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V. Poulaki, N. Mitsiades, E. Iliaki, C. S. Mitsiades, E. S. Gragoudas, J. W. Miller; TIMP3 Inhibits Vascular Leakage and Leukostasis in an Animal Model of Streptozotocin-Induced Diabetes. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1383.
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Diabetic retinopathy is one of the leading cause of blindness in adults and the vision loss frequently results from retinal vascular leakage and nonperfusion. Vascular endothelial growth factor VEGF) and tumor necrosis factor-α (TNF-α) play an important role in both processes. It was recently found that tissue metalloproteinase inhibitor-3 (TIMP3) inhibits the VEGF signal cascade by blocking its binding to the VEGF receptor 2. We studied the effects of TIMP3 in a streptozotocin (STZ)-induced rodent diabetes model.
Twelve days after the induction of diabetes with streptozotocin (STZ), rats received intravitreal injections of recombinant TIMP3 or the control protein (IgG). Blood retinal leakage (n=10) and leukostasis (n=12) were measured with the Evans Blue and concanavalin A perfusion method respectively two days after the injections. Retinal VEGF and TNF-α levels were measured with a commercially available ELISA method (n=8).
Intravitreal administration of 0.5µg TIMP3 reduced the diabetes-induced blood retinal barrier breakdown and vascular leakage in the STZ-induced diabetes model. In addition timp3 administration reduced the diabetes-induced upregulation of VEGF and TNF-α retinal levels.
The current study demonstrates that TIMP3 inhibits key manifestations of diabetic retinopathy such as vascular leakage and leukostasis by inhibiting the upregulation of angiogenic growth factors VEGF and TNF-α. Our findings underscore the potential role of TIMP3 in the treatment of diabetic retinopathy.
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