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

Nat Med. 2007 Feb;13(2):181-8. doi: 10.1038/nm1534. Epub 2007 Jan 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetazolamide / pharmacology
  • Animals
  • Blotting, Western
  • Bradykinin Receptor Antagonists
  • Capillary Permeability / drug effects*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Carbonic Anhydrase Inhibitors / therapeutic use*
  • Carbonic Anhydrases / metabolism*
  • Carbonic Anhydrases / toxicity
  • Complement C1 / antagonists & inhibitors
  • Diabetic Retinopathy / drug therapy*
  • Eye Proteins / metabolism*
  • Factor XIIa / metabolism
  • Humans
  • Kallikrein-Kinin System / physiology*
  • Mass Spectrometry
  • Papilledema / chemically induced
  • Proteomics
  • Rats
  • Rats, Sprague-Dawley
  • Statistics, Nonparametric
  • Vitreous Body / enzymology*


  • Bradykinin Receptor Antagonists
  • Carbonic Anhydrase Inhibitors
  • Complement C1
  • Eye Proteins
  • Factor XIIa
  • Carbonic Anhydrases
  • Acetazolamide