Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy.
Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy.
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作者：
McVicar CM;Hamilton R;Colhoun LM;Gardiner TA;Brines M;Cerami A;Stitt AW
促红细胞生成素（EPO）可能对早期糖尿病视网膜病变有保护作用，尽管它可能加剧视网膜血管生成和血栓形成。一种基于EPO螺旋- b结构域的肽（螺旋b表面肽[pHBSP]）是非红细胞性的，但保留了组织保护特性，本研究评估了其在糖尿病视网膜病变中的治疗潜力。在链脲佐菌素诱导糖尿病6个月后，将大鼠（n = 12）和年龄匹配的非糖尿病对照组（n = 12）均匀分为pHBSP组和炒肽组，每天注射10 μg/kg / d，持续1个月。研究视网膜的神经胶质功能障碍、小胶质细胞激活和神经元DNA损伤。分离素和IV型胶原双染色，实时荧光定量pcr检测视网膜细胞因子表达。同时，用氧致视网膜病变（OIR）评价pHBSP （1 ~ 30 μg/kg pHBSP或对照肽）对视网膜缺血和新生血管的影响。pHBSP或混乱肽治疗没有改变红细胞压积。在糖尿病视网膜中，与非糖尿病对照组相比，突触神经胶质纤维酸性蛋白的表达增加，但pHBSP显著降低了这种应激相关反应（P < 0.001）。CD11b+小胶质细胞和促炎细胞因子在糖尿病视网膜反应中升高，pHBSP使部分反应减弱（P < 0.01-0.001）。通过8-羟基脱氧鸟苷和转移酶介导的dUTP镍端标记阳性检测，pHBSP显著降低糖尿病相关DNA损伤，并阻止脱细胞毛细血管形成（P < 0.05）。在OIR中，pHBSP在任何剂量下都对视网膜前新生血管没有影响。在糖尿病完全建立后，用epo衍生肽治疗可以显著保护神经胶质和血管退行性病理，而不会改变红细胞压积或加剧新生血管。这些发现对糖尿病视网膜病变等疾病具有治疗意义。
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. 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). 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. 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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