Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo

Yohei Maeshima, Naoki Kashihara, Tatsuji Yasuda, Hitoshi Sugiyama, Takashi Sekikawa, Kazunori Okamoto, Koichiro Kanao, Yuzo Watanabe, Yashpal S. Kanwar, Hirofumi Makino

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Abstract

The transcription factor E2F coordinately activates several cell cycle- regulatory genes. We attempted to inhibit the proliferation of mesangial cells in vitro and in vivo by inhibiting E2F activity using a 25-bp decoy oligodeoxynucleotide that contained consensus E2F binding site sequence (E2F- decoy) as a competitive inhibitor. The decoy's effect on human mesangial cell proliferation was evaluated by [3H]thymidine incorporation. The E2F decoy inhibited proliferation in a concentration-dependent manner, whereas a mismatch control oligodeoxynucleotide had little effect. Electrophoretic mobility shift assays demonstrated that the decoy's inhibitory effect was due to the binding of the decoy oligodeoxynucleotide to E2F. The effect of the E2F decoy was then tested in a rat anti-Thy 1.1 glomerulonephritis model. The E2F decoy oligodeoxynucleotide was introduced into the left kidney 36 h after the induction of glomerulonephritis. The administration of E2F decoy suppressed the proliferation of mesangial cells by 71%. Furthermore, treatment with the E2F decoy inhibited the glomerular expression of proliferating cell nuclear antigen at the protein level as well as the mRNA level. These findings indicate that decoy oligonucleotides can suppress the activity of the transcription factor E2F, and may thus have a potential in treating glomerulonephritis.

Original languageEnglish
Pages (from-to)2589-2597
Number of pages9
JournalJournal of Clinical Investigation
Volume101
Issue number11
DOIs
Publication statusPublished - Jun 1 1998

Keywords

  • Cationic liposomes
  • Glomerulonephritis
  • Kidney
  • Transcription factor
  • Transfection

ASJC Scopus subject areas

  • Medicine(all)

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    Maeshima, Y., Kashihara, N., Yasuda, T., Sugiyama, H., Sekikawa, T., Okamoto, K., Kanao, K., Watanabe, Y., Kanwar, Y. S., & Makino, H. (1998). Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo. Journal of Clinical Investigation, 101(11), 2589-2597. https://doi.org/10.1172/JCI429