Targeting Bone Morphogenetic Protein 4/Smad1 signaling is a new approach for the treatment of glomerulosclerosis

• Project/Area Number: 16K09613
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: Takeshi Matsubara 京都大学, 医学研究科, 講師 (90422964)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糸球体硬化 / 糖尿病性腎症 / BMP 4 / Fibronectin / Smad1 / 糸球体腎炎 / 病理学

Outline of Final Research Achievements

Glomerulosclerosis is common final pathological features, characterized by the accumulation of extracellular matrix, of which the main component is α1/α2 type IV collagen (Col4α1/α2). Recently, we identified Smad1 as a direct regulator of Col4α1/α2, and showed that diabetic mice treated with a neutralizing antibody against BMP4, upstream factor of Smad1, exhibit less mesangial expansion. However, They did not show any improvement of albuminuria. Therefore, we checked molecules involved in albuminuria and found that glomerular expression of fibronectin was increased with the treatment of this antibody. We also generated conditional deletion of Smad1 (Smad1-CKO). Mesangial matrix expansion was ameliorated in Smad1-CKO mice after the induction of nephritis. Furthermore, after 36 weeks, some Smad1-CKO mice showed glomerular endotheliosis and mesangiolysis. Thus, Smad1 plays a key role for matrix expansion, and possible role for the homeostasis of glomerular endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

本研究結果により、BMP4-Smad1シグナルは糸球体硬化の治療標的となることが判明したが、我々のBMP4中和抗体投与では、糸球体Fibronectin沈着と蛋白尿の増加という有害事象が発生した。In vitroで検証により、この機序は本抗体の持つBMP7抑制作用と考えられた。しかし、BMP4の受容体であるALK3の阻害薬dorsomorphinを用いた結果から、BMP4シグナルの創薬応用として、ALK3が新たな治療標的となる可能性も示唆された。さらに、誘導型Smad1欠損マウスの検討から、Smad1が糸球体細胞外基質の制御のみならず、糸球体内皮細胞の恒常性にも関与している可能性が示唆された。

Research Products

• [Journal Article] Long-term Survival and Renal Dysfunction in a Patient With Recurrent Colorectal Cancer Treated With Bevacizumab (2019)
  • Author(s): Shigeki Kataoka , Yoshitaka Nishikawa , Taro Funakoshi , Takahiro Horimatsu , Naoya Kondo , Takeshi Matsubara , Motoko Yanagita , Shigemi Matsumoto , Manabu Muto
  • Journal Title: Clin J Gastroenterol . Volume: 06 Issue: 3 Pages: 1-4
  • DOI: 10.1007/s12328-019-01060-z
  • Peer Reviewed / Open Access
• [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: Internal Medicine Volume: 57 Issue: 19 Pages: 2873-2877
  • DOI: 10.2169/internalmedicine.0836-18
  • NAID: 130007490877
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-10-01
  • Peer Reviewed / Open Access
• [Journal Article] Acetaminophen administration and the risk of acute kidney injury: a self-controlled case series study. (2018)
  • Author(s): Hiragi S, Yamada H, Tsukamoto T, Yoshida K, Kondo N, Matsubara T, Yanagita M, Tamura H, Kuroda T.
  • Journal Title: Clin Epidemiol Volume: 10 Pages: 265-276
  • DOI: 10.2147/clep.s158110
  • Peer Reviewed / Open Access
• [Journal Article] Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan. (2018)
  • Author(s): Funakoshi T, Horimatsu T, Nakamura M, Shiroshita K, Suyama K, Mukoyama M, Mizukami T, Sakurada T, Baba E, Tsuruya K, Nozaki A, Yahata K, Ozaki Y, Ubara Y, Yasui H, Yoshimoto A, Fukuma S, Kondo N, Matsubara T, Matsubara K, Fukuhara S, Yanagita M, Muto M.
  • Journal Title: ESMO Open Volume: 23 Issue: 2 Pages: e000301-e000301
  • DOI: 10.1136/esmoopen-2017-000301
  • Peer Reviewed / Open Access
• [Journal Article] Rationale and study design of a clinical trial to assess the effects of LDL apheresis on proteinuria in diabetic patients with severe proteinuria and dyslipidemia (2017)
  • Author(s): Wada T, Muso E, Maruyama S, Hara A, Furuichi K, Yoshimura K, Miyazaki M, Sato E, Abe M, Shibagaki Y, Narita I, Yokoyama H, Mori N, Yuzawa Y, Matsubara T, Tsukamoto T, Wada J, Ito T, Masutani K, Tsuruya K, Fujimoto S, Tsuda A, Suzuki H, Kasuno K, Terada Y, Nakata T, Iino N, Kobayashi S.
  • Journal Title: Clin Exp Nephrol Volume: 22 Issue: 3 Pages: 591
  • DOI: 10.1007/s10157-017-1488-4
  • URL: https://pure.teikyo.jp/en/publications/54488e35-2eca-42fb-b659-6555ab16bcba
  • Peer Reviewed / Open Access
• [Journal Article] Membranous nephropathy associated with pregnancy: an anti-phospholipase A2 receptor antibody-positive case report. (2017)
  • Author(s): Uchino E, Takada D, Mogami H, Matsubara T, Tsukamoto T, Yanagita M
  • Journal Title: CEN Case Rep Volume: - Issue: 1 Pages: 101-106
  • DOI: 10.1007/s13730-018-0304-7
  • Peer Reviewed
• [Journal Article] Automated Electronic Alert Systems for Acute Kidney Injury: Current Status and Future Perspectives. (2017)
  • Author(s): Uchino E, Kondo N, Matsubara T, Yanagita M.
  • Journal Title: Contrib Nephrol Volume: 189 Pages: 124-129
  • DOI: 10.1159/000452260
  • ISBN: 9783318059281, 9783318059298
  • Peer Reviewed
• [Journal Article] Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia. (2017)
  • Author(s): Nishikawa Y, Funakoshi T, Horimatsu T, Miyamoto S, Matsubara T, Yanagita M, Nakagawa S, Yonezawa A, Matsubara K, Muto M.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 79 Issue: 3 Pages: 619-633
  • DOI: 10.1007/s00280-017-3249-1
  • Peer Reviewed
• [Journal Article] Renal-limited vasculitis with elevated levels of multiple antibodies (2017)
  • Author(s): Sato N, Yokoi H, Imamaki H, Uchino E, Sakai K, Matsubara T, Tsukamoto T, Minamiguchi S, Yanagita N
  • Journal Title: CEN Case Reports Volume: - Issue: 1 Pages: 1-6
  • DOI: 10.1007/s13730-017-0248-3
  • Peer Reviewed
• [Journal Article] Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis (2016)
  • Author(s): Araki M, Matsubara T, Abe H, Torikoshi K, Mima A, Iehara N, Fukatsu A, Kita T, Arai H, Doi T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 31216-31216
  • DOI: 10.1038/srep31216
  • NAID: 120006345067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy. (2016)
  • Author(s): Inada A, Inada O, Fujii NL, Nagafuchi S, Katsuta H, Yasunami Y, Matsubara T, Arai H, Fukatsu A, Nabeshima YI.
  • Journal Title: J Am Soc Nephrol. Volume: 27 Issue: 10 Pages: 3035-3050
  • DOI: 10.1681/asn.2015070741
  • Peer Reviewed / Open Access
• [Journal Article] 慢性維持透析患者のがん治療薬標準化に向けた疫学および薬物モニタリングに関する研究 (2016)
  • Author(s): 松原 雄, 近藤尚哉, 柳田素子, 船越太郎, 堀松高博, 武藤 学, 福原俊一, 中川俊作, 松原和夫
  • Journal Title: 日本透析医会雑誌 Volume: 31 Pages: 402-407
• [Journal Article] Onco－nephrology－透析患者の診療実態 (2016)
  • Author(s): 松原 雄
  • Journal Title: 日本透析医会雑誌 Volume: 31 Pages: 420-421
• [Journal Article] Cancer screening and treatment in patients with end-stage renal disease: remaining issues in the field of onco-nephrology (2016)
  • Author(s): Yuichiro Kitai, Takeshi Matsubara, Taro Funakoshi, Takahiro Horimatsu, Muto Manabu and Motoko Yanagita.
  • Journal Title: Renal Replacement Therapy Volume: 2 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s41100-016-0046-y
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 悪性腫瘍に関連した腎障害について-臨床の立場から- (2019)
  • Author(s): 松原 雄
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] 透析患者への抗がん剤投与 (2018)
  • Author(s): 松原 雄、船越 太郎、柳田 素子
  • Organizer: 第63会日本透析医学会学術集会
• [Presentation] 透析患者のがん診療実態調査 (2018)
  • Author(s): 松原 雄、近藤 尚哉、柳田 素子
  • Organizer: 第63会日本透析医学会学術集会
• [Presentation] 慢性維持透析がん患者のErythropoiesis stimulating agents(ESA)低反応に関する検討～Japan CAncer and hemoDialYsis Cohort (J-CANDY-C)の解析結果報告～ (2018)
  • Author(s): 松原 雄、近藤 尚哉、船越 太郎、堀松 高博、武藤 学、福原 俊一、柳田 素子
  • Organizer: 第63会日本透析医学会学術集会
• [Presentation] CANCER DIAGNOSIS AND TREATMENT FOR PATIENTS UNDER HEMODIALYSIS; MULTICENTER SURVEILLANCE (2017)
  • Author(s): Takeshi Matsubara, Naoya Kondo, Taro Funakoshi, Takahiro Horimatsu, Tatsuo Tsukamoto, Manabu Muto, Shunichi Fukuhara, Motoko Yanagita
  • Organizer: 54th ERA-EDTA Congress, Madrid, Spain
  • Int'l Joint Research
• [Presentation] Management of anticancer therapy in patients under chronic dialysis (2017)
  • Author(s): Takeshi Matsubara
  • Organizer: International conference of OncoNephrology: an emerging field in medicine, Naples, Italy
  • Int'l Joint Research / Invited
• [Presentation] 慢性維持透析患者のがん診療実態調査 Japan Cancer and hemoDialYsis Cohort(J-CANDY-C)の解析結果報告 (2017)
  • Author(s): 松原 雄, 近藤 尚哉, 船越 太郎, 堀松 高博, 福間 真悟, 福原 俊一, 武藤 学, 塚本 達雄, 柳田 素子
  • Organizer: 日本腎臓学会学術集会, 仙台
  • Int'l Joint Research
• [Presentation] 慢性維持透析患者のがん診療実態調査 Japan CAncer and hemoDialYsis Cohort(J-CANDY-C)の解析結果報告 (2017)
  • Author(s): 松原 雄, 近藤 尚哉, 船越 太郎, 堀松 高博, 福間 真悟, 福原 俊一, 武藤 学, 塚本 達雄, 柳田 素子
  • Organizer: 日本透析医学会学術集会, 横浜
  • Int'l Joint Research
• [Presentation] Cancer Diagnosis and Treatment for Patients under Hemodialysis; Multicenter Surveillance (2016)
  • Author(s): Takeshi Matsubara, Tatsuo Tsukamoto, and Motoko Yanagita, on behalf of Japan Onco-nephrology consortium
  • Organizer: American Society of Nephrology, Annual meeting
  • Place of Presentation: シカゴ
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] シンポジウム10, Onconephrology, 腎臓とがんの新領域, 慢性維持透析患者のがん診療実態調査 -Japan CAncer and hemoDialYsis Cohort (J-CANDY-C)- (2016)
  • Author(s): 松原 雄、船越太郎、堀松高博、福間真悟、武藤 学、福原 俊一、柳田 素子
  • Organizer: 日本腎臓学会 東部学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] Cancer Diagnosis and Treatment for Patients under Hemodialysis; Multicenter Surveillance (2016)
  • Author(s): Takeshi Matsubara, Taro Funakoshi, Naoya Kondo, Takahiro Horimatsu, Tatsuo Tsukamoto, Manabu Muto, Shunichi Fukuhara, and Motoko Yanagita, on behalf of Japan Onco-nephrology consortium
  • Organizer: ISBP(International Society of Blood Purification)
  • Place of Presentation: 広島
  • Year and Date: 2016-09-08
  • Int'l Joint Research
• [Presentation] 慢性維持透析患者のがん診療実態調査 -Japan CAncer and hemoDialYsis Cohort (J-CANDY-C)の解析結果報告- (2016)
  • Author(s): 松原 雄、近藤尚哉、西岡敬祐、船越太郎、堀松高博、福間真悟、武藤 学、福原 俊一、塚本達雄、柳田 素子
  • Organizer: 日本腎臓学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-06-17
• [Presentation] 慢性維持透析患者のがん診療実態調査 Japan CAncer and hemoDialYsis Cohort (J-CANDY-C)の解析結果報告 (2016)
  • Author(s): 松原 雄、近藤尚哉、船越太郎、堀松高博、福間真悟、武藤 学、福原 俊一、柳田 素子
  • Organizer: 日本透析学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2016-06-09
• [Remarks] 京都大学大学院医学研究科 腎臓内科学
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp