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Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy.

McVicar CM, Hamilton R, Colhoun LM, Gardiner TA, Brines M, Cerami A, Stitt AW - Diabetes (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, Northern Ireland, UK.

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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Characterization of STZ-induced diabetes. The extent of diabetes was assessed in the various rat groups at the end of the experiment (8.5 months of age) using body weight and hyperglycemia as indicators. Cntl, control; Sc, scrambled pHBSP; and Db, diabetic. A: Analysis of body weight showed a 50% reduction in diabetic rats compared with age-matched controls. B: HbA1c levels were elevated by 2.5-fold in diabetic rat blood compared with control. Neither pHBSP nor the scrambled peptide influenced these parameters. (***P < 0.001). C: The hematocrit levels (% blood volume occupied by erythrocytes) were not altered in the blood of the animals that received the pHBSP. D: Diabetes increased the percentage of circulating reticulocytes (*P < 0.05), while treatment with pHBSP prevented this change. Data are mean ± SEM; n = 6 per group. One-way ANOVA.
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Figure 1: Characterization of STZ-induced diabetes. The extent of diabetes was assessed in the various rat groups at the end of the experiment (8.5 months of age) using body weight and hyperglycemia as indicators. Cntl, control; Sc, scrambled pHBSP; and Db, diabetic. A: Analysis of body weight showed a 50% reduction in diabetic rats compared with age-matched controls. B: HbA1c levels were elevated by 2.5-fold in diabetic rat blood compared with control. Neither pHBSP nor the scrambled peptide influenced these parameters. (***P < 0.001). C: The hematocrit levels (% blood volume occupied by erythrocytes) were not altered in the blood of the animals that received the pHBSP. D: Diabetes increased the percentage of circulating reticulocytes (*P < 0.05), while treatment with pHBSP prevented this change. Data are mean ± SEM; n = 6 per group. One-way ANOVA.

Mentions: Analysis of body weight revealed a 50% reduction in diabetic rats compared with age-matched nondiabetic controls (Fig. 1A). HbA1c at killing showed a 2.5-fold increase in diabetic rats compared with control rats (P < 0.001) (Fig. 1B). pHBSP peptide did not alter these diabetes parameters, nor did it alter hematocrit counts (Fig. 1C). Diabetes induced a significant increase in the number of reticulocytes and pHBSP prevented this change (Fig. 1D).


Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy.

McVicar CM, Hamilton R, Colhoun LM, Gardiner TA, Brines M, Cerami A, Stitt AW - Diabetes (2011)

Characterization of STZ-induced diabetes. The extent of diabetes was assessed in the various rat groups at the end of the experiment (8.5 months of age) using body weight and hyperglycemia as indicators. Cntl, control; Sc, scrambled pHBSP; and Db, diabetic. A: Analysis of body weight showed a 50% reduction in diabetic rats compared with age-matched controls. B: HbA1c levels were elevated by 2.5-fold in diabetic rat blood compared with control. Neither pHBSP nor the scrambled peptide influenced these parameters. (***P < 0.001). C: The hematocrit levels (% blood volume occupied by erythrocytes) were not altered in the blood of the animals that received the pHBSP. D: Diabetes increased the percentage of circulating reticulocytes (*P < 0.05), while treatment with pHBSP prevented this change. Data are mean ± SEM; n = 6 per group. One-way ANOVA.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198080&req=5

Figure 1: Characterization of STZ-induced diabetes. The extent of diabetes was assessed in the various rat groups at the end of the experiment (8.5 months of age) using body weight and hyperglycemia as indicators. Cntl, control; Sc, scrambled pHBSP; and Db, diabetic. A: Analysis of body weight showed a 50% reduction in diabetic rats compared with age-matched controls. B: HbA1c levels were elevated by 2.5-fold in diabetic rat blood compared with control. Neither pHBSP nor the scrambled peptide influenced these parameters. (***P < 0.001). C: The hematocrit levels (% blood volume occupied by erythrocytes) were not altered in the blood of the animals that received the pHBSP. D: Diabetes increased the percentage of circulating reticulocytes (*P < 0.05), while treatment with pHBSP prevented this change. Data are mean ± SEM; n = 6 per group. One-way ANOVA.
Mentions: Analysis of body weight revealed a 50% reduction in diabetic rats compared with age-matched nondiabetic controls (Fig. 1A). HbA1c at killing showed a 2.5-fold increase in diabetic rats compared with control rats (P < 0.001) (Fig. 1B). pHBSP peptide did not alter these diabetes parameters, nor did it alter hematocrit counts (Fig. 1C). Diabetes induced a significant increase in the number of reticulocytes and pHBSP prevented this change (Fig. 1D).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, Northern Ireland, UK.

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.

Show MeSH
Related in: MedlinePlus