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

2012 Fiscal Year Final Research Report

• 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
• Keywords: BMP4 / 糖尿病性腎症 / Smad1

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.
  • DOI: 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: Intern Med Volume: 51 Pages: 2197-2201
  • DOI: DOI:10.2169/internalmedicine.51.7919
  • Peer Reviewed
• [Journal Article] Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1 protein-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: Journal of Biological Chemistry Volume: 287 Pages: 20430-20442.
  • DOI: DOI:10.1074/jbc.M111.275610.
  • Peer Reviewed
• [Journal Article] SOX9 protein 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 K, Doi T
  • Journal Title: Jbiol Chem Volume: 286 Pages: 32162-32169.
  • DOI: 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 Pages: 622-625
  • DOI: 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 Pages: 626-631
  • DOI: 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, Matsubara T, Mima A, Nagai K, Araoka T, Kishi S, Fukushima N, Jishage K, Doi T.
  • Journal Title: J Biol Chem. Volume: 286 Pages: 20109-20116
  • DOI: 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 Pages: e17929.
  • DOI: 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: Intern Med. Volume: 50 Pages: 591-595
  • DOI: DOI:org/10.2169/internalmedicine.50.3958
  • 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] rophoblast glycoprotein: possible candidate mediating podocyte injuries in glomerulonephritis (2010)
  • Author(s): Murakami T, Abe H, Nagai K, Tominaga T, Takamatsu N, Araoka T, Kishi S, Takahashi T, Mima A, Takai Y, Kopp JB, Doi T
  • Journal Title: Am J Nephrol. Volume: 32 Pages: 505-521
  • DOI: 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 Pages: 209-218.
  • DOI: DOI:10.1007/s10059-010-0109-9.
  • Peer Reviewed