Hypoxia induces the expression of membrane-type 1 matrix metalloproteinase in retinal glial cells

Kousuke Noda, Susumu Ishida, Hajime Shinoda, Takashi Koto, Takanori Aoki, Kazuo Tsubota, Yoshihisa Oguchi, Yasunori Okada, Eiji Ikeda

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3817-3824
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number10
DOIs
Publication statusPublished - 2005 Oct

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Matrix Metalloproteinase 14
Neuroglia
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
Reverse Transcription
Vascular Endothelial Growth Factor Receptor-1
Cell Hypoxia
Polymerase Chain Reaction
Retina
Real-Time Polymerase Chain Reaction
Vascular Endothelial Growth Factor Receptor
Hypoxia
Diabetic Retinopathy
Neutralizing Antibodies
Signal Transduction
Protein Isoforms
Western Blotting
Immunohistochemistry
Rabbits
Antibodies

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Hypoxia induces the expression of membrane-type 1 matrix metalloproteinase in retinal glial cells. / Noda, Kousuke; Ishida, Susumu; Shinoda, Hajime; Koto, Takashi; Aoki, Takanori; Tsubota, Kazuo; Oguchi, Yoshihisa; Okada, Yasunori; Ikeda, Eiji.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 10, 10.2005, p. 3817-3824.

Research output: Contribution to journalArticle

Noda, Kousuke ; Ishida, Susumu ; Shinoda, Hajime ; Koto, Takashi ; Aoki, Takanori ; Tsubota, Kazuo ; Oguchi, Yoshihisa ; Okada, Yasunori ; Ikeda, Eiji. / Hypoxia induces the expression of membrane-type 1 matrix metalloproteinase in retinal glial cells. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 10. pp. 3817-3824.
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AU - Ishida, Susumu

AU - Shinoda, Hajime

AU - Koto, Takashi

AU - Aoki, Takanori

AU - Tsubota, Kazuo

AU - Oguchi, Yoshihisa

AU - Okada, Yasunori

AU - Ikeda, Eiji

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N2 - 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.

AB - 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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