Notch2 activation ameliorates nephrosis

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 Takagi, Akemi Koyanagi, Shuki Mizutani, Hideo Yagita and Yasuhiko Tomino ()
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Eriko Tanaka: Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Katsuhiko Asanuma: Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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
Yasuhiko Tomino: Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4296

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