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Kousuke Noda, Susumu Ishida, Hajime Shinoda, Takashi Koto, Takanori Aoki, Kazuo Tsubota, Yoshihisa Oguchi, Yasunori Okada, Eiji Ikeda; Hypoxia Induces the Expression of Membrane-Type 1 Matrix Metalloproteinase in Retinal Glial Cells. Invest. Ophthalmol. Vis. Sci. 2005;46(10):3817-3824. doi: 10.1167/iovs.04-1528.
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purpose. Fibrovascular tissue formation in diabetic retinopathy necessitates not only angiogenic activity but also proteolytic activity, which is at least in part attributable to the induction of membrane-type 1 matrix metalloproteinase (MT1-MMP) in retinal glial cells. However, little is known about the triggers for MT1-MMP induction in the diabetic retina. In the present study, the effect of tissue hypoxia on MT1-MMP expression in retinal glial cells was investigated.
methods. Retinal glial cells were isolated from the rabbit retina and cultured under either normoxic (20% O2) or hypoxic (1% O2) conditions in the presence or absence of the inhibitor for vascular endothelial growth factor (VEGF) receptor signal transduction or a neutralizing antibody against VEGF. The expression level of MT1-MMP in retinal glial cells was analyzed by reverse transcription–polymerase chain reaction (RT-PCR), real-time PCR, Western blot analysis and immunocytochemistry. Expression of VEGF and VEGF receptors, VEGFR-1 and VEGFR-2, was also examined by RT-PCR.
results. RT-PCR and real-time PCR analyses showed a 2.3-fold induction of MT1-MMP expression in retinal glial cells under hypoxic conditions. VEGF, especially its isoform VEGF165, and VEGFR-2 were also upregulated in retinal glial cells by hypoxia, and hypoxia-induced MT1-MMP expression was inhibited in the presence of the VEGFR-2 inhibitor SU1498 or the anti-VEGF antibody.
conclusions. Hypoxia can induce MT1-MMP expression in retinal glial cells, and the hypoxia-induced expression of MT1-MMP is mediated by VEGF in an autocrine fashion.
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