title: Functional links between gelatinase B/matrix metalloproteinase-9 and prominin-1/CD133 in diabetic retinal vasculopathy and neuropathy.
abstract: Retinopathy, a common cause of blindness, is a hallmark of diabetes and depends on two pathological mechanisms: vasculopathy and neuropathy. Whereas vasculopathy is well understood and has been associated with changes in gelatinase B/matrix metalloproteinase-9 (MMP-9) and other vasculotropic factors, specific markers for diabetes-induced retinal neuropathy are not yet described. Neuropathy may result from damages to the blood-retinal barrier (BRB) and from loss of neuroprotective factors. We studied diabetes-induced changes in vascular, inflammatory and regenerative markers and demonstrated that MMP-9 was increased, whereas prominin-1/CD133 was decreased in retinal extracts. In vitro, MMP-9 specifically destroyed prominin-1/CD133. Streptozotocin-induced diabetes resulted in BRB breakdown as a sign of vasculopathy and in prominin-1/CD133 destruction in photoreceptors as an in situ parameter of diabetic neuropathy. Both in vivo phenotypes were completely reversed in single MMP-9 gene knockout mice, demonstrating that MMP-9 mediates both diabetes-induced retinal vasculopathy and neuropathy, with prominin-1/CD133 being a critical and specific substrate of MMP-9. This functional link between gelatinase B/MMP-9 and prominin-1/CD133 explains mechanistically both the vasculopathy and neuropathy of diabetic retinopathy and suggests that specific MMP-9 inhibition is an interesting therapeutic avenue to investigate.
authors: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Ghulam
authors: G
authors: Mohammad
authors: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Belgium.
authors: Jennifer
authors: J
authors: Vandooren
authors: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Mohammad Mairaj
authors: MM
authors: Siddiquei
authors: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Belgium.
authors: Erik
authors: E
authors: Martens
authors: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: abuasrar@ksu.edu.sa.
authors: Ahmed M
authors: AM
authors: Abu El-Asrar
authors: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Belgium. Electronic address: ghislain.opdenakker@rega.kuleuven.be.
authors: Ghislain
authors: G
authors: Opdenakker
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010455:Peptides / Q000502:physiology*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D020780:Matrix Metalloproteinase 9
keywords: Angiogenesis; Diabetes; Gelatinase B; Matrix metalloproteinase-9; Prominin-1/CD133; Retinopathy; Vasculogenesis