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.

1. Research Division, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, Massachusetts 02215, USA.
2. Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
3. Department of Electrical Engineering and Computer Science, and Research Laboratory of Electronics, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
4. Santa Barbara Cottage Hospital Eye Center, 515 E Micheltorena Street, Santa Barbara, California 93103, USA.
5. Beetham Eye Institute, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, Massachusetts 02215, USA.
6. Department of Ophthalmology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.

Correspondence to: Edward P Feener^1,2 e-mail: edward.feener@joslin.harvard.edu

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