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Xiaorong Li, Yan Zhang, Lijuan Zhang, Xiaomin Zhang, Xun Liu, Lingjun Zhang; Anti-oxidative and anti-apoptotic effects of α-melanocyte stimulating hormone in early diabetic retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1059.
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To study anti-oxidative and anti-apoptotic effects of α-melanocyte stimulating hormone (α-MSH) in early diabetic retina and the underlying mechanism.
Sprague Dawley rats were intravenously injected with streptozocin to induce diabetes. At the 1st and 3rd w after induction, diabetic rats were injected intravitreally with α-MSH or saline, and normal controls with saline. At the 5th w after diabetes, retinas were analyzed for expression of melanocortin receptors (MCRs) and proinflammatory factors; the level of reactive oxygen species (ROS), including NO2-/NO3- and H2O2, were measured. One week later, eye cups were processed for transmission electron microscopy (TEM) and TUNEL staining after trypsin digestion or cryosection. In vitro, retinal vascular endothelial cells were stimulated with high glucose (HG) for 8 h with or without α-MSH, expression of Forkhead box O proteins (FOXOs) was examined by real-time RT-PCR. The significantly up-regulated FOXO gene, FOXO4, was cloned into pcDNA3.0 vector. Following transfection with pcDNA-FOXO4 or empty vector, the cells were subjected to α-MSH and/or HG treatment, oxidative stress and apoptosis of the cells were analyzed by CM-H2DCFDA and annexin-V assay, respectively.
In diabetic rat retina, MC1, 3, 4, 5R were expressed; NO2-/NO3- and H2O2 levels were elevated (p<0.05 vs normal) and normalized by α-MSH administration. TUNEL staining revealed that α-MSH substantially reduced apoptotic cell number in diabetic retina. TEM showed that α-MSH ameliorated ultrastructural injuries in diabetic retina. Real-time PCR showed that eNOS expression was down-regulated, iNOS, ICAM-1, and TNF-α expression were up-regulated in diabetic retina (p<0.05 vs normal), and α-MSH could correct these aberrant gene expression (p<0.05). In retinal vessel endothelial cells, α-MSH inhibited significant up-regulation of FOXO4 induced by HG. CM-H2DCFDA and annexin-V assay demonstrated that over-expression of FOXO4 abrogated the anti-oxidative and anti-apoptotic effects of α-MSH in the endothelial cells exposed to HG for 8 h.
α-MSH normalizes oxidative stress, reduces apoptosis, ameliorates ultrastructural impairments, and corrects aberrant gene expression in early diabetic retina. The anti-oxidative and anti-apoptotic effects of α-MSH in retinal vessel endothelial cells may be due to its inhibiting FOXO4 up-regulation induced by HG.
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