Development of Specific Biomarker and Molecular Targeting Therapy for Diabetic Nephropathy by RAS-independent Pathway

• Project/Area Number: 22390169
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokushima
• Principal Investigator: DOI Toshio 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (60183498)
• Co-Investigator(Kenkyū-buntansha): ABE Hideharu 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (60399342) ; NAGAI Kojiro 徳島大学, 病院, 講師 (40542048) ; MIMA Akira 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教 (00432401) ; TOMINAGA Tatsuya 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教 (80425446)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2010: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
• Keywords: BMP4 / 糖尿病性腎症 / Smad1 / Sox9 / バイオマーカー / 抗体医療 / BMP / ALK3/6 / 分子標的治療

Research Abstract

BMP4 directly regulated Smad1 signaling in vitro. Both BMP4 and phosphorylated Smad1 were expressed in association with mesangial matrix hyperplasia in diabetic kidney. BMP4 knock-in transgenic mice showed typical mesangial matrix increase as well as BMP4 expression after induction by tamoxifen. On the other hand, BMP4 knock-out (BMP4(+/-)) mice showed amelioration of glomerular matrix hyperplasia induced by streptozotocin. Furthermore, neutralizing antibody for BMP4 normalized glomerular matrix hyperplasia and phosphorylated Smad1 expression in glomeruli of diabetic mice. These results suggest that BMP4/Smad1 signaling plays the critical pathogenetic role for diabetic nephropathy.

Research Products

• [Journal Article] Polymorphism in the human matrix Gla protein gene is associated with the progression of vascular calcification in maintenance hemodialysis patients (2013)
  • Author(s): Yoshikawa K, Abe H, Tominaga T, Nakamura M, Kishi S, Matsuura M, Nagai K, Tsuchida K, Minakuchi J, Doi T
  • Journal Title: Clin Exp Nephrol. Volume: 17 Issue: 6 Pages: 882-889
  • DOI: 10.1007/s10157-013-0785-9
  • Peer Reviewed
• [Journal Article] Acute Glomerulonephritis in an Immunocompetent Elderly Woman after Contact with a Child who Had Been Diagnosed as Erythema Infectiosum (2012)
  • Author(s): Kishi S, Yamada S, Kishi F, Shibata E, Matsuura M, Nagai K, Mima A, Abe H, Doi T.
  • Journal Title: Internal Medicine Volume: 51 Issue: 16 Pages: 2197-2201
  • DOI: 10.2169/internalmedicine.51.7919
  • NAID: 130002062315
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1-smooth muscle α actin(SMA) signal transduction in diabetic nephropathy (2012)
  • Author(s): Abe H, Tominaga T, Matsubara T, Abe N, Kishi S, Nagai K, Murakami T, Araoka T, Doi T.
  • Journal Title: J Biol Chem Volume: 287 Issue: 24 Pages: 20430-20442
  • DOI: 10.1074/jbc.m111.275610
  • Peer Reviewed
• [Journal Article] PIASy regulates α-smooth muscle actin expression by interacting with E12 in mesangial cells (2012)
  • Author(s): Torikoshi K. et al.
  • Journal Title: Plos ONE Volume: 7(7) Issue: 7 Pages: e41186-e41186
  • DOI: 10.1371/journal.pone.0041186
  • Peer Reviewed
• [Journal Article] Sox9 induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy (2011)
  • Author(s): Kishi S, Abe H, Akiyama H, Tominaga T, Murakami T, Mima A, Nagai K, Kishi F, Matsuura M, Matsubara T, Iehara N, Ueda O, Fukushima N, Jishage KI, Doi T.
  • Journal Title: J Biol Chem Volume: 286(37) Issue: 37 Pages: 32162-9
  • DOI: 10.1074/jbc.m111.244541
  • Peer Reviewed
• [Journal Article] An autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure (2011)
  • Author(s): Mima A, Shiota F, Matsubara T, Iehara N, Akagi T, Abe H, Nagai K, Matsuura M, Murakami T, Kishi S, Araoka T, Kishi F, Kondo N, Shigeta R, Yoshikawa K, Kita T, Doi T, Fukatsu A
  • Journal Title: Ren Fail. Volume: 33 Issue: 6 Pages: 622-625
  • DOI: 10.3109/0886022x.2011.585730
  • Peer Reviewed
• [Journal Article] MPO-ANCA-positive anti-glomerular basement membrane antibody disease successfully treated byplasma exchange and immunosuppressive therapy. (2011)
  • Author(s): Murakami T, Nagai K, Matsuura M, Kondo N, Kishi S, Araoka T, Kishi F, Sakiyama T, Mima A, Bando Y, Abe H, Doi T.
  • Journal Title: Ren Fail Volume: 33 Issue: 6 Pages: 626-631
  • DOI: 10.3109/0886022x.2011.581401
  • Peer Reviewed
• [Journal Article] Activation of bone morphogenetic protein 4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy (2011)
  • Author(s): Tominaga T, Abe H, Ueda O, Goto C, Nakahara K, Murakami T, Mima A, Nagai K, Araoka T, Kishi S, Fukushima N, Jishage KI, Doi T
  • Journal Title: J Biol Chem Volume: 286(22) Issue: 22 Pages: 20109-16
  • DOI: 10.1074/jbc.m110.179382
  • Peer Reviewed
• [Journal Article] Activation of Src mediates PDGF-induced Smad1 phosphorylation and contributes to the progression of glomerulosclerosis in glomerulonephritis (2011)
  • Author(s): Mima A, Abe H, Nagai K, Arai H, Matsubara T, Araki M, Torikoshi K, Tominaga T, Iehara N, Fukatsu A, Kita T, Doi T
  • Journal Title: PLoS One. Volume: 6(3) Issue: 3 Pages: e17929-e17929
  • DOI: 10.1371/journal.pone.0017929
  • Peer Reviewed
• [Journal Article] Mixed Connective Tissue Disease Developing into MPO-ANCA-positive Polyangiitis (2011)
  • Author(s): Murakami T, Endo S, Moriki T, Doi T, Matsumoto Y.
  • Journal Title: Internal Medicine Volume: 50 Issue: 6 Pages: 591-595
  • DOI: 10.2169/internalmedicine.50.3958
  • NAID: 130000649891
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Role of Smad1 in diabetic nephropathy: Molecular mechanisms and implications as a diagnostic marker (2011)
  • Author(s): Abe H, Matsubara T, Arai H, Doi T
  • Journal Title: Histol Histopathol. Volume: 26 Pages: 531-541
  • URL: http://www.hh.um.es/Abstracts/Vol_26/26_4/26_4_531.htm
  • Peer Reviewed
• [Journal Article] Sox9 induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy (2011)
  • Author(s): Kishi S., et al
  • Journal Title: J Blol Chem Volume: 286(37) Pages: 32162-32169
  • Peer Reviewed
• [Journal Article] Activation of bone morphogenetic protein 4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy (2011)
  • Author(s): Tominaga T., et al
  • Journal Title: J Biol Chem Volume: 286(22) Pages: 20109-20116
  • Peer Reviewed
• [Journal Article] BMP4・Smad1シグナルと糖尿病性腎症 (2011)
  • Author(s): 安部秀斉, ら
  • Journal Title: 日本腎臓学会誌 Volume: 53 Pages: 1000-1005
  • NAID: 10030343457
  • Peer Reviewed
• [Journal Article] Role of Smad1 in diabetic nephropathy : Molecular mechanisms and implications as a diagnostic marker. (2011)
  • Author(s): Abe H., et al.
  • Journal Title: Histol Histopathol. Volume: 26 Pages: 531-541
  • Peer Reviewed
• [Journal Article] Trophoblast glycoprotein : possible candidate mediating podocyte injuries in glomerulonephritis (2010)
  • Author(s): Murakami T, Abe H, Nagai K, Tominaga T, Takamatsu N, Matsubara T, Araoka T, Kishi S, Takahashi T, Mima A, Takai Y, Kopp JB, Doi T.
  • Journal Title: Am J Nephrol Volume: 32(6) Issue: 6 Pages: 505-521
  • DOI: 10.1159/000321366
  • Peer Reviewed
• [Journal Article] Transcription factor 7-like 2(TCF7L2) regulates activin receptor-like kinase 1(ALK1)/ Smad1 pathway for development of diabetic nephropathy (2010)
  • Author(s): Araoka T, Abe H, Tominaga T, Mima A, Matsubara T, Murakami T, Kishi S, Nagai K, Doi T
  • Journal Title: Mol Cells Volume: 30(3) Issue: 3 Pages: 209-218
  • DOI: 10.1007/s10059-010-0109-9
  • Peer Reviewed
• [Presentation] BMP4 regulates podocyte injury in the diabetic nephropathy (2012)
  • Author(s): Tominaga T. et al.
  • Organizer: American Society of Nephrology, Kidney Week 2012
  • Place of Presentation: San Diego Convention Center(USA)
• [Presentation] Role of BMP4 for regulating podocyte injury in the diabetic nephropathy (2012)
  • Author(s): Tominaga T. el al.
  • Organizer: American Society for Cell biology
  • Place of Presentation: The Moscone Center(USA)
• [Presentation] 糖尿病性腎症の分子病態-BMP4-Smad1シグナル (2011)
  • Author(s): 安部秀斉
  • Organizer: 第41回日本腎臓学会西部学術総会シンポジウム
  • Place of Presentation: 徳島市あわぎんホール(徳島県郷土文化会館)
  • Year and Date: 2011-09-30
• [Presentation] Overexpression of Smad1 Causes Remarkable Glomerulosclerosis in Diabetic Mice (2011)
  • Author(s): Matsubara T., et al
  • Organizer: American Diabetes Association 69th Scientific Session
  • Place of Presentation: San Diego Convention Center -San Diego., U.S.A.
  • Year and Date: 2011-06-07
• [Presentation] BMP4における糖尿病性腎症の発症とアルブミン尿排泄に関する新たな機序 (2011)
  • Author(s): 冨永辰也, ら
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市さっぽろ芸術文化の館(旧北海道厚生年金会館)・札幌市教育文化会館・ロイトン札幌・札幌プリンスホテル国際館パミール・東京ドームホテル札幌(旧札幌後楽園ホテル)
  • Year and Date: 2011-05-21
• [Presentation] 糖尿病性腎症発症とアルブミン尿排泄に関与するBMP4の分子機構 (2011)
  • Author(s): 冨永辰也, ら
  • Organizer: 第52回日本生化学会中国・四国支部総会
  • Place of Presentation: 広島市広島大学・広仁会館
  • Year and Date: 2011-05-13
• [Presentation] 糖尿病性腎症に関わる新たな治療標的分子の検討 (2010)
  • Author(s): 松原雄, 他
  • Organizer: 第53回 日本腎臓学会学術総会
  • Place of Presentation: 神戸国際会議場(神戸市)
  • Year and Date: 2010-06-16
• [Presentation] ヒトIgA腎症における増殖因子Gas6 とその受容体Axlの発現
  • Author(s): 三好雅士他
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] BMP4 regulates podocyte injury in the diabetic nephropathy
  • Author(s): Tominaga T. el al.
  • Organizer: The American Diabetes Association’s 72nd Scientific Sessions
  • Place of Presentation: Philadelphia Convention Center(USA)
• [Presentation] Expression of Gas6 and Axl in Human IgA Nephropathy: A Possible Involvement of Gas6 in Podocyte Damage
  • Author(s): Miyoshi M. et al.
  • Organizer: American Society of Nephrology, Kidney Week 2012
  • Place of Presentation: San Diego Convention Center(USA)
• [Presentation] 腎機能低下予測バイオマーカーとしてのポドサイト由来エクソゾーム内転写因子
  • Author(s): 安部尚子他
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場（福岡県）
• [Presentation] 糸球体腎炎におけるCD44作用機序の解析
  • Author(s): 金井麻衣他
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場（福岡県）