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Allen Clermont, Qunfang Zhou, Takeshi Kita, Jia Liu, Lloyd Aiello, Edward Feener; Plasma Kallikrein Deficiency is protective against diabetes induced retinal vascular dysfunction. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1137.
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Components of the kallikrein-kinin system (KKS) including plasma kallikrein (PK) were shown to increase in the vitreous of patients with diabetic macular edema (DME). While pharmacological inhibition of PK reduces retinal vascular permeability (RVP) in diabetic rats the effects of PK gene deficiency on retinal function and structure has not been reported. The current study examines the effect of PK gene deletion upon systemic parameters, RVP, and retinal thickeness in diabetic and nondiabetic mice and on the neovascular response induced by oxygen-induced retinopathy (OIR).
Diabetes was induced in 3 month old male and female KlKb1 knockout (KO) and wildtype (WT) mice by injection of streptozotocin (45mg/kg) with age-matched non-diabetic control groups. Retinal scans were obtained by SD-OCT (Bioptigen) after 3 months. RVP was determined by extravasation of Evans blue dye (90mg/kg). PK, FXII, and their endogenous inhibitor, C1 inhibitor, were measured from plasma by western blot. OIR was induced by 75% oxygen for 5 days in p7 mice.
PPK deficiency in DM mice did not alter body weight gain and blood glucose. FXII was increased and C1-INH was decreased in DM-WT by 40% compared to NDM-WT, indicating KKS activation in diabetes. Retinal RVP was increased by 203% in DM-WT versus NDM-WT (p<0.001). RVP in male and female DM-KO was reduced by 58% (42.0±4.8 vs 63.3±8.4 ul/g/hr, p=0.033) and 78% (22.1±3.4 vs 59.1±7.5 ul/g/hr, p<0.001) compared to DM-WT, respectively. Total retinal thickness was reduced in both male (197±1.7 vs 209±1.2um, p<0.001) and female (199±1.2 vs 206±1.5um, p=0.002) DM-WT compared to NDM-WT. Total thickness in female DM-KO was similar to NDM-WT (205±1.3um) while male DM-KO was slightly increased (199±1.7um, p<0.001). Analysis of mice subjected to oxygen-induced retinopathy model showed no significant difference in the non-perfusion area and the area of neovascularization in the KO mice (31.78±3.33% and 6.60±2.3%) compared with WT mice (33.34±3.31% and 5.70±1.64%, respectively)
Plasma prekallikrein gene (Klkb1) knockout is well tolerated in diabetic mice and is protective against diabetes induced retinal vascular hyperpermeability. In contrast, Klkb1 deficiency does not significantly influence OIR-induced retinal neovascularization. These data extend previous pharmacological findings, which have implicated PK as a therapeutic target for DME.
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