Abstract
Oxidative stress is a contributing factor to the development and progression of diabetic retinopathy, a leading cause of blindness in people at working age worldwide. Recent studies showed that Müller cells play key roles in diabetic retinopathy and produce vascular endothelial growth factor (VEGF) that regulates retinal vascular leakage and proliferation. Melatonin is a potent antioxidant capable of protecting variety of retinal cells from oxidative damage. In addition to the pineal gland, the retina produces melatonin. In the current study, we investigated whether melatonin protects against hyperglycemia-induced oxidative injury to Müller cells and explored the potential underlying mechanisms. Our results show that both melatonin membrane receptors, MT1 and MT2, are expressed in cultured primary Müller cells and are upregulated by elevated glucose levels. Both basal and high glucose-induced VEGF production was attenuated by melatonin treatment in a dose-dependent manner. Furthermore, we found that melatonin is a potent activator of Akt in Müller cells. Our findings suggest that in addition to functioning as a direct free radical scavenger, melatonin can elicit cellular signaling pathways that are protective against retinal injury during diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is a common and potentially devastating microvascular complication of diabetes; it is a leading cause of acquired blindness among people at occupational age [1,2]
We showed that melatonin attenuated high glucose induced vascular endothelial growth factor (VEGF) overproduction (Figure 2) and glutathione depletion (Figure 3A)
We showed that melatonin exhibited indirect antioxidant effects by enhancing the expression of various antioxidant genes, including GCLC, GCLM, heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) (Figure 3 and Figure 4), which contributed to maintaining the cellular redox status and preventing against oxidative injury
Summary
Diabetic retinopathy (DR) is a common and potentially devastating microvascular complication of diabetes; it is a leading cause of acquired blindness among people at occupational age [1,2]. Developing novel, mechanism-based therapeutic strategies is highly desirable for DR patients [1,6]. Muller cells, which are glial cells supporting the retinal neurons, have been recognized as a major source of VEGF production in the retina. Conditional knockout of Muller cellderived VEGF reduced retinal angiogenesis and vascular leakage due to ischemia-reperfusion or hyperglycemia [7,8]. Dysregulated retinal VEGF production during DR is among the most devastating responses to oxidative stress [9,10]
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