title: Notch2 activation ameliorates nephrosis.
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.
authors: 1] Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan [2] Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Eriko
authors: E
authors: Tanaka
authors: 1] Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan [2] Medical Innovation Center, Laboratory for Kidney Research(TMK project), Kyoto University Graduate School of Medicine, Kyoto 606-8506, Japan.
authors: Katsuhiko
authors: K
authors: Asanuma
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Eunhee
authors: E
authors: Kim
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Yu
authors: Y
authors: Sasaki
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Juan Alejandro
authors: JA
authors: Oliva Trejo
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Takuto
authors: T
authors: Seki
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Kanae
authors: K
authors: Nonaka
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Rin
authors: R
authors: Asao
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Yoshiko
authors: Y
authors: Nagai-Hosoe
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Miyuki
authors: M
authors: Akiba-Takagi
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Teruo
authors: T
authors: Hidaka
authors: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Masatoshi
authors: M
authors: Takagi
authors: Division of Cell Biology, Biomedical Reseach Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors: Akemi
authors: A
authors: Koyanagi
authors: Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Shuki
authors: S
authors: Mizutani
authors: 1] Division of Cell Biology, Biomedical Reseach Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan [2] Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Yasuhiko
authors: Y
authors: Tomino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004317:Doxorubicin; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051883:Receptor, Notch2 / Q000819:agonists*
chemical_list: D000911:Antibodies, Monoclonal; D051883:Receptor, Notch2; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt