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A.C. Clermont, B. Gao, S. Rook, V. Srinivasen, J. Fujimoto, S. Bursell, L.P. Aiello, E. Feener; Extracellular Carbonic Anhydrase I (CA–I) Induces Retinal Vascular Permeability (RVP) and Intraretinal Edema: A Potential Target Against Diabetic Macular Edema . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5516.
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While VEGF is associated with increased RVP and angiogenesis in proliferative diabetic retinopathy (PDR), the trigger for macular edema remains elusive. Proteomic analysis identified extracellular CA–I in the vitreous of patients with PDR. This study investigates whether extracellular CA–I affects RVP and leads to intraretinal edema.
The vitreous proteomes from non–diabetic (NDM), no diabetic retinopathy (NoDR) or PDR subjects were characterized by tandem mass spectroscopy. RVP was measured by vitreous fluorophotometry in male Sprague–Dawley rats. After baseline measurements, 10 µL intravitreal injections of CA–I (Sigma), balanced salt solution (BSS), or human vitreous from NDM,noDR or PDR subjects were performed. High–speed ultrahigh resolution optical coherence tomography (OCT) was performed at 48 hours post intraviteal injection of CA–I or BSS in 2 week duration STZ–induced diabetic rats.
CA–I concentration was elevated in PDR compared with NDM and NoDR samples 13.5 & 7.1 fold, respectively (p<0.05). Injection of PDR human vitreous into rat vitreous increased RVP compared with vitreous from subjects without PDR (p<0.02) or BSS alone (p<0.05). PDR–induced RVP was reduced by co–injection with 10µM acetazolamide (13.7±5.2 vs 9.2±3.9, p=0.017) CA–I alone increased RVP in a dose–dependent manner, with a maximal increase of 120% (20.7±4.4au, p<0.05) at 2ng/µL compared with BSS control (9.8±3.4au). The EC50 of CA–I was 670 pg/µL and the CA–I mediated increase in RVP was sustained for over 24 hrs. OCT demonstrated a CA–I induced increase in diabetic retinal thickness (12%) primarily in the outer nuclear layer (31%) as compared to BSS. No difference was observed in NDM rats.
CA–I is a potent retinal permeability factor that induces intraretinal edema. Elevated concentrations of CA–I in the vitreous of patients with advanced DR and marked induction of retinal edema in diabetic animals suggest that inhibition of CA–I might have therapeutic benefit in these disorders.
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