Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions.
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-kappaB 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-kappaB-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy.
Perrone
Lorena
L
Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Devi
Takhellambam S
TS
Hosoya
Ken-ichi
K
Terasaki
Tetsuya
T
Singh
Lalit P
LP
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002417:Cattle; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D018836:Inflammation Mediators; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493796:TXNIP protein, rat; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose