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J. Liu, D. Marcus, M. Labazi, M. Rojas, T. Lemtalsi, R. B. Caldwell, M. Bartoli; Diabetes-Induced Increases in Retinal Expression of VEGF and ICAM-1 and Vascular Permeability Is Inhibited by Selective Blockade of STAT3 Activity. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4984.
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Hyperglycemia-induced expression of VEGF and of the intercellular adhesion molecule 1 (ICAM-1) significantly contribute to the etiology of diabetic retinopathy (DR) by inducing retinal vascular inflammation and permeability. The signal transducer and activator of transcription 3 (STAT3) has been shown to be a critical modulator of inflammatory responses in several cell types and an important regulator of VEGF expression and activity. In order to establish STAT3’s role in the development of DR, we analyzed the effects of selective inhibition of STAT3 transcriptional activity on VEGF and ICAM-1 expression and vascular permeability in the diabetic rat retina.
We conducted experiments on streptozotocin-induced diabetic rats (STZ-rats) and in age-matched normoglycemic control rats. Selective inhibition of STAT3 transcriptional activity was obtained by in vivo over-expression of the transcriptionally inactive mutant STAT3D. Retinal gene transduction was achieved by intravitreal (ivt) injection of 109 particles of adenovirus carrying the dominant negative STAT3D (adSTAT3D) or the reporter gene (adGFP). Ivt. injections were performed after 1 week of hyperglycemia and the animals were sacrifice 1 week later. Retinas were excised and processed for Western blotting and immunohystochemical analyses to assess and quantify expression of ICAM-1 and VEGF. In addition, vascular permeability was measured by assessing extravasation of FITC albumin.
Gene transduction in the injected retinas was detected 48 hours after ivt injection and persisted after 1 week. VEGF and ICAM-1 protein levels were significantly increased after 2 weeks of diabetes as compared with controls. Ivt injection of adSTAT3D blocked hyperglycemia -induced expression of VEGF and ICAM-1 whereas ivt injections with adGFP had no effect. In addition we found that increased vascular permeability in the diabetic rats was inhibited by the ivt injection with adSTAT3D but not with adGFP.
Our results demonstrate that selective inhibition of STAT3 transcriptional activity prevents expression of VEGF and ICAM -1 in the diabetic retina and significantly inhibits hyperglycemia-induced vascular permeability. These data, therefore, suggest a critical role for STAT3 in the development of DR.
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