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Activation of NFkB and Increased Pro‐Inflammatory ICAM‐1 in Retinal Glial (Müller) Cells in High Glucose, a Model of Diabetic Retinopathy, is Mediated via Upregulation of Glutaredoxin
Author(s) -
Shelton Melissa DeAnn,
Kern Timothy S,
Mieyal John J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1036
Subject(s) - glutaredoxin , oxidative stress , microbiology and biotechnology , txnip , downregulation and upregulation , thioredoxin , chemistry , nf κb , retinal , nfkb1 , intercellular adhesion molecule 1 , signal transduction , cell adhesion molecule , biology , biochemistry , transcription factor , gene
Reversible S‐glutathionylation of proteins (protein‐SSG) is central to redox signaling, and cellular defense against oxidative stress (Shelton et al . 2005). This modification alters protein function, and its reversal (de‐glutathionylation) is catalyzed specifically and efficiently by glutaredoxin (GRx). We hypothesize that changes in GRx are important in diabetic retinopathy (DR), a disease of oxidative stress. GRx is increased in homogenized retinas from streptozotocin‐diabetic rats and in rat retinal glial Müller cells cultured in diabetic‐like conditions (25mM glucose), while the thioredoxin system does not change. Müller cells in 25mM glucose also display increased NFκB nuclear translocation and expression of ICAM‐1 (intercellular adhesion molecule), an inflammatory molecule associated with DR lesions and transcribed by NFκB. GRx overexpression in cells in normal glucose (5 mM) leads to increased NFκB luciferase activity and nuclear translocation, and ICAM‐1 expression, suggesting that GRx regulates NFκB via deglutathionylation of NFκB or upstream mediators. Knocking down GRx in 25mM glucose prevented induction of GRx and ICAM‐1, implicating GRx as a therapeutic target in DR. We are currently testing inhibitors at various steps of the NFκB pathway to investigate the mechanism of GRx regulation. Supported by NEI 5 T32 EY07157 (MDS); NIH PO1 AG 15885, R01 AG024413 , and VA Merit Review (JJM).