Abstract
Background: Oxidative stress (OS) plays a central role in diabetic retinopathy (DR), triggering expression and release of vascular endothelial growth factor (VEGF), the increase of which leads to deleterious vascular changes. We tested the hypothesis that OS-stimulated VEGF induces its own expression with an autocrine mechanism. Methods: MIO-M1 cells and ex vivo mouse retinal explants were treated with OS, with exogenous VEGF or with conditioned media (CM) from OS-stressed cultures. Results: Both in MIO-M1 cells and in retinal explants, OS or exogenous VEGF induced a significant increase of VEGF mRNA, which was abolished by VEGF receptor 2 (VEGFR-2) inhibition. OS also caused VEGF release. In MIO-M1 cells, CM induced VEGF expression, which was abolished by a VEGFR-2 inhibitor. Moreover, the OS-induced increase of VEGF mRNA was abolished by a nuclear factor erythroid 2-related factor 2 (Nrf2) blocker, while the effect of exo-VEGF resulted Nrf2-independent. Finally, both the exo-VEGF- and the OS-induced increase of VEGF expression were blocked by a hypoxia-inducible factor-1 inhibitor. Conclusions: These results are consistent with the existence of a retinal VEGF autocrine loop triggered by OS. This mechanism may significantly contribute to the maintenance of elevated VEGF levels and therefore it may be of central importance for the onset and development of DR.
Highlights
Vascular endothelial growth factor (VEGF) is a key factor involved in the pathogenesis of diabetic retinopathy (DR)
The results showed that the treatment of MIO-M1 cells with exo-vascular endothelial growth factor (VEGF) did not induce any changes in nuclear nuclear factor erythroid 2-related factor 2 (Nrf2), as assessed with immunofluorescence analysis (Figure 6A–D), while Nrf2 blockade did not influence the increase of VEGF mRNA expression induced by treatment with exo-VEGF (Figure 6E)
This conclusion is supported by the results obtained in this study, which can be summarized as follows: i) both Oxidative stress (OS) and exo-VEGF induce a VEGF receptor 2 (VEGFR2)-mediated increase of VEGF mRNA expression; ii) in both cases, this increase is blocked by an inhibitor of hypoxia-inducible factor-1 (HIF-1) dimerization, indicating that HIF-1 acts as a sort of final common effector for VEGF expression; iii) OS
Summary
Vascular endothelial growth factor (VEGF) is a key factor involved in the pathogenesis of diabetic retinopathy (DR). Prolonged expression and release of VEGF in the retina is responsible for the breakdown of the blood–retina barrier and the proliferation of retinal neovessels causing major visual deficits in DR patients. Oxidative stress (OS) plays a central role in diabetic retinopathy (DR), triggering expression and release of vascular endothelial growth factor (VEGF), the increase of which leads to deleterious vascular changes. Methods: MIO-M1 cells and ex vivo mouse retinal explants were treated with OS, with exogenous VEGF or with conditioned media (CM) from. Results: Both in MIO-M1 cells and in retinal explants, OS or exogenous VEGF induced a significant increase of VEGF mRNA, which was abolished by VEGF receptor 2 (VEGFR-2). In MIO-M1 cells, CM induced VEGF expression, which was abolished by a VEGFR-2 inhibitor. The OS-induced increase of VEGF mRNA was abolished by a nuclear factor erythroid 2-related factor 2 (Nrf2) blocker, while the effect of exo-VEGF resulted
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