ＰＤの腹膜機能不全、慢性腎臓病に対するリンパ管新生を標的とした新規治療戦略

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24591228
• Research Institution: Nagoya University
• Principal Investigator: 伊藤 恭彦 名古屋大学, 医学(系)研究科(研究院), 寄附講座教授 (60402632)
• Co-Investigator(Kenkyū-buntansha): 水野 正司 名古屋大学, 医学(系)研究科(研究院), 寄附講座准教授 (20303638) ; 鈴木 康弘 名古屋大学, 医学(系)研究科(研究院), 寄附講座助教 (20584676) ; 松尾 清一 名古屋大学, 医学(系)研究科(研究院), 教授 (70190410) ; 武井 佳史 名古屋大学, 医学(系)研究科(研究院), 准教授 (70362233)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: リンパ管 / VEGF-C / VEGFR-3 / TGF-b

Outline of Annual Research Achievements

(1) 腹膜機能障害におけるリンパ管新生について
PD排液中のVEGF-C濃度はD/P Crと相関を認め、排液中TGF-b1濃度とも相関を認めた。UFFおよび腹膜炎腹膜組織においてVEGF-C、リンパ管の発現亢進を認めた。培養中皮細胞、macrophageにおいてのみTGF-b1刺激によりVEGF-C発現は増加し、TGF-b受容体阻害剤投与によりVEGF-C発現増加が抑制された。ヒトPD排液由来腹膜中皮細胞においてTGF-b1刺激によるVEGF-C増加はD/P Crと相関を認めた。CGモデル腹膜において増加したVEGF-C、VEGF Receptor3 (VEGFR3)、リンパ管の発現はTGF-b受容体阻害剤による線維化抑制治療により軽減した。CGモデルにおいて、腹腔内投与したFITC-dextranの吸収、体循環へのドレナージはリンパ管新生によって増加し、COX2阻害剤およびadenovirus VEGFR3-Ig投与によるリンパ管新生抑制により減少した。腹膜線維化とともにTGF-b-VEGF-C pathwayを介しリンパ管新生が進行することが明らかとなり論文化した(JASN 2013)。線維化にともなったリンパ管新生が、PDにおける透析液吸収を介しUFFに深く関与することが明らかとなり、VEGFR3が新たな治療ターゲットとなりうることを示し、現在、投稿中である。
(2) VEGF-C transgenic miceについて
Collagen Iをプロモーターとした、線維化に伴いVEGF-Cが過剰発現するTgマウスを作製した。低コピーgene発現マウス、高コピーgene発現マウスででき、腹膜擦過モデルでリンパ管新生の亢進が確認できた。今後さらなる検討が必要であると考えられる。

Research Products

• [Journal Article] Expression of membrane complement regulators, CD46, CD55 and CD59, in mesothelial cells of patients one peritoneal dialysis therapy. (2015)
  • Author(s): Sei Y, Mizuno M, Suzuki Y, Imai M, Higashide K, Harris CL, Sakata F, Iguchi D, Fujiwara M, Kodera Y, Maruyama S, Matsuo S, Ito Y
  • Journal Title: Molecular Imunology Volume: 65(2) Pages: 302-309
  • DOI: 10.1016/j.molimm.2015.02.005.
  • Peer Reviewed
• [Journal Article] Calcified amorphous tumor in the left atrium of a patient on long-term peritoneal dialysis. (2015)
  • Author(s): Tanaka A, Mizuno M, Suzuki Y, Oshima H, Sakata F, Ishikawa H, Tsukushi S, Ito Y
  • Journal Title: Internal Medicine Volume: 54（5） Pages: 481-485
  • DOI: 10.2169/internalmedicine.54.2967.
  • Peer Reviewed
• [Journal Article] Morphological caracteristics in peritoneum in patients with neutral peritoneal dialysis solution. (2015)
  • Author(s): Hamada C, Honda K, Kawanishi K, Nakamoto H, Ito Y, Sakurada T, Tanno Y, Mizumasa T, Miyazaki M, Moriishi M, Nakayama M
  • Journal Title: Journal of Artifical Organs(in press 2015) Volume: Epub Pages: Epub
  • DOI: 10.1007/s10047-015-0822-4
  • Peer Reviewed
• [Journal Article] Long-term effects of Spironolactone in peritoneal dialysis patients. (2014)
  • Author(s): Ito Y, Mizuno M, Suzuki Y, Tamai H, Hiramatsu T, Ohashi H, Ito I, Kasuga H, Horie M, Maruyama S, Yuzawa Y, Matsubara T, Matsuo S, Nagoya Spiro Study Group
  • Journal Title: Journal of the American society of nephrology Volume: 25(5) Pages: 1094-1102
  • DOI: 10.1681/ASN.201303273
  • Peer Reviewed
• [Journal Article] Rat adipose tissue-derived stem cells attenuate peritoneal injuries in rat zymosan-induced peritonitis accompanied by complement activation. (2014)
  • Author(s): Kim H, Mizuno M, Furuhashi K, Katsuno T, Ozaki T, Yasuda K, Tsuboi N, Sato W, Suzuki Y, Matsuo S, Ito Y, Maruyama S
  • Journal Title: Cytotherapy Volume: 16(3) Pages: 357-368
  • DOI: 10.1016/j.jcyt.2013.10.011.
  • Peer Reviewed
• [Journal Article] Geriatric nutritional risk index accurately predicts cardiovascular mortality in incident hemodialysis patients. (2014)
  • Author(s): Takahashi H, Ito Y, Ishii H, Aoyama T, Kamoi D, Kasuga H, Yasuda K, Maruyama S, Matsuo S, Murohara T, Yuzawa Y
  • Journal Title: Journal of Cardiology Volume: 64(1) Pages: 32-36
  • DOI: 10.1016/j.jjcc.2013.10.018.
  • Peer Reviewed
• [Journal Article] Efficacy and safety of fluoroscopic manipulation using the alpha-replacer for peritoneal catheter malposition. (2014)
  • Author(s): Saka Y, Ito Y, Iida Y, Maruyama S, Matsuo S
  • Journal Title: Clinical and Experimental Nephrology(Epub ahead of print) Volume: Epub Pages: Epub
  • DOI: 10.1007/s10157-014-1007-9.
  • Peer Reviewed
• [Journal Article] Successful treatment of Cryptococcus laurentii peritonitis in a patient on peritoneal dialysis. (2014)
  • Author(s): Asano M, Mizutani M, Nagahara Y, Inagaki K, Kariya T, Masamoto D, Urai M, Kaneko Y, Ohno H, Miyazaki Y, Mizuno M, Ito Y
  • Journal Title: Internal Medicine(in press 2014) Volume: Epub Pages: Epub
  • Peer Reviewed
• [Journal Article] Smoking is a risk factor for the progression of ideopathic membranous nephropathy. (2014)
  • Author(s): Yamaguchi M, Ando M, Yamamoto R, Akiyama S, Kato S, Katsuno T, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S
  • Journal Title: PLOS ONE Volume: 9(6) Pages: 1-8
  • DOI: 10.371/journal.pone.0100835
  • Peer Reviewed
• [Journal Article] Tubulointerstitial fibrosis in patients with lgG4-related kidney disease: pathological findings on repeat renal biopsy. (2014)
  • Author(s): Arai H, Hayashi H, Takahashi K, Koide S, Sato W, Hasegawa M, Yamaguchi Y, Aten J, Ito Y, Yuzawa Y
  • Journal Title: Rheumatology International(in press 2014) Volume: Epub Pages: Epub
  • DOI: 10.1007/s00296-014-3153-5
  • Peer Reviewed
• [Presentation] Vascular Endothelial Growth Factor Receptor-3 Can Be a New Target to Improve Ultrafiltration Dysfunction in Methylglyoxal-Induced Peritoneal Injury (2014)
  • Author(s): Terabayashi T, Ito Y, Mizuno M, Suzuki Y, Kinashi H, Sakata F, Maruyama S, Takei Y, Matsuo S
  • Organizer: American Society of Nephrology Kidney Week 2014
  • Place of Presentation: Pennsylvania Convention Center, America
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] The Effects of Rotigotine Patch for Restless Legs Syndrome in Japanese HD Patients (2014)
  • Author(s): Kasuga H, Takahashi R, Kimura K, Matsubara C, Kawashima K, Ito Y
  • Organizer: American Society of Nephrology Kidney Week 2014
  • Place of Presentation: Pennsylvania Convention Center, America
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] Levels of soluble C5B-9 complex fluid may be a predictor of poor prognosis in peritonitis in peritoneal dialysis patients, especially in culture negative peritonitis (2014)
  • Author(s): Mizuno M, Ito Y, Higashide K, Sei Y, Iguchi D, Sakata F, Suzuki Y, Ito I, Horie M, Morgan BP, Matsuo S
  • Organizer: XXV International Complement Workshop
  • Place of Presentation: Brazil,Rio de Janeiro
  • Year and Date: 2014-09-14 – 2014-09-18
• [Presentation] Calcified amorphous tumor of the heart in a peritoneal dialysis patient (2014)
  • Author(s): Tanaka A, Mizuno M, Sakata F, Suzuki Y, Ohshima H, Ishikawa H, Tsukushi S, Maruyama S, Matsuo S, Ito Y
  • Organizer: 15th Congress of the International Society for Peritoneal Dialysis
  • Place of Presentation: Spain,Madrid
  • Year and Date: 2014-09-07 – 2014-09-10
• [Presentation] Zinc deficiency is associated with an inadequate protein intake in peritoneal dialysis patients (2014)
  • Author(s): Saka Y, Ito Y, Iida Y, Naruse T, Maruyama S, Watanabe Y, Matsuo S
  • Organizer: 15th Congress of the International Society for Peritoneal Dialysis
  • Place of Presentation: Spain,Madrid
  • Year and Date: 2014-09-07 – 2014-09-10
• [Presentation] Assisted PDをめざした名古屋地区における取り組み (2014)
  • Author(s): 伊藤恭彦
  • Organizer: 第20回腹膜透析医学会学術集会・総会
  • Place of Presentation: 山形国際ホテル（山形県山形市）
  • Year and Date: 2014-09-06 – 2014-09-07
  • Invited
• [Presentation] より長期の腹膜透析療法を目指して (2014)
  • Author(s): 伊藤恭彦
  • Organizer: 第59回日本透析医学会学術集会・総会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県神戸市）
  • Year and Date: 2014-06-12 – 2014-06-15
  • Invited
• [Presentation] Lymphangiogenesis develops during peritoneal fibrosis in rat peritonitis models (2014)
  • Author(s): Terabayashi T, Ito Y, Kinashi H, Mizuno M, Suzuki Y, Sakata F, Tomita T, Tawada M, Sei Y, Iguchi D, Matsuo S
  • Organizer: The 14th Asian Pacific Congress of Nephrology
  • Place of Presentation: Shinagawa Prince Hotel(東京都港区)
  • Year and Date: 2014-05-14 – 2014-05-17
• [Presentation] Cryptococcus laurentii peritonitis in a peritoneal dialysis patient (2014)
  • Author(s): Asano M, Nagahara Y, Inagaki K, Kariya T, Masamoto D, Mizutani M, Ito Y
  • Organizer: The 14th Asian Pacific Congress of Nephrology
  • Place of Presentation: 品川プリンスホテル(東京都港区)
  • Year and Date: 2014-05-14 – 2014-05-17