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Notch2 activation ameliorates nephrosis

Author

Listed:
  • Eriko Tanaka

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
    Graduate School of Medicine, Tokyo Medical and Dental University)

  • Katsuhiko Asanuma

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
    Medical Innovation Center, Laboratory for Kidney Research(TMK project), Kyoto University Graduate School of Medicine)

  • Eunhee Kim

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Yu Sasaki

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Juan Alejandro Oliva Trejo

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Takuto Seki

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Kanae Nonaka

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Rin Asao

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Yoshiko Nagai-Hosoe

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Miyuki Akiba-Takagi

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Teruo Hidaka

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

  • Masatoshi Takagi

    (Graduate School of Medicine, Tokyo Medical and Dental University)

  • Akemi Koyanagi

    (Biomedical Reseach Center, Juntendo University Graduate School of Medicine)

  • Shuki Mizutani

    (Graduate School of Medicine, Tokyo Medical and Dental University)

  • Hideo Yagita

    (Biomedical Reseach Center, Juntendo University Graduate School of Medicine
    Juntendo University School of Medicine)

  • Yasuhiko Tomino

    (Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan)

Abstract

Activation of Notch1 and Notch2 has been recently implicated in human glomerular diseases. Here we show that Notch2 prevents podocyte loss and nephrosis. Administration of a Notch2 agonistic monoclonal antibody ameliorates proteinuria and glomerulosclerosis in a mouse model of nephrosis and focal segmental glomerulosclerosis. In vitro, the specific knockdown of Notch2 increases apoptosis in damaged podocytes, while Notch2 agonistic antibodies enhance activation of Akt and protect damaged podocytes from apoptosis. Treatment with triciribine, an inhibitor of Akt pathway, abolishes the protective effect of the Notch2 agonistic antibody. We find a positive linear correlation between the number of podocytes expressing activated Notch2 and the number of residual podocytes in human nephrotic specimens. Hence, specific activation of Notch2 rescues damaged podocytes and activating Notch2 may represent a novel clinical strategy for the amelioration of nephrosis and glomerulosclerosis.

Suggested Citation

  • Eriko Tanaka & Katsuhiko Asanuma & Eunhee Kim & Yu Sasaki & Juan Alejandro Oliva Trejo & Takuto Seki & Kanae Nonaka & Rin Asao & Yoshiko Nagai-Hosoe & Miyuki Akiba-Takagi & Teruo Hidaka & Masatoshi Ta, 2014. "Notch2 activation ameliorates nephrosis," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4296
    DOI: 10.1038/ncomms4296
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