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

Ben Bo Gao, Allen Clermont, Susan Rook, Stephanie J. Fonda, Vivek Srinivasan, Maciej Wojtkowski, James G. Fujimoto, Robert L. Avery, Paul G. Arrigg, Sven Erik Bursell, Lloyd Paul Aiello, Edward P. Feener

Research output: Contribution to journalArticle

209 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)181-188
Number of pages8
JournalNature Medicine
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

Fingerprint

Carbonic Anhydrase I
Prekallikrein
Retinal Vessels
Carbonic Anhydrases
Capillary Permeability
Chemical activation
Papilledema
Kallikreins
Complement Inactivating Agents
Diabetic Retinopathy
Rats
Edema
Factor XIIa
Bradykinin Receptors
Complement C1
Retinal Hemorrhage
Macular Edema
Brain Edema
Proteome
Neutralizing Antibodies

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. / Gao, Ben Bo; Clermont, Allen; Rook, Susan; Fonda, Stephanie J.; Srinivasan, Vivek; Wojtkowski, Maciej; Fujimoto, James G.; Avery, Robert L.; Arrigg, Paul G.; Bursell, Sven Erik; Aiello, Lloyd Paul; Feener, Edward P.

In: Nature Medicine, Vol. 13, No. 2, 01.02.2007, p. 181-188.

Research output: Contribution to journalArticle

Gao, BB, Clermont, A, Rook, S, Fonda, SJ, Srinivasan, V, Wojtkowski, M, Fujimoto, JG, Avery, RL, Arrigg, PG, Bursell, SE, Aiello, LP & Feener, EP 2007, 'Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation', Nature Medicine, vol. 13, no. 2, pp. 181-188. https://doi.org/10.1038/nm1534
Gao, Ben Bo ; Clermont, Allen ; Rook, Susan ; Fonda, Stephanie J. ; Srinivasan, Vivek ; Wojtkowski, Maciej ; Fujimoto, James G. ; Avery, Robert L. ; Arrigg, Paul G. ; Bursell, Sven Erik ; Aiello, Lloyd Paul ; Feener, Edward P. / Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. In: Nature Medicine. 2007 ; Vol. 13, No. 2. pp. 181-188.
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