Treatment of focal segmental glomerulosclerosis by Notch signaling inhibition

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590877
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: University of Tsukuba
• Principal Investigator: NAGATA Michio 筑波大学, 医学医療系, 教授 (10192238)
• Project Period (FY): 2010 – 2012
• 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.

Research Products

• [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, Kobayashi N, Nakayama M, Takashima Y, Uesugi N, Pastan D, Pippin J, Shankland S, Matsusaka Nagata M.
  • Journal Title: Kidney Int
  • Peer Reviewed
• [Journal Article] Remission of proteinuria in renal amyloidosis secondary to rheumatoid arthritis (2012)
  • Author(s): Ueno T, Takeda Y, Nagata M
  • Journal Title: Nephrol Dial Transplant Volume: 27(2) Pages: 633-9
  • Peer Reviewed
• [Journal Article] Histological heterogeneity of glomerular segmental lesions in focal segmental glomerulo sclerosis (2012)
  • Author(s): Honda K, Taneda S, Yumura W Nitta K, Oda H, Nagata M
  • Journal Title: Nephrol Volume: 44(1) Pages: 183-96
  • Peer Reviewed
• [Journal Article] Characteristic tubulointerstitial nephritis in IgG4-related disease (2012)
  • Author(s): Yamaguchi Y, Kanetsuna Y, Honda K, Kawano M, Yamanaka N, Nagata M
  • Journal Title: Human Pathol Volume: 43(4) Pages: 536-549
  • 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) Pages: e1621-5
  • Peer Reviewed
• [Journal Article] Henoch-Schonlein purpura nephritis in a patient with IgG4-related disease: A possible association (2012)
  • 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
  • Peer Reviewed
• [Journal Article] Focal segmental glomerulosclerosis as a complication of hepatitis B virus infection (2011)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Resolution of Henoch-Schonlein purpura nephritis after acquired IgA deficiency (2010)
  • 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
  • Peer Reviewed
• [Journal Article] Successful treatment of collapsing focal segmental glomerulosclerosis with a combination of rituximab, steroids and ciclosporin (2010)
  • 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
  • Peer Reviewed
• [Journal Article] Cyclic stretch induces proliferation and TGF-beta1-mediated apoptosis via p38 and ERK in ureteric bud cells (2010)
  • Author(s): Fujita H, Hida M, Kanemoto K, Fukuda K, Nagata M, Awazu M
  • Journal Title: Am J Physiol Renal Physiol Volume: 299(3) Pages: F648-5
  • Peer Reviewed
• [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
• [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
• [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
• [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
• [Presentation] シンポジウムPodocytology and FSGS (2011)
  • 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
• [Presentation] Downregulation of mTOR signaling pathway by maternal nutrient restriction in rat metanephros (2011)
  • 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
• [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