1. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.
- Author
-
Gao BB, Clermont A, Rook S, Fonda SJ, Srinivasan VJ, Wojtkowski M, Fujimoto JG, Avery RL, Arrigg PG, Bursell SE, Aiello LP, and Feener EP
- Subjects
- Acetazolamide pharmacology, Animals, Blotting, Western, Bradykinin Receptor Antagonists, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases toxicity, Complement C1 antagonists & inhibitors, Factor XIIa metabolism, Humans, Mass Spectrometry, Papilledema chemically induced, Proteomics, Rats, Rats, Sprague-Dawley, Statistics, Nonparametric, Capillary Permeability drug effects, Carbonic Anhydrase Inhibitors therapeutic use, Carbonic Anhydrases metabolism, Diabetic Retinopathy drug therapy, Eye Proteins metabolism, Kallikrein-Kinin System physiology, Vitreous Body enzymology
- 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.
- Published
- 2007
- Full Text
- View/download PDF