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Open AccessArticle

Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy

1
Department of Biology, University of Pisa, 56126 Pisa, Italy
2
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
3
Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56124 Pisa, Italy
*
Authors to whom correspondence should be addressed.
These authors equally contributed to this study.
Cells 2020, 9(6), 1452; https://doi.org/10.3390/cells9061452
Received: 10 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 11 June 2020
(This article belongs to the Special Issue Redox Signaling in Health and Disease)
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. View Full-Text
Keywords: Nrf2; VEGFR2; MIO-M1; retinal explant; Müller cell; HIF-1; diabetic retinopathy; conditioned medium Nrf2; VEGFR2; MIO-M1; retinal explant; Müller cell; HIF-1; diabetic retinopathy; conditioned medium
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MDPI and ACS Style

Rossino, M.G.; Lulli, M.; Amato, R.; Cammalleri, M.; Dal Monte, M.; Casini, G. Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy. Cells 2020, 9, 1452.

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