of C57BL/6J-Ins2Akita mice and high glucose (HG)–treated ARPE-19. Our results demonstrated that retinal phosphorylation of LRP6 and nuclear β-catenin were increased in C57BL/6J-Ins2Akita mice suggesting activation of Wnt/β-catenin signaling. Meanwhile, C57BL/6J-Ins2Akita showed upregulation of oxidant enzyme Nox4 and Nox2 and downregulation of antioxidant enzyme SOD1 and SOD2. All these alterations were reversed in C57BL/6J-Ins2Akita mice with fenofibrate treatment. Moreover, fenofibrate significantly ameliorated diabetes-induced retinal vascular leakage in C57BL/6J-Ins2Akita mice. In cultured ARPE-19, fenofibrate decreased HG-induced Nox2 and Nox4 upregulation, attenuated SOD1 and SOD2 downregulation and inhibited LRP6 phosphorylation. Moreover, activation of Wnt/β-catenin by Wnt3a conditional medium (WCM) reduced SOD1 and SOD2 and did not affect Nox2 and Nox4. Fenofibrate suppressed WCM-induced LRP6 phosphorylation and reversed SOD downregulation. Importantly, Nox4 overexpression directly phosphorylated LPR6 in ARPE19; conversely, Nox4 knockdown suppressed HG-induced LPR6 phosphorylation. Taken together, Nox-mediated oxidative stress contributes to Wnt/β-catenin activation in DR. Fenofibrate ameliorated DR through coordinate attenuation of oxidative stress and blockade of Wnt/β-catenin signaling.

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Funding

This study was financially supported by NSFC Grants 81460163, 81741058, 81400427 and 81300786; Young Talent Scholar Grant from Shaanxi Science and Technology Department 2016KJXX-12; FRFCU Grant xjj2015015; RFDP Grant 20133601120012; Research Grants from Jiangxi Education Department GJJ14094, GJJ13175; Research Grants from Jiangxi Science and Technology Department 20142BDH80005, 20142BAB215029 and 20132BAB205024.

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  1. Qiuping Liu and Xian Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Affiliated Eye Hospital of Nanchang University, 463 Bayi Road, Nanchang, 330006, Jiangxi, China

    Qiuping Liu, Xian Zhang, Jinglin Yi & Jingming Li

  2. Department of Physiology, Health Sciences Center, University of Oklahoma, 941 Stanton L. Young Blvd, Oklahoma City, OK, 73104, USA

    Rui Cheng & Jian-xing Ma

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  1. Qiuping Liu
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  2. Xian Zhang
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Correspondence to Jinglin Yi or Jingming Li.

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Liu, Q., Zhang, X., Cheng, R. et al. Salutary effect of fenofibrate on type 1 diabetic retinopathy via inhibiting oxidative stress–mediated Wnt/β-catenin pathway activation. Cell Tissue Res 376, 165–177 (2019). https://doi.org/10.1007/s00441-018-2974-z

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