期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 8, 页码 3006-3022出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI84767
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资金
- Canadian Diabetes Association [OG-3-11-3329-PS]
- Wolfe Professorship in Translational Vision Research
- Alcon Research Institute Young Investigator Award
- Fond de Recherches Quebec Sante (FRQS) Chercheur National award
- Killam Foundation
- Foundation Fighting Blindness Canada (FFB)
- Canadian Institutes of Health Research [324573, 221478]
- Natural Sciences and Engineering Research Council of Canada [418637]
- Multiple Sclerosis Society of Canada [2120]
- Fondation HMR
- Reseau en Recherche en Sante de la Vision du Quebec
- Fond en Recherche en Opthalmologie de l'Universite de Montreal
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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