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

被引:259
作者
Gao, Ben-Bo
Clermont, Allen
Rook, Susan
Fonda, Stephanie J.
Srinivasan, Vivek J.
Wojtkowski, Maciej
Fujimoto, James G.
Avery, Robert L.
Arrigg, Paul G.
Bursell, Sven-Erik
Aiello, Lloyd Paul
Feener, Edward P.
机构
[1] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA
[3] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
[4] MIT, Elect Res Lab, Cambridge, MA 02139 USA
[5] Santa Barbara Cottage Hosp Eye Ctr, Santa Barbara, CA 93103 USA
[6] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA
[7] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA
关键词
D O I
10.1038/nm1534
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:181 / 188
页数:8
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