Abstract
Vascular endothelial growth factor (VEGF) is considered a major role player in the pathogenesis of diabetic retinopathy, yet the mechanisms regulating its expression are not fully understood. Our laboratory previously demonstrated that diabetes-induced VEGF expression in the retina was dependent on the repressor of mRNA translation 4E-BP1. Interaction of 4E-BP1 with the cap-binding protein eIF4E regulates protein expression by controlling the selection of mRNAs for translation. The process is regulated by the master kinase mTOR in complex 1 (mTORC1), which phosphorylates 4E-BP1, thus promoting its disassociation from eIF4E. In the present study, we investigated the role of the Akt/mTORC1 repressor REDD1 (regulated in development and DNA damage) in diabetes-induced VEGF expression. REDD1 expression was induced by hyperglycemia in the retina of diabetic rodents and by hyperglycemic conditions in Müller cells concomitant with increased VEGF expression. In Müller cells, hyperglycemic conditions attenuated global rates of protein synthesis and cap-dependent mRNA translation concomitant with up-regulated cap-independent VEGF mRNA translation, as assessed by a bicistronic luciferase reporter assay. Hyperglycemic conditions also attenuated mTORC1 signaling and enhanced 4E-BP1 binding to eIF4E. Furthermore, ectopic expression of REDD1 in Müller cells was sufficient to promote both increased 4E-BP1 binding to eIF4E and VEGF expression. Whereas the retina of wild-type mice exhibited increased expression of VEGF and tumor necrosis factor alpha (TNF-α) 4 weeks after streptozotocin administration, the retina of REDD1 knock-out mice failed to do so. Overall, the results demonstrate that REDD1 contributes to the pathogenesis of diabetes in the retina by mediating the pathogenic effects of hyperglycemia.
Highlights
Vascular endothelial growth factor (VEGF) plays a causal role in diabetic retinopathy
Normalization of serum glucose concentrations reduced the abundance of Regulated in Development and DNA Damage 1 (REDD1) (Fig. 1A), enhanced phosphorylation of 4E-BP1 (Fig. 1B), and reduced VEGF abundance (Fig. 1C) in the retina of diabetic rats, such that levels were no longer different than those observed in non-diabetic controls
We recently reported the existence of a diabetesinduced hyperglycemia-mediated shift in gene expression that was associated with down-regulation of cap-dependent and concomitant up-regulation of cap-independent mRNA translation in both STZ-treated mice and cells in culture [9]
Summary
VEGF plays a causal role in diabetic retinopathy. Results: Hyperglycemia induced VEGF and REDD1 expression in the retina of wild-type, but not REDD1 knock-out mice. REDD1 expression was induced by hyperglycemia in the retina of diabetic rodents and by hyperglycemic conditions in Müller cells concomitant with increased VEGF expression. We showed that 4E-BP1, but not 4E-BP2, is necessary for increased VEGF expression in both the retina during diabetes and in cells maintained under hyperglycemic conditions [9, 10] These previous studies from our laboratory [18] demonstrate that the effect of diabetesinduced hyperglycemia on 4E-BP1 is mediated at least in part through the covalent addition of O-linked N-acetylglucosamine (O-GlcNAcylation). In the present study we set out to test the hypothesis that diabetes-induced REDD1 protein expression represents a translational control mechanism that contributes to enhanced VEGF expression in the retina. Diabetes failed to promote expression of either VEGF or the proinflammatory marker TNF-␣ in the retina of REDD1 knockout mice, demonstrating a critical role for REDD1 in diabetesinduced pathology of the retina
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