Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy

Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in the working-age population. Impaired blood-retinal barrier function leads to macular edema that is closely associated with the deterioration of central vision. We previously demonstrated that the neuron...

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Published inThe Journal of clinical investigation Vol. 126; no. 8; pp. 3006 - 3022
Main Authors Miloudi, Khalil, Binet, François, Wilson, Ariel, Cerani, Agustin, Oubaha, Malika, Menard, Catherine, Henriques, Sullivan, Mawambo, Gaelle, Dejda, Agnieszka, Nguyen, Phuong Trang, Rezende, Flavio A, Bourgault, Steve, Kennedy, Timothy E, Sapieha, Przemyslaw
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 01.08.2016
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Summary:Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in the working-age population. Impaired blood-retinal barrier function leads to macular edema that is closely associated with the deterioration of central vision. We previously demonstrated that the neuronal guidance cue netrin-1 activates a program of reparative angiogenesis in microglia within the ischemic retina. Here, we provide evidence in both vitreous humor of diabetic patients and in retina of a murine model of diabetes that netrin-1 is metabolized into a bioactive fragment corresponding to domains VI and V of the full-length molecule. In contrast to the protective effects of full-length netrin-1 on retinal microvasculature, the VI-V fragment promoted vascular permeability through the uncoordinated 5B (UNC5B) receptor. The collagenase matrix metalloprotease 9 (MMP-9), which is increased in patients with diabetic macular edema, was capable of cleaving netrin-1 into the VI-V fragment. Thus, MMP-9 may release netrin-1 fragments from the extracellular matrix and facilitate diffusion. Nonspecific inhibition of collagenases or selective inhibition of MMP-9 decreased pathological vascular permeability in a murine model of diabetic retinal edema. This study reveals that netrin-1 degradation products are capable of modulating vascular permeability, suggesting that these fragments are of potential therapeutic interest for the treatment of DR.
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ISSN:0021-9738
1558-8238
DOI:10.1172/jci84767