alpha-Melanocyte-Stimulating Hormone Protects Retinal Vascular Endothelial Cells from Oxidative Stress and Apoptosis in a Rat Model of Diabetes

作者：Zhang, Lijuan; Dong, Lijie; Liu, Xun; Jiang, Yuanfeng; Zhang, Lingjun; Zhang, Xiaomin; Li, Xiaorong^*; Zhang, Yan

来源：PLos One, 2014, 9(4): e93433.

DOI：10.1371/journal.pone.0093433

• MELANOCORTIN SYSTEM
• NEURAL APOPTOSIS
• GLYCEMIC CONTROL
• MAP KINASE
• RETINOPATHY
• EXPRESSION
• INSULIN
• TYPE-1
• MECHANISMS
• RECEPTORS

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 alpha-melanocyte-stimulating hormone (alpha-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 alpha-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 alpha-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 alpha-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 alpha-MSH. Treatment with alpha-MSH also corrected the aberrant changes in eNOS, iNOS, ICAM-1, and TNF-alpha expression levels in diabetic retinas. Furthermore, alpha-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 alpha-MSH in HG-stimulated retinal vascular endothelial cells.
Conclusions: alpha-MSH normalized oxidative stress, reduced apoptosis and ultrastructural injuries, and corrected gene expression levels in early diabetic retinas. The protective effects of alpha-MSH in retinal vascular endothelial cells may be mediated through the inhibition of Foxo4 up-regulation induced by HG. This study suggests an alpha-MSH-mediated potential intervention approach to early diabetic retinopathy and a novel regulatory mechanism involving Foxo4.

• 出版日期2014-4-2
• 单位天津医科大学