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J. Biol. Chem., Vol. 282, Issue 17, 12467-12474, April 27, 2007

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Glutaredoxin Regulates Nuclear Factor -B and Intercellular Adhesion Molecule in Müller Cells

MODEL OF DIABETIC RETINOPATHY^*

Melissa D. Shelton, Timothy S. Kern, and John J. Mieyal¹

From the Departments of Pharmacology and Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

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 Müller 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-B (p50-p65) translocated to the nucleus, and expression of ICAM-1 (intercellular adhesion molecule-1), a transcriptional product of NF-B, 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-B nuclear translocation, NF-B 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-B activation and a pro-inflammatory response. Thus, GRx may represent a novel therapeutic target to inhibit diabetic retinopathy.

Received for publication, November 24, 2006 , and in revised form, February 23, 2007.

^* This work was supported by NIA, National Institutes of Health Grants R01 AG024413 and P01 AG 15885 (to J. J. M.), a Merit Review grant from the Department of Veteran's Affairs (to J. J. M.), and Visual Sciences Research Training Grant 5 T32 EY07157 from the NEI, National Institutes of Health (to M. D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine Case Western Reserve University, 2109 Adelbert Rd., WRT300-9, Cleveland, OH 44106-4965. Tel.: 216-368-3383; Fax: 216-368-3395; E-mail: JJM5{at}case.edu.

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