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A. C. Clermont, B. Gao, D. Bursell, S. Rook, S.-E. Bursell, L. P. Aiello, E. P. Feener; Activation of the Kallikrein/Kinin-Mediated Innate Inflammation in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4982.
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Excessive retinal vascular permeability (RVP) contributes to the pathogenesis of diabetic retinopathy and macular edema. This study utilized a multi-disciplinary approach of human vitreous proteomics, bioinformatics, retinal physiology, and biochemistry to uncover novel mechanisms that contribute to retinal inflammation and RVP.
The vitreous proteomes from non-diabetic (NDM) and proliferative diabetic retinopathy (PDR) subjects were characterized by tandem mass spectroscopy. RVP and leukostasis were measured by vitreous fluorophotometry and fluorescein angiography in Sprague-Dawley rats.
We identify a 15.3- & 5.6- fold increase in extracellular carbonic anhydrase -I (CA-I)and II (CA-II), respectively, in vitreous from patients with NPDR or PDR compared with NDM samples (p<0.05). In rats, intravitreal injection of CA-I at concentrations observed in human vitreous during PDR resulted in a potent dose-responsive induction of RVP (EC50 = 670 pg/µL) and retinal vascular leukostasis, which required CA enzymatic activity. CA-I induced RVP was inhibited by bradykinin receptor antagonists, complement 1 inhibitor, and a neutralizing antibody that blocks factor XII-mediated prekallikrein (PK) activation. Intravitreal injection of CA-1 induced a rapid (< 10 min) increase in vitreous pH (7.81±0.21, p=0.002), compared with baseline or saline injections (pH 7.41±0.15). Alkalization alone was sufficient to induce PK-mediated RVP and increased contact activation of the Factor XII and PK system by 4 fold. Activated forms of Factor XIIa and kallikrein were present in the vitreous of PDR patients.
Release of CA-I internal to the blood retinal barrier results in increased extracellular pH, which lead to the activation of the kallikrein-kinin pathway. These data suggests a novel pathway for the activation of innate inflammation in diabetic retinopathy.
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