Establishment of new strategy targeting lymphangiogenesis in the patients with renal diseases

• Project/Area Number: 15K09287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Aichi Medical University (2017-2018); Nagoya University (2015-2016)
• Principal Investigator: Yasuhiko Ito 愛知医科大学, 医学部, 教授 (60402632)
• Co-Investigator(Kenkyū-buntansha): 水野 正司 名古屋大学, 医学系研究科, 寄附講座教授 (20303638) ; 鈴木 康弘 名古屋大学, 医学系研究科, 寄附講座講師 (20584676) ; 坂田 史子 名古屋大学, 医学系研究科, 特任助教 (20726484) ; 武井 佳史 愛知学院大学, 薬学部, 教授 (70362233)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腹膜透析 / 腹膜機能不全 / リンパ管新生 / 血管新生 / 炎症 / 透過性亢進 / D/P Cr / リンパ管 / 食塩 / Lyve-1 / VEGFR-3 / VEGF-C / 腹膜透過性 / 腎間質障害

Outline of Final Research Achievements

Appropriate fluid balance is important for good outcomes in patients on peritoneal dialysis. The characteristic features of peritoneal injury with PD are fibrosis, inflammation and neoangiogenesis; however, these precise mechanisms remain unclear.
We investigated the 1) roles and pathophysiology of lymphangiogenesis in PD, 2) relationship between peritoneal fibrosis and angiogenesis, and 3) roles of high salt intake in PD. We conducted the studies using animal models, in vitro studies with mesothelial cells, fibroblasts, and macrophages, and human materials including peritoneal biopsy samples and PD effluent. In animal models Adeno-soluble VEGFR-3 effectively improve the drained volume by suppression of lymphangiogenesis, suggesting thatVEGFR-3 could be the new target to improve UF. Neoangiogenesis is associated with fibrosis by TGF-β1-VEGF-A pathway in mesothelial cells and fibroblasts. High salt intake induces the inflammation leading to the increase of peritoneal transport rates.

Academic Significance and Societal Importance of the Research Achievements

腹膜透析(PD)における除水不全の機序、対策が明らかになることによって、PD治療が長期に可能となり、PD患者負担が軽減する。ひいては医療経済にも好影響を与える。

Research Products

• [Journal Article] Sodium chloride promotes tissue inflammation via osmotic stimuli in sub-total-nephrectomized mice. (2017)
  • Author(s): Sakata F., Ito Y., Mizuno M, Sawai A, Suzuki Y, Tomita T, Tawada M, Tanaka A, Hirayama A, Sagara A, Wada T, Maruyama S, Soga T, Matsuo S, Imai E, Takei Y.
  • Journal Title: Lab Invest Volume: 97(4) Issue: 4 Pages: 432-446
  • DOI: 10.1038/labinvest.2017.4
  • Peer Reviewed / Open Access
• [Journal Article] High level of soluble C5b-9 complex in dialysis fluid is a predictor of poor prognosis in peritonitis in peritoneal dialysis patients. (2017)
  • Author(s): Matsuo S, Morgan BP, Ito Y.
  • Journal Title: PLoS One Volume: in press
• [Journal Article] Rat Models of Acute and/or Chronic Peritoneal Injuries Including Peritoneal Fibrosis and Peritoneal Dialysis Complications. (2016)
  • Author(s): Mizuno M, Ito Y.
  • Journal Title: Methods Mol Biol Volume: 1397 Pages: 35-43
  • DOI: 10.1007/978-1-4939-3353-2_4
  • ISBN: 9781493933518, 9781493933532
• [Journal Article] Recent analysis of status and outcomes of peritoneal dialysis (2016)
  • Author(s): Mizuno M., Ito Y, Skata F, Saka Y, Hiramatsu T, Tamai H, Mizutani M, Naruse T, Ohashi N, Kasuga H, Shimizu H, Kurata H, Kurata K, Suzuki S, Kido S, Tsuruta Y, Matsuoka T, Horie M, Naruyama S, Matsuo S.
  • Journal Title: Clin Exp Nephrol Volume: in press Issue: 6 Pages: 961-971
  • DOI: 10.1007/s10157-016-1249-9
  • Peer Reviewed
• [Journal Article] Vascular endothelial cell injury is an important factor in the development of encapsulating peritoneal sclerosis in long-term peritoneal dialysis patients. (2016)
  • Author(s): Tawada M, Ito Y, Hamada C, Honda K, Mizuno M, Suzuki Y, Sakata F, Terabayashi T, Matsukawa Y, Maruyama S, Imai E, Matsuo S, Takei Y.
  • Journal Title: PLoS One Volume: 11 Issue: 4 Pages: e0154644-e0154644
  • DOI: 10.1371/journal.pone.0154644
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury (2015)
  • Author(s): Terabayashi T, Ito Y, Mizuno M, Suzuki Y, Kinashi H, Sakata F, Tomita T, Iguchi D, Tawada M, Nishio R, Maruyama S, Imai E, Matsuo S, Takei Y.
  • Journal Title: Laboratory Investigation Volume: 95(9) Issue: 9 Pages: 1029-1043
  • DOI: 10.1038/labinvest.2015.87
  • Peer Reviewed
• [Journal Article] Expression of membrane complement regulators, CD46, CD55 and CD59, in mesothelial cells of patients on 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 Immunology Volume: 153 Issue: 2 Pages: 302-309
  • DOI: 10.1016/j.molimm.2015.02.005
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 3 Pages: 243-250
  • DOI: 10.1007/s10047-015-0822-4
  • Peer Reviewed
• [Journal Article] Successful Treatment of <i>Cryptococcus laurentii</i> Peritonitis in a Patient on Peritoneal Dialysis (2015)
  • 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 Volume: 54 Issue: 8 Pages: 941-944
  • DOI: 10.2169/internalmedicine.54.3586
  • NAID: 130005065248
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Calcified Amorphous Tumor in the Left Atrium in 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 Issue: 5 Pages: 481-485
  • DOI: 10.2169/internalmedicine.54.2967
  • NAID: 130004724006
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Tubulointerstitial Fibrosis in Patients with IgG4 Related Kidney Disease: Pathological Findings on Repeat Renal Biopsy (2015)
  • Author(s): Haruna Arai, Hiroki Hayashi, Kazuo Takahashi, Shigehisa Koide, Waichi Sato, Midori Hasegawa, Yutaka Yamaguchi, Jan Aten, Yasuhiko Ito, Yukio Yuzawa
  • Journal Title: Rheumatology International Volume: 印刷中 Issue: 6 Pages: 1093-1101
  • DOI: 10.1007/s00296-014-3153-5
  • Peer Reviewed
• [Journal Article] The efficacy of tolvaptan as a diuretic for chronic kidney disease patients (2015)
  • Author(s): Tanaka A, Katsuno T, Ozaki T, Sakata F, Kato N, Suzuki Y, Kosugi T, Kato S, Tsuboi N, Sato W, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S.
  • Journal Title: Acta Cariologica Volume: 70(2) Pages: 217-223
  • Peer Reviewed / Open Access
• [Presentation] High Salt Intake Increases Baseline Peritoneal Transport Rate Through Local TonEBP Activation in Subtotal Nephrectomized Mice (2018)
  • Author(s): Sun T
  • Organizer: 米国腎臓学会（サンディエゴ）
  • Int'l Joint Research
• [Presentation] High Salt Intake Increases Baseline Peritoneal Transport Rate Through Local TonEBP Activation in Subtotal Nephrectomized Mice (2018)
  • Author(s): Sun T
  • Organizer: 国際腹膜透析学会（バンクーバー）
  • Int'l Joint Research
• [Presentation] Neutral peritoneal dialysis solutions reduce morphological damages in the patients with long-term peritoneal membrane treatment (2017)
  • Author(s): Ito Y., Tawada M, Hamada C, Mizuno M, Suzuki Y, Sakata F, Maruyama S
  • Organizer: the 8th Asia Pacific Chapter Meeting of International Society for PeritonealDialysis
  • Place of Presentation: Guangzhou, China,
  • Year and Date: 2017-03-24
  • Int'l Joint Research
• [Presentation] VEGF-D plays a subtle role in the development of lymphangiogenesis in methylglyoxal-induced peritoneal injury (2017)
  • Author(s): T Sun, Y Ito, M Mizuno, Y Suzuki, F Sakata, T Terabayashi, T Tomita, S Maruyama
  • Organizer: the 8th Asia Pacific Chapter Meeting of International Society for PeritonealDialysis
  • Place of Presentation: Guangzhou, China,
  • Year and Date: 2017-03-24
• [Presentation] Pathophysiology of peritoneal dysfunction in PD (2017)
  • Author(s): Yasuhiko Ito
  • Organizer: the 8th Asia Pacific Chapter Meeting of International Society for PeritonealDialysis
  • Place of Presentation: Guangzhou, China,
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] Pathophysiology of peritoneal dysfunction in PD (2017)
  • Author(s): Yasuhiko Ito
  • Organizer: International Society of Peritoneal Dialysis Asian-Pacific Chapter
  • Int'l Joint Research / Invited
• [Presentation] Neutral peritoneal dialysis solutions prevent morphological changes in the patients with long-term peritoneal membrane treatment (2017)
  • Author(s): Yasuhiko Ito
  • Organizer: International Society of Peritoneal Dialysis Asian-Pacific Chapter
  • Int'l Joint Research
• [Presentation] VEGF-D plays a subtle role in the development of lymphangiogenesis in methylglyoxal-induced peritoneal injury (2017)
  • Author(s): Ting Sun, Yasuhiko Ito
  • Organizer: International Society of Peritoneal Dialysis Asian-Pacific Chapter
  • Int'l Joint Research
• [Presentation] TGF-β-VEGF-A pathway induces neoangiogenesis in peritoneal fibrosis of peritoneal dialysis. (2016)
  • Author(s): T Kariya, Y Ito, M Mizuno, Y Suzuki, F Sakata, T Terabayashi, T Ishii, M Tawada, D Iguchi, S Maruyama, S Matsuo.
  • Organizer: 53RD ERA-EDTA CONGRESS
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-05-23
  • Int'l Joint Research
• [Presentation] Sodium Chloride Promotes Tissue Inflammation via Osmotic Stimuli in Subtotal Nephrectomized Mice. (2015)
  • Author(s): Fumiko Sakata, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Takeshi Terabayashi, Takako Tomita, Mitsuhiro Tawada, Shoichi Maruyama, Enyu Imai, Yoshifumi Takei, Seiichi Matsuo
  • Organizer: ASN Kidney Week 2015
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] Vascular Endothelial Cell Damage Is an Important Factor in the Development of Encapsulating Peritoneal Sclerosis. (2015)
  • Author(s): Mitsuhiro Tawada, Yasuhiko Ito, Chieko Hamada, Kazuho Honda, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Shoichi Maruyama, Yoshifumi Takei, Seiichi Matsuo
  • Organizer: ASN Kidney Week 2015
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] Pathophysiology of the peritoneal membrane damage: fibrosis, angiogenesis and lymphangiogenesis (2015)
  • Author(s): Yasuhiko Ito
  • Organizer: The 7th Asia Pacific Chapter Meeting of International Society for Peritoneal Dialysis
  • Place of Presentation: 大邱（Korea）
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Presentation] Development of encapsular peritoneal sclerosis(EPS)-like peritonitis in rat and complement activation (2015)
  • Author(s): Daiki iguchi, Masashi Mizuno, Emi Shigemoto, Fumiko Sakata, Yasuhiro Suzuki, Alan Okada, Hidechika Okada, Shoichi Maruyama, Seiichi Matsuo, Yasuhiko Ito
  • Organizer: The 15th European Meeting on Complement in Human Disease
  • Place of Presentation: Uppsala(Sweden)
  • Year and Date: 2015-06-27
  • Int'l Joint Research
• [Presentation] 腎不全マウスにおいて食塩負荷は、浸透圧刺激によってMCP-1、sgk-1を誘導し炎症を惹起する (2015)
  • Author(s): 坂田 史子、伊藤 恭彦、狩谷 哲芳、多和田 光弘、富田 貴子、寺林 武、鈴木 康弘、水野 正司、松尾 清一
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-06
• [Presentation] ANCA関連血管炎における喫煙と再燃との関係について (2015)
  • Author(s): 山口 真、安藤 昌彦、加藤 佐和子、小杉 智規、佐藤 和一、坪井 直毅、安田 宜成、水野 正司、伊藤 恭彦、松尾 清一、丸山 彰一
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-06
• [Presentation] 排液中TGF-β1蛋白濃度は腹膜組織線維化、腹膜機能低下を反映する (2015)
  • Author(s): 鈴木 康弘、寺林 武、坂田 史子、坪井 直毅、水野 正司、丸山 彰一、伊藤 恭彦、松尾 清一
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-06
• [Presentation] 血管内皮細胞障害がEPS発症の最大のリスクファクターである (2015)
  • Author(s): 多和田 光弘、伊藤 恭彦、寺林 武、坂田 史子、鈴木 康弘、水野 正司、濱田 千江子、本田 一穂、丸山 彰一、松尾 清一
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05
• [Presentation] 腹膜透析患者の腹膜中皮細胞における膜補体制御因子の発現 (2015)
  • Author(s): 水野 正司、清 祐美、井口 大旗、東出 慶子、坂田 史子、鈴木 康弘、今井 優樹、松尾 清一、伊藤 恭彦
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05
• [Presentation] メタボローム解析を用いた腹膜透過性の検討 (2015)
  • Author(s): 富田 貴子、伊藤 恭彦、坂田 史子、鈴木 康弘、水野 正司、丸山 彰一、平山 明由、松尾 清一
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05