RGD Reference Report - Glutaredoxin regulates nuclear factor kappa-B and intercellular adhesion molecule in Muller cells: model of diabetic retinopathy. - Rat Genome Database

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Glutaredoxin regulates nuclear factor kappa-B and intercellular adhesion molecule in Muller cells: model of diabetic retinopathy.

Authors: Shelton, MD  Kern, TS  Mieyal, JJ 
Citation: Shelton MD, etal., J Biol Chem. 2007 Apr 27;282(17):12467-74. Epub 2007 Feb 26.
RGD ID: 9686046
Pubmed: (View Article at PubMed) PMID:17324929
DOI: Full-text: DOI:10.1074/jbc.M610863200

Reversible S-glutathionylation of proteins is a focal point of redox signaling and cellular defense against oxidative stress. This post-translational modification alters protein function, and its reversal (deglutathionylation) is catalyzed specifically and efficiently by glutaredoxin (GRx, thioltransferase), a thioldisulfide oxidoreductase. We hypothesized that changes in glutaredoxin might be important in the development of diabetic retinopathy, a condition characterized by oxidative stress. Indeed, GRx protein and activity were increased in retinal homogenates from streptozotocin-diabetic rats. Also, incubation of rat retinal Muller cells (rMC-1) in normal glucose (5 mm) or diabetic-like glucose (25 mm) medium led to selective upregulation of GRx in contrast to thioredoxin, the other thioldisulfide oxidoreductase system. Under analogous conditions, NF-kappaB (p50-p65) translocated to the nucleus, and expression of ICAM-1 (intercellular adhesion molecule-1), a transcriptional product of NF-kappaB, increased. Proinflammatory ICAM-1 is increased in diabetic retinae, and it is implicated in pathogenesis of retinopathy. To evaluate the role of GRx in mediating these changes, intracellular GRx content and activity in rMC-1 cells were increased independently under normal glucose via infection with an adenoviral GRx1 construct (Ad-GRx). rMC-1 cells exhibited adenovirus concentration-dependent increases in GRx and corresponding increases in NF-kappaB nuclear translocation, NF-kappaB luciferase reporter activity, and ICAM-1 expression. Blocking the increase in GRx1 via small interfering RNA in rMC-1 cells in high glucose prevented the increased ICAM-1 expression. These data suggest that redox regulation by glutaredoxin in retinal glial cells is perturbed by hyperglycemia, leading to NF-kappaB activation and a pro-inflammatory response. Thus, GRx may represent a novel therapeutic target to inhibit diabetic retinopathy.



Disease Annotations    

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Glrx  (glutaredoxin)

Genes (Mus musculus)
Glrx  (glutaredoxin)

Genes (Homo sapiens)
GLRX  (glutaredoxin)


Additional Information