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Junichi Fukuhara, Kousuke Noda, Miyuki Murata, Shiho Namba, Satoshi Kinoshita, Zhenyu Dong, Ryo Ando, Anton Lennikov, Atsuhiro Kanda, Susumu Ishida; Tissue Kallikrein Attenuates Choroidal Neovascularization via Cleavage of Vascular Endothelial Growth Factor. Invest. Ophthalmol. Vis. Sci. 2013;54(1):274-279. doi: https://doi.org/10.1167/iovs.12-10512.
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To investigate the antiangiogenic properties of tissue kallikrein in a murine model of laser-induced choroidal neovascularization (CNV).
CNV was induced in male C57BL/6J mice by laser photocoagulation. The animals received daily subcutaneous injections of tissue kallikrein (50 μg/kg) or vehicle control for 2 days before the laser photocoagulation, and this treatment continued until sample collection. Seven days after laser injury, the CNV size was quantified. The levels of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and interleukin (IL)-6 were assessed by enzyme-linked immunosorbent assay 3 days after laser injury. Cleavage of mouse VEGF with tissue kallikrein was assessed in vivo and in vitro. The protein levels of bradykinin were assessed in the RPE-choroid complexes and hearts.
A significant decrease in CNV size was observed in animals treated with tissue kallikrein (27,168.3 ± 2432.2 μm2) compared with vehicle-treated controls (36,374.6 ± 3204.1 μm2, P < 0.05). Tissue kallikrein treatment significantly reduced MCP-1, ICAM-1, and IL-6 levels in RPE-choroid complexes. Furthermore, immunoblotting showed the bands, presumably corresponding to the fragmented VEGF164 protein, in the samples of both mouse VEGF preincubated with tissue kallikrein and RPE-choroid complexes obtained from animals treated with tissue kallikrein. In addition, bradykinin was unchanged in the RPE-choroid complexes of animals treated with tissue kallikrein, whereas the level of bradykinin was increased in the heart obtained from these experimental animals.
The current data indicate that kallikrein exhibits antiangiogenic properties by cleaving VEGF164 in a laser-induced CNV model.
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