2012 Fiscal Year Final Research Report
Treatment of focal segmental glomerulosclerosis by Notch signaling inhibition
Project/Area Number |
22590877
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Kidney internal medicine
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Research Institution | University of Tsukuba |
Principal Investigator |
NAGATA Michio 筑波大学, 医学医療系, 教授 (10192238)
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Project Period (FY) |
2010 – 2012
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Keywords | ポドサイト / FSGS / ノッチシグナル |
Research Abstract |
Collapsing focal segmental glomerulosclerosis (cFSGS) is a progressive kidney disease characterized by glomerular collapse with epithelial hyperplasia. Here we used a transgenic mouse model of cFSGS with immunotoxin-induced podocyte-specific injury to determine the role for Notch signaling in its pathogenesis. The mice exhibited progressive loss of podocytes and severe proteinuria concomitant with histological features of cFSGS. Hyperplastic epithelium was negative for genetic podocyte tags, but positive for the parietal epithelial cell marker claudin-1, and expressed Notch1, Jagged1, and Hes1 mRNA and protein. Enhanced Notch mRNA expression induced by transforming growth factor-β1 in cultured parietal epithelial cells was associated with mesenchymal markers (α-smooth muscle actin, vimentin, and Snail1). Notch inhibition in vitro suppressed these phenotypic transcripts and Notch-dependent cell migration. Moreover, Notch inhibition in vivo significantly decreased parietal epithelial cell lesions but worsened proteinuria and histopathology in our cFSGS model. Thus, aberrant Notch1-mediated parietal epithelial cell migration with phenotypic changes appears to underlie the pathogenesis of cFSGS. Parietal epithelial cell hyperplasia may also represent an adaptive response to compensate for a disrupted filtration barrier with progressive podocyte loss.
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[Journal Article] Henoch-Schonlein purpura nephritis in a patient with IgG4-related disease: A possible association2012
Author(s)
Ito K, Yamada K, Mizushima I, Aizu M, Fujii H, Mizutomi K, Matsumura M, Hayashi K, Yamagish M, Umehara H, Yamaguchi Y, Nagata M, Kawano M
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Journal Title
Peer Reviewed
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[Journal Article] Focal segmental glomerulosclerosis as a complication of hepatitis B virus infection2011
Author(s)
Sakai K, Morito N, Usui J, Hagiwara M, Hiwatashi A, Fukuda K, Nanmoku T, Toda T, Matsui N, Nagata M, Yamagata K.
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Journal Title
Nephrol Dial Transplant
Volume: 26(1)
Pages: 371-3
Peer Reviewed
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[Presentation] A Novel Case of Nephrotic Syndrome Caused by Immune-Mediated SevereLCAT Deficiency.2011
Author(s)
Satoshi Takahashi, Keiju Hiromura, Mayuko Tsukida, Yuko Ohishi, Hiroko Hamatani, Noriyuki Sakurai, Toru Sakairi, Hidekazu Ikeuchi, Akito Maeshima,Takashi Kuroiwa, Michio Nagata, Yoshihisa Nojima
Organizer
American Society of Nephrology Kidney week
Place of Presentation
アメリカ
Year and Date
2011-11-12
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