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      Intervention With an Erythropoietin-Derived Peptide Protects Against Neuroglial and Vascular Degeneration During Diabetic Retinopathy

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          Abstract

          OBJECTIVE

          Erythropoietin (EPO) may be protective for early stage diabetic retinopathy, although there are concerns that it could exacerbate retinal angiogenesis and thrombosis. A peptide based on the EPO helix-B domain (helix B-surface peptide [pHBSP]) is nonerythrogenic but retains tissue-protective properties, and this study evaluates its therapeutic potential in diabetic retinopathy.

          RESEARCH DESIGN AND METHODS

          After 6 months of streptozotocin-induced diabetes, rats ( n = 12) and age-matched nondiabetic controls ( n = 12) were evenly split into pHBSP and scrambled peptide groups and injected daily (10 μg/kg per day) for 1 month. The retina was investigated for glial dysfunction, microglial activation, and neuronal DNA damage. The vasculature was dual stained with isolectin and collagen IV. Retinal cytokine expression was quantified using real-time RT-PCR. In parallel, oxygen-induced retinopathy (OIR) was used to evaluate the effects of pHBSP on retinal ischemia and neovascularization (1–30 μg/kg pHBSP or control peptide).

          RESULTS

          pHBSP or scrambled peptide treatment did not alter hematocrit. In the diabetic retina, Müller glial expression of glial fibrillary acidic protein was increased when compared with nondiabetic controls, but pHBSP significantly reduced this stress-related response ( P < 0.001). CD11b+ microglia and proinflammatory cytokines were elevated in diabetic retina responses, and some of these responses were attenuated by pHBSP ( P < 0.01–0.001). pHBSP significantly reduced diabetes-linked DNA damage as determined by 8-hydroxydeoxyguanosine and transferase-mediated dUTP nick-end labeling positivity and also prevented acellular capillary formation ( P < 0.05). In OIR, pHBSP had no effect on preretinal neovascularization at any dose.

          CONCLUSIONS

          Treatment with an EPO-derived peptide after diabetes is fully established can significantly protect against neuroglial and vascular degenerative pathology without altering hematocrit or exacerbating neovascularization. These findings have therapeutic implications for disorders such as diabetic retinopathy.

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          Most cited references40

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          A central role for inflammation in the pathogenesis of diabetic retinopathy.

          Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory treatment in diabetic retinopathy.
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            VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.

            Vascular endothelial growth factor (VEGF) has been shown to promote neovascularization in animal models and, more recently, in human subjects. This feature has been assumed to result exclusively from its direct effects on fully differentiated endothelial cells, i.e. angiogenesis. Given its regulatory role in both angiogenesis and vasculogenesis during fetal development, we investigated the hypothesis that VEGF may modulate endothelial progenitor cell (EPC) kinetics for postnatal neovascularization. Indeed, we observed an increase in circulating EPCs following VEGF administration in vivo. VEGF-induced mobilization of bone marrow-derived EPCs resulted in increased differentiated EPCs in vitro and augmented corneal neovascularization in vivo. These findings thus establish a novel role for VEGF in postnatal neovascularization which complements its known impact on angiogenesis.
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              Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.

              Diabetes leads to vascular leakage, glial dysfunction, and neuronal apoptosis within the retina. The goal of the studies reported here was to determine the role that retinal microglial cells play in diabetic retinopathy and assess whether minocycline can decrease microglial activation and alleviate retinal complications. Immunohistochemical analyses showed that retinal microglia are activated early in diabetes. Furthermore, mRNAs for interleukin-1beta and tumor necrosis factor-alpha, proinflammatory mediators known to be released from microglia, are also increased in the retina early in the course of diabetes. Using an in vitro bioassay, we demonstrated that cytokine-activated microglia release cytotoxins that kill retinal neurons. Furthermore, we showed that neuronal apoptosis is increased in the diabetic retina, as measured by caspase-3 activity. Minocycline represses diabetes-induced inflammatory cytokine production, reduces the release of cytotoxins from activated microglia, and significantly reduces measurable caspase-3 activity within the retina. These results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.
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                Author and article information

                Journal
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                November 2011
                17 October 2011
                : 60
                : 11
                : 2995-3005
                Affiliations
                [1] 1Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, Northern Ireland, U.K.
                [2] 2Araim Pharmaceuticals, Ossining, New York
                Author notes
                Corresponding author: Alan W. Stitt, a.stitt@ 123456qub.ac.uk .

                C.M.M. and R.H. contributed equally to this study.

                Article
                0026
                10.2337/db11-0026
                3198080
                21911748
                cba68bde-4877-4166-a7fa-8dd66b6a49bf
                © 2011 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 10 January 2011
                : 25 July 2011
                Categories
                Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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