Abstract
AimsOxidative stress and apoptosis are among the earliest lesions of diabetic retinopathy. This study sought to examine the anti-oxidative and anti-apoptotic effects of α-melanocyte-stimulating hormone (α-MSH) in early diabetic retinas and to explore the underlying mechanisms in retinal vascular endothelial cells.MethodsSprague-Dawley rats were injected intravenously with streptozocin to induce diabetes. The diabetic rats were injected intravitreally with α-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 α-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 α-MSH or HG treatment, and oxidative stress and apoptosis were analyzed through CM-H2DCFDA and annexin-V assays, respectively.ResultsIn 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 α-MSH. Treatment with α-MSH also corrected the aberrant changes in eNOS, iNOS, ICAM-1, and TNF-α expression levels in diabetic retinas. Furthermore, α-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 α-MSH in HG-stimulated retinal vascular endothelial cells.Conclusionsα-MSH normalized oxidative stress, reduced apoptosis and ultrastructural injuries, and corrected gene expression levels in early diabetic retinas. The protective effects of α-MSH in retinal vascular endothelial cells may be mediated through the inhibition of Foxo4 up-regulation induced by HG. This study suggests an α-MSH-mediated potential intervention approach to early diabetic retinopathy and a novel regulatory mechanism involving Foxo4.
Highlights
Diabetic retinopathy (DR) is the vascular and neural injury of the retina caused by metabolic disorders in diabetes
These results demonstrate the protective effects of a-melanocyte-stimulating hormone (a-MSH) in the retina of STZ-induced diabetic rats and suggest the possibility that intravitreal application of a-MSH could be developed into a novel and effective intervention for early DR
With regard to the mechanism underlying these protective effects, gene expression analyses showed that Foxo4 is the only member of Forkhead box O genes (Foxos) transcription factor family that was significantly up-regulated in diabetic retinas (Fig. 7) and in high glucose (HG)-stimulated retinal vascular endothelial cells (Fig. 8B), and the up-regulation was suppressed by a-MSH (Fig. 7 and 8B)
Summary
Diabetic retinopathy (DR) is the vascular and neural injury of the retina caused by metabolic disorders in diabetes. Research in diabetic patients and animal models demonstrates that the earliest injuries in the retina occur in microvessel endothelial cells and manifest as the breakdown of the retinal blood barrier and leukostasis [4,5]. If the metabolic disorder is not corrected, apoptosis of microvessel endothelial cells and loss of pericytes may occur [6], after which the typical pathological changes in non-proliferative diabetic retinopathy are observed [7,8]. It appears clear that high glucose (HG) levels associated with metabolic disorders in diabetes are the direct cause of endothelial cell injury in retinal microvessels. Reports in the literature indicate that if type I diabetic patients are not subjected
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