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Treatment of focal segmental glomerulosclerosis by Notch signaling inhibition

Research Project

Project/Area Number 22590877
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionUniversity of Tsukuba

Principal Investigator

NAGATA Michio  筑波大学, 医学医療系, 教授 (10192238)

Project Period (FY) 2010 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsポドサイト / FSGS / ノッチシグナル / ノッチ / 壁側上皮細胞 / Notchシグナル / 糸球体硬化 / γ-secretase
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.

Report

(4 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • Research Products

    (23 results)

All 2013 2012 2011 2010

All Journal Article (12 results) (of which Peer Reviewed: 12 results) Presentation (11 results)

  • [Journal Article] Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss2013

    • Author(s)
      Ueno T, Kobayashi N, Nakayama M, Takashima Y, Uesugi N, Pastan D, Pippin J, Shankland S, Matsusaka Nagata M.
    • Journal Title

      Kidney Int

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss.2013

    • Author(s)
      Ueno T
    • Journal Title

      Kindney Int

      Volume: 83

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Remission of proteinuria in renal amyloidosis secondary to rheumatoid arthritis2012

    • Author(s)
      Ueno T, Takeda Y, Nagata M
    • Journal Title

      Nephrol Dial Transplant

      Volume: 27(2) Pages: 633-9

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Histological heterogeneity of glomerular segmental lesions in focal segmental glomerulo sclerosis2012

    • Author(s)
      Honda K, Taneda S, Yumura W Nitta K, Oda H, Nagata M
    • Journal Title

      Nephrol

      Volume: 44(1) Pages: 183-96

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Characteristic tubulointerstitial nephritis in IgG4-related disease2012

    • Author(s)
      Yamaguchi Y, Kanetsuna Y, Honda K, Kawano M, Yamanaka N, Nagata M
    • Journal Title

      Human Pathol

      Volume: 43(4) Pages: 536-549

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Focal segmental glomerulosclerosis in patients with complete deletion of one WT1 allele.2012

    • Author(s)
      Iijima K, Someya T, Ito S, Nozu K, Nakanishi K, Matsuoka K, Ohashi H, Nagata M, Kamei K, Sasaki S
    • Journal Title

      Pediatrics

      Volume: 129(6)

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [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
    • Journal Title

      Clin Nephrol

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Nephrol Dial Transplant

      Volume: 26(1) Pages: 371-3

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Aberrantly glycosylated IgA1 as a factor in the pathogenesis of IgA nephropathy. Clin Dev Immunol.2011

    • Author(s)
      Tanaka M, Seki G, Someya T, Nagata M, Fujita T.
    • Journal Title

      Clin Dev Immunol

      Volume: 2011 Pages: 470803-470803

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Resolution of Henoch-Schonlein purpura nephritis after acquired IgA deficiency2010

    • Author(s)
      Tanaka M, Seki G, Ishizawa K, Hirahashi J, Miura K, Sekine T, Someya T, Hataya H, Nagata M, Fujita T
    • Journal Title

      Pediatr Nephrol

      Volume: 25(11) Pages: 2355-8

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Successful treatment of collapsing focal segmental glomerulosclerosis with a combination of rituximab, steroids and ciclosporin2010

    • Author(s)
      Kaito H, Kamei K, Kikuchi E, Ogura M, Matsuoka K, Nagata M, Iijima K, Ito S
    • Journal Title

      Pediatr Nephrol

      Volume: 25(5) Pages: 957-9

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cyclic stretch induces proliferation and TGF-beta1-mediated apoptosis via p38 and ERK in ureteric bud cells2010

    • Author(s)
      Fujita H, Hida M, Kanemoto K, Fukuda K, Nagata M, Awazu M
    • Journal Title

      Am J Physiol Renal Physiol

      Volume: 299(3)

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Presentation] Notch signal induced parietal cells hyperplasia in collapsing FSGS with progressive podocyte loss.2012

    • Author(s)
      Ueno T
    • Organizer
      アメリカ腎臓学会
    • Place of Presentation
      フィラデルフィア
    • Related Report
      2012 Annual Research Report
  • [Presentation] シンポジウム、腎糸球体のリモデリングと分節性硬化2011

    • Author(s)
      長田道夫
    • Organizer
      第57回日本病理学会秋期特別総会
    • Place of Presentation
      東京
    • Year and Date
      2011-11-18
    • Related Report
      2012 Final Research Report
  • [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
    • Related Report
      2012 Final Research Report
  • [Presentation] Podocyte Injury Specific Microangiopathy in Collapsing FSGS; the Role of PAI-1 and the Beneficial Effect of Its Inhibitor TM5484.2011

    • Author(s)
      Namiko Kobayashi, Toshiharu Ueno, Toshio Miyata, Taiji Matsusaka, Michio Nagata
    • Organizer
      American Society of Nephrology Kidney week
    • Place of Presentation
      アメリカ
    • Year and Date
      2011-11-11
    • Related Report
      2012 Final Research Report
  • [Presentation] Novel Roles of Notch Signal in the Pathogenesis of Collapsing FSGS.2011

    • Author(s)
      Toshiharu Ueno, Namiko Kobayashi, Takamoto Ohse, Taiji Matsusaka, Jeffrey W. Pippin, Stuart J. Shankland, Michio Nagata
    • Organizer
      American Society of Nephrology Kidney week 2011.
    • Place of Presentation
      アメリカ
    • Year and Date
      2011-11-11
    • Related Report
      2012 Final Research Report
  • [Presentation] Novel role of Notch signal in the pathogenesis of collapsing FSGS2011

    • Author(s)
      上野智敏
    • Organizer
      American Society of Nephrology
    • Place of Presentation
      フィラデルフィア(USA)
    • Year and Date
      2011-11-11
    • Related Report
      2011 Annual Research Report
  • [Presentation] Collapsing glomerulopathyにおけるNotchシグナルの発現2011

    • Author(s)
      上野智敏
    • Organizer
      日本腎臓学会
    • Place of Presentation
      横浜
    • Year and Date
      2011-06-17
    • Related Report
      2011 Annual Research Report
  • [Presentation] シンポジウムPodocytology and FSGS2011

    • Author(s)
      Michio Nagata:
    • Organizer
      第46回日本小児腎臓病学会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2011-06-13
    • Related Report
      2012 Final Research Report
  • [Presentation] Downregulation of mTOR signaling pathway by maternal nutrient restriction in rat metanephros2011

    • Author(s)
      Mariko Hida, Michio Nagata, Midori Awazul:
    • Organizer
      第46回日本小児腎臓病学会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2011-06-13
    • Related Report
      2012 Final Research Report
  • [Presentation] Two patients of atypical infantile nephritic syndrome.2011

    • Author(s)
      Shigeru Fukuyama, Tomoo Kise, Hiroshi Yoshimura, Michio Nagata, Kunihiko Aya
    • Organizer
      第46回日本小児腎臓病学会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2011-06-13
    • Related Report
      2012 Final Research Report
  • [Presentation] FSGSにおけるポドサイト障害と糸球体応答2011

    • Author(s)
      長田道夫
    • Organizer
      第6回弥彦ポドサイトセミナー
    • Place of Presentation
      新潟
    • Year and Date
      2011-03-05
    • Related Report
      2010 Annual Research Report

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Published: 2010-08-23   Modified: 2019-07-29  

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