title: Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.
abstract: Excessive retinal vascular permeability contributes to the pathogenesis of proliferative diabetic retinopathy and diabetic macular edema, leading causes of vision loss in working-age adults. Using mass spectroscopy-based proteomics, we detected 117 proteins in human vitreous and elevated levels of extracellular carbonic anhydrase-I (CA-I) in vitreous from individuals with diabetic retinopathy, suggesting that retinal hemorrhage and erythrocyte lysis contribute to the diabetic vitreous proteome. Intravitreous injection of CA-I in rats increased retinal vessel leakage and caused intraretinal edema. CA-I-induced alkalinization of vitreous increased kallikrein activity and its generation of factor XIIa, revealing a new pathway for contact system activation. CA-I-induced retinal edema was decreased by complement 1 inhibitor, neutralizing antibody to prekallikrein and bradykinin receptor antagonism. Subdural infusion of CA-I in rats induced cerebral vascular permeability, suggesting that extracellular CA-I could have broad relevance to neurovascular edema. Inhibition of extracellular CA-I and kallikrein-mediated innate inflammation could provide new therapeutic opportunities for the treatment of hemorrhage-induced retinal and cerebral edema.
authors.affiliation: Research Division, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Ben-Bo
authors.initials: BB
authors.lastname: Gao
authors.forename: Allen
authors.initials: A
authors.lastname: Clermont
authors.forename: Susan
authors.initials: S
authors.lastname: Rook
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Fonda
authors.forename: Vivek J
authors.initials: VJ
authors.lastname: Srinivasan
authors.forename: Maciej
authors.initials: M
authors.lastname: Wojtkowski
authors.forename: James G
authors.initials: JG
authors.lastname: Fujimoto
authors.forename: Robert L
authors.initials: RL
authors.lastname: Avery
authors.forename: Paul G
authors.initials: PG
authors.lastname: Arrigg
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Bursell
authors.forename: Lloyd Paul
authors.initials: LP
authors.lastname: Aiello
authors.forename: Edward P
authors.initials: EP
authors.lastname: Feener
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D065168:Bradykinin Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000378:metabolism* / Q000633:toxicity; D003172:Complement C1 / Q000037:antagonists & inhibitors; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D005136:Eye Proteins / Q000378:metabolism*; D015956:Factor XIIa / Q000378:metabolism; D006801:Humans; D016234:Kallikrein-Kinin System / Q000502:physiology*; D013058:Mass Spectrometry; D010211:Papilledema / Q000139:chemically induced; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014822:Vitreous Body / Q000201:enzymology*
chemical_list: D065168:Bradykinin Receptor Antagonists; D002257:Carbonic Anhydrase Inhibitors; D003172:Complement C1; D005136:Eye Proteins; D015956:Factor XIIa; D002256:Carbonic Anhydrases; D000086:Acetazolamide