The role of CTGF in peritoneal fibrosis and renal-peritoneal interactions

• Project/Area Number: 17K16080
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: Toda Naohiro 京都大学, 医学研究科, 客員研究員 (30760615)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: CTGF / 腹膜透析 / 腹膜機能 / 腹膜線維化 / 血管新生 / 腎ー腹膜連関

Outline of Final Research Achievements

Connective tissue growth factor (CTGF) regulates the signalling of other growth factors and promotes fibrosis. CTGF is shown to be an aggravating factor in thickening peritoneum.To study the role of CTGF in peritoneal fibrosis of adult mice, we generated CTGF conditional knockout (cKO) mice. We induced peritoneal fibrosis in wild-type and Rosa-CTGF cKO mice.
Induction of peritoneal fibrosis in wild-type mice increased CTGF expression and produced severe thickening of the peritoneum. In contrast, CG-treated Rosa-CTGF cKO mice exhibited reduced thickening of the peritoneum. Peritoneal equilibration test revealed that the excessive peritoneal permeability by CG treatment was normalized by CTGF deletion. CG-treated Rosa-CTGF cKO mice exhibited a reduced number of αSMA- and Ki67-positive cells in the peritoneum. These results indicate that a deficiency of CTGF can reduce peritoneal thickening and help to maintain peritoneal function.

Academic Significance and Societal Importance of the Research Achievements

腹膜透析は在宅で生活できるなどの多くの利点を有するが、腹膜線維化によって治療中止を余儀なくされることがある。腹膜線維化は腹膜透析における最も重要な合併症である。CTGFの抑制は腹膜線維化を軽減するだけでなく、腹膜機能の改善も示した。抗CTGF中和抗体は肺線維症などの分野ですでに臨床試験が行われており、他の論文ではこの中和抗体で腹膜線維化が軽減することが示されている。腹膜透析におけるCTGF抑制は臨床応用につながりうると考える。

Research Products

• [Int'l Joint Research] ユトレヒト大学(オランダ)
• [Journal Article] Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation. (2018)
  • Author(s): Toda N, Mori K, Kasahara M, Koga K, Ishii A, Mori KP, Osaki K, Mukoyama M, Yanagita M, Yokoi H.
  • Journal Title: Nephrol Dial Transplant. Volume: 33(6) Pages: 945-953
  • Peer Reviewed
• [Journal Article] A Refractory Case of Secondary Membranous Nephropathy Concurrent with IgG4-related Tubulointerstitial Nephritis. (2018)
  • Author(s): Arai H, Toda N, Kamimatsuse R, Nishioka K, Endo S, Akiyama S, Maruyama S, Matsubara T, Yokoi H, Yanagita M.
  • Journal Title: Intern Med. Volume: 57(19) Pages: 2873-2877
  • NAID: 130007490877
  • Peer Reviewed
• [Journal Article] CTGF in kidney fibrosis and glomerulonephritis. (2018)
  • Author(s): Toda N, Mukoyama M, Yanagita M, Yokoi H.
  • Journal Title: Inflamm Regen. Volume: 38
  • Peer Reviewed / Open Access
• [Journal Article] Peritonitis due to Mycobacterium abscessus in peritoneal dialysis patients: Case presentation and minireview (2018)
  • Author(s): Erina Ono, M.D.; Eiichiro Uchino, M.D.; Keita P. Mori, M.D., Ph.D.; Hideki Yokoi, M.D., Ph.D.; Naohiro Toda, M.D., Ph.D.; Kenichi Koga, M.D., Ph.D.; Masato Kasahara, M.D., Ph.D.; Takeshi Matsubara, M.D., Ph.D.; Motoko Yanagita, M.D., Ph.D.
  • Journal Title: Renal Replacement Therapy Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation (2017)
  • Author(s): Toda Naohiro、Mori Kiyoshi、Kasahara Masato、Koga Kenichi、Ishii Akira、Mori Keita P、Osaki Keisuke、Mukoyama Masashi、Yanagita Motoko、Yokoi Hideki
  • Journal Title: Nephrology Dialysis Transplantation Volume: - Issue: 6 Pages: 943-953
  • DOI: 10.1093/ndt/gfx317
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of mesangial cell-derived connective tissue growth factor in a mouse model of anti-glomerular basement membrane glomerulonephritis. (2017)
  • Author(s): Toda N, Mori K, Kasahara M, Ishii A, Koga K, Ohno S, Mori KP. Kato Y, Osaki K, Kuwabara T, Kojima K, Taura D, Sone M, Matsusaka T, Nakao K, Mukoyama M, Yanagita M, Yokoi H.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 42114-42114
  • DOI: 10.1038/srep42114
  • NAID: 120005997757
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition. (2017)
  • Author(s): Y. Kato, K. Mori, M. Kasahara, K. Osaki, A. Ishii, K.P. Mori, N. Toda, S. Ohno, T. Kuwabara, T. Tokudome, I. Kishimoto, M.A. Saleem, T. Matsusaka, K. Nakao, M. Mukoyama, M. Yanagita, H. Yokoi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 46624-46624
  • DOI: 10.1038/srep46624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy. (2017)
  • Author(s): Mori KP, Yokoi H, Kasahara M, Imamaki H, Ishii A, Kuwabara T, Koga K, Kato Y, Toda N, Ohno S, Kuwahara K, Endo T, Nakao K, Yanagita M, Mukoyama M, Mori K.
  • Journal Title: J Am Soc Nephrol. Volume: 28 Issue: 1 Pages: 278-289
  • DOI: 10.1681/asn.2015101168
  • NAID: 120005820888
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of CTGF in Peritoneal Fibrosis in Mice. (2018)
  • Author(s): Naohiro Toda
  • Organizer: 16th Congress of the International Society for Peritoneal Dialysis (ISPD 2018)
  • Int'l Joint Research
• [Presentation] 腹膜線維化治療標的としてのCTGFの検討 (2018)
  • Author(s): 戸田 尚宏
  • Organizer: 第24回日本腹膜透析医学会学術集会・総会