Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation.
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.
Gao
Ben-Bo
BB
Research Division, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, Massachusetts 02215, USA.
Clermont
Allen
A
Rook
Susan
S
Fonda
Stephanie J
SJ
Srinivasan
Vivek J
VJ
Wojtkowski
Maciej
M
Fujimoto
James G
JG
Avery
Robert L
RL
Arrigg
Paul G
PG
Bursell
Sven-Erik
SE
Aiello
Lloyd Paul
LP
Feener
Edward P
EP
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D065168:Bradykinin Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000378:metabolism* / Q000633:toxicity; D003172:Complement C1 / Q000037:antagonists & inhibitors; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D005136:Eye Proteins / Q000378:metabolism*; D015956:Factor XIIa / Q000378:metabolism; D006801:Humans; D016234:Kallikrein-Kinin System / Q000502:physiology*; D013058:Mass Spectrometry; D010211:Papilledema / Q000139:chemically induced; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014822:Vitreous Body / Q000201:enzymology*
D065168:Bradykinin Receptor Antagonists; D002257:Carbonic Anhydrase Inhibitors; D003172:Complement C1; D005136:Eye Proteins; D015956:Factor XIIa; D002256:Carbonic Anhydrases; D000086:Acetazolamide