Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions

Authors

  • Lorena Perrone,

    1. Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, Michigan
    Current affiliation:
    1. IPBS, CNRS UMR 5089, 205 Route de Narbonne, 31 077 Toulouse, France.
    Search for more papers by this author
  • Takhellambam S. Devi,

    1. Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, Michigan
    Search for more papers by this author
  • Ken-ichi Hosoya,

    1. Department of Pharmaceutics, University of Toyama, Toyama, Japan
    Search for more papers by this author
  • Tetsuya Terasaki,

    1. Department of Molecular Biopharmacy and Genetics, Tohoku University, Aoba, Japan
    Search for more papers by this author
  • Lalit P. Singh

    Corresponding author
    1. Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, Michigan
    2. Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan
    • Department of Anatomy/Cell Biology, Wayne State University School of Medicine, 540 East Canfield Avenue, #8332, Detroit, MI 48201.
    Search for more papers by this author

Abstract

Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-κB signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-κB-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262–272, 2009. © 2009 Wiley-Liss, Inc

Ancillary