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A. C. Clermont, J. Phipps, J. Liu, B. Gao, E. P. Feener; Intravitreal Plasma Kallikrein Induces Retinal Vascular Permeability (RVP) and Inflammation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4805.
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© ARVO (1962-2015); The Authors (2016-present)
Proteomic studies have demonstrated the presence of the kallikrein kinin system components, including plasma kallikrein (PK), in the vitreous from people with diabetic retinopathy. Previously, we have shown that intravitreal carbonic anhydrase-I increases retinal vascular permeability (RVP) in rats and that this reponse is blocked by co-injection with a prekallikrein (prePK) neutralizing antibody, suggesting that intraocular plasma kallikrein activation induces blood retinal barrier dysfunction and edema. In this study, we examine the direct effect of PK on RVP and inflammation, and the role of diabetes in modulating the effects of PK on the retina.
Activated plasma kallikrein PK(act) or the combination of prePK, Factor XII, and high molecular weight kininogen (PK/FXII/HK) were injected into the vitreous of nondiabetic (NDM) or 3 week duration diabetic (DM) rats and 3 month Akita DM mice. RVP was measured by vitreous fluorophotometry after 40 minutes. Leukocyte adhesion was measured by acridine orange infusion at 24 hours. Retinal focal leakage was observed by perfusion of 200kDa FITC-dextran conjugate after 48 hours.
In NDM rats, intravitreal injection of PK(act) and PK/FII/HK complex increased acute RVP by 65% and 88%, respectively, compared to vehicle-injected eyes (both P<0.05). PK(act) and PK/FXII/HK also increased retinal leukocyte adhesion by 100% (7.0±0.9 vs 3.5±0.7 cells/pixel, p<0.05) and 325% (16.6±8.5 vs 3.9±0.3 cells/pixel, p<0.01), respectively, compared to vehicle. PK/FXII/HK induced leukocyte adhesion was reduced by 76% (6.9±8.0 cells/pixel) in rats pretreated with bradykinin receptor 2 (B2-R) antagonist HOE140 by osmotic pump (1µg/kg/hr). A single intravitreal injection of 20 ng PK(act) into NDM rats also induced the appearance of focal areas of vascular leakage to FITC-Dextran at 48 hrs post injection and the extent of focal leakage was increased in DM rats. Intravitreal injection of PK(act) in Akita mice with 3 months of diabetes induces numerous focal areas of vascular leakage whereas no focal leakage was observed in NDM or DM mice that received control injections with saline (BSS) vehicle.
These results show that PK is a potent agonist of retinal inflammation, accompanied by increased RVP and leukocyte adhesion. Diabetes increases extent of PK-induced focal retinal leakage, suggesting that diabetes facilitates PK-mediated blood retinal barrier dysfunction.
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