%0 Journal Article
%T ¦Á-Melanocyte-Stimulating Hormone Protects Retinal Vascular Endothelial Cells from Oxidative Stress and Apoptosis in a Rat Model of Diabetes
%A Lijuan Zhang
%A Lijie Dong
%A Xun Liu
%A Yuanfeng Jiang
%A Lingjun Zhang
%A Xiaomin Zhang
%A Xiaorong Li
%A Yan Zhang
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0093433
%X Aims Oxidative stress and apoptosis are among the earliest lesions of diabetic retinopathy. This study sought to examine the anti-oxidative and anti-apoptotic effects of ¦Á-melanocyte-stimulating hormone (¦Á-MSH) in early diabetic retinas and to explore the underlying mechanisms in retinal vascular endothelial cells. Methods Sprague-Dawley rats were injected intravenously with streptozocin to induce diabetes. The diabetic rats were injected intravitreally with ¦Á-MSH or saline. At week 5 after diabetes, the retinas were analyzed for reactive oxygen species (ROS) and gene expression. One week later, the retinas were processed for terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and transmission electron microscopy. Retinal vascular endothelial cells were stimulated by high glucose (HG) with or without ¦Á-MSH. The expression of Forkhead box O genes (Foxos) was examined through real-time PCR. The Foxo4 gene was overexpressed in endothelial cells by transient transfection prior to ¦Á-MSH or HG treatment, and oxidative stress and apoptosis were analyzed through CM-H2DCFDA and annexin-V assays, respectively. Results In diabetic retinas, the levels of H2O2 and ROS and the total anti-oxidant capacity were normalized, the apoptotic cell number was reduced, and the ultrastructural injuries were ameliorated by ¦Á-MSH. Treatment with ¦Á-MSH also corrected the aberrant changes in eNOS, iNOS, ICAM-1, and TNF-¦Á expression levels in diabetic retinas. Furthermore, ¦Á-MSH inhibited Foxo4 up-regulation in diabetic retinas and in endothelial cells exposed to HG, whereas Foxo4 overexpression abrogated the anti-oxidative and anti-apoptotic effects of ¦Á-MSH in HG-stimulated retinal vascular endothelial cells. Conclusions ¦Á-MSH normalized oxidative stress, reduced apoptosis and ultrastructural injuries, and corrected gene expression levels in early diabetic retinas. The protective effects of ¦Á-MSH in retinal vascular endothelial cells may be mediated through the inhibition of Foxo4 up-regulation induced by HG. This study suggests an ¦Á-MSH-mediated potential intervention approach to early diabetic retinopathy and a novel regulatory mechanism involving Foxo4.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0093433