title: Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy.
abstract: 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.
authors.forename: Khalil
authors.initials: K
authors.lastname: Miloudi
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.forename: Ariel
authors.initials: A
authors.lastname: Wilson
authors.forename: Agustin
authors.initials: A
authors.lastname: Cerani
authors.forename: Malika
authors.initials: M
authors.lastname: Oubaha
authors.forename: Catherine
authors.initials: C
authors.lastname: Menard
authors.forename: Sullivan
authors.initials: S
authors.lastname: Henriques
authors.forename: Gaelle
authors.initials: G
authors.lastname: Mawambo
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dejda
authors.forename: Phuong Trang
authors.initials: PT
authors.lastname: Nguyen
authors.forename: Flavio A
authors.initials: FA
authors.lastname: Rezende
authors.forename: Steve
authors.initials: S
authors.lastname: Bourgault
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001813:Blood-Retinal Barrier; D002199:Capillary Permeability; D016022:Case-Control Studies; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008269:Macular Edema / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D000072417:Protein Domains; D012160:Retina / Q000378:metabolism; D013311:Streptozocin; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D013311:Streptozocin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9