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A. Das, S. Rangasamy, J. Maestas, P. McGuire; The Chemokine Ccl2/MCP-1: A Possible Therapeutic Target in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3829.
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One of the hallmarks of diabetic retinopathy is the alteration of the blood-retinal barrier resulting in macular edema. Although the VEGF has been identified as an important mediator of this process, other molecules may also play a role. In this study, we examined the angiogenesis related gene expression in retinas of diabetic rats. Furthermore, we investigated in depth one of the most upregulated proteins, Ccl2 (MCP-1), and the molecular mechanisms of the actions of this molecule.
Diabetes was induced in Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Human retinal microvascular endothelial cells (HREC) were grown to confluence, and treated with high glucose (30.5 mM) for 5 days. RNA was extracted from the rat retina and HREC. The expression pattern of angiogenesis related gene was analyzed using PCR based arrays from SA Biosciences.
The rat angiogenesis array revealed that the Ccl2 gene was significantly up-regulated in the retinas of rats with 4 weeks (p=0.005) and 8 weeks (p=0.02) of diabetes by more than 20 fold over the non-diabetic group. We found that the Ccl2 is most prominently up-regulated compared to other genes. We also found that Ccl2 gene was significantly increased (p<0.01) by more than two fold in HRECs treated with high glucose for 5 days compared to low glucose treated cells. Furthermore, angiopoetin-2 (Ang-2), an important vasopermeability factor, significantly up-regulated the expression of Ccl2 in the HRECs.
Hyperglycemia induces the expression of Ccl2 in the retina of diabetic rats at early stages as well as in isolated human retinal endothelial cells. We also find that Ang-2 upregulated the Ccl2 expression indicating a cross talk between Ccl2 and Ang-2. An understanding of the role of Ccl2 during the early stages of diabetic retinopathy may help us to elucidate the molecular mechanisms and possibly lead to the development of novel therapeutic targets for this disease.
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