Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation

BB Gao, A Clermont, S Rook, SJ Fonda… - Nature medicine, 2007 - nature.com
BB Gao, A Clermont, S Rook, SJ Fonda, VJ Srinivasan, M Wojtkowski, JG Fujimoto…
Nature medicine, 2007nature.com
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 …
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.
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