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Arup Das, Sampathkumar Rangasamy, Joann Maestas, Paul McGuire; CC Chemokines Play an Important Role in Alteration of The Blood-Retinal Barrier in Diabetes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):997.
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Alteration of the blood-retinal barrier and increased vascular permeability is the hallmark of diabetic macular edema (DME). Currently, VEGF is considered an important therapeutic target for the treatment of DME. This study examined the role of various other factors beyond VEGF in the pathogenesis of DME.
Sprague-Dawley rats were made diabetic by streptozotocin injection. Human retinal microvascular endothelial cells (HREC) were examined under hyperglycemic condition (30.5 mM glucose). The expression of angiogenesis/cytokine related genes was analyzed using PCR based microarrays. MMP activity in the rat retina was measured after the intraocular injection of CCl2. Further, to study the role of CCL2 in the alteration of blood-retinal barrier, Ccl2–/– mice were made diabetic and the retinal vascular permeability was measured using FITC-BSA.
The Cytokine gene array revealed that CC chemokines (CCL2, CCL5 and CCL7) were significantly up-regulated in the retinas of rats with 4 weeks of diabetes. In HRECs, the expression of CCl2 was significantly increased by two fold with hyperglycemia. We also found that intravitreal injection of recombinant CCl2 in rat eyes leads to the upregulation MMP 2 and 9. Importantly, CCl2 knockout mice made diabetic have significantly less retinal vascular leakage, indicating the important role of this chemokine in alteration of the blood-retinal barrier.
We conclude that diabetes up-regulates the CC chemokine expression in the retinas, and the increased concentration of CC chemokines play an important role in the BRB breakdown. The genetic deletion of CCl2 prevents the diabetes-induced alteration in the blood retinal barrier. Thus, CC chemokines may serve as an important therapeutic target for diabetic retinopathy.
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