Molecular mechanisms for irreversible phenotypic changes leading to renal failure in chronic kidney diseases.

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591033
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokushima
• Principal Investigator: 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)
• Co-Investigator(Kenkyū-buntansha): AKIYAMA Haruhiko 京都大学, 医学研究科, 准教授 (60402830)
• Co-Investigator(Renkei-kenkyūsha): KISHI Seiji 徳島大学, 病院, 助教 (10519507)
• Project Period (FY): 2009 – 2011
• Keywords: 糖尿病性腎症

Research Abstract

Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of HIF-1, and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of chondrocyte markers. Glomerular expressions of HIF-1, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. SOX9 was colocalized with HIF-1 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. HIF-1 and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.

Research Products

• [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
  • DOI: doi:10.1074/jbc.M111.275610
  • 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) Pages: 32162-9
  • DOI: doi:10.1074/jbc.M111.244541
  • Peer Reviewed
• [Journal Article] Recent progress in understanding the molecular pathogenesis of diabetic nephropathy (2011)
  • Author(s): Abe H
  • Journal Title: Rinsho Byori Volume: 59(2) Pages: 179-86
  • 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) Pages: 20109-16
  • 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(3) Pages: e17929
  • URL: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017929
  • 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(4) Pages: 531-541
  • URL: http://www.hh.um.es/Abstracts/Vol_26/26_4/26_4_531.htm
  • 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) 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(3) Pages: 209-218
  • DOI: DOI:10.1007/s10059-010-0109-9
  • Peer Reviewed
• [Presentation] Overexpression of Smad1 Causes Remarkable Glomerulosclerosis in Diabetic Mice (2011)
  • Author(s): Matsubara T, Abe H, Ueda O, Jishage K, Mima A, Goto C, Tominaga T, Nagai K, Iehara N, Fukushima N, Fukatsu A, Arai H, Doi T
  • Organizer: American Diabetes Association 71th Scientific Session, San Diego Convention Center-San
  • Place of Presentation: Diego U.S.A.
  • Year and Date: 20110605-09
• [Presentation] Trophoblast glycoprotein regulates the podocyte injuries in experimental glomerulonephritis. (2011)
  • Author(s): Murakami T, Abe H, Nagai K, Tominaga T, Matsuura M, Kishi S, Kishi F, Yoshikawa K, Kondo N, Jeffrey Kopp, Doi T
  • Organizer: World Congress of Nephrology 2011
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 20110408-12
• [Presentation] Chondrogenic phenotypic change contributes to the irreversible progression of the diabetic nephropathy (2010)
  • Author(s): Kishi S, Abe H, Murakami T, Tominaga T, Nagai K, Mima A, Doi T
  • Organizer: 50th The American Society for Cell Biology Annual Meeting,
  • Place of Presentation: Philadelphia, U.S.A.
  • Year and Date: 20101211-15
• [Presentation] PIASy Regulates SMα-Actin Expression by Interacting with E12 in Mesangial Proliferative Glomerulonephritis (2010)
  • Author(s): Torikoshi K, Araki M, Matsubara T, Mima A, Hirano T, Abe H, Fukatsu A, Arai H, Doi T
  • Organizer: 43^<rd> American Society of Nephrology(ASN) Annual Meeting
  • Place of Presentation: Denver, CO, U.S.A.
  • Year and Date: 2010-11-21
• [Presentation] Conditional Knockout of Smad1 Ameliorates Glomerulosclerosis in Progressive Glomerulonephritis (2010)
  • Author(s): Araki M, Abe H, Torikoshi K, Mima A, Matsubara T, Iehara N, Fukatsu A, Salant DJ, Arai H, Doi T
  • Organizer: 43^<rd> American Society of Nephrology(ASN) Annual Meeting
  • Place of Presentation: Denver, CO, U.S.A.
  • Year and Date: 2010-11-21
• [Presentation] BMP4/ Smad1 Signaling Is a Critical Therapeutic Target for Diabetic Nephropathy (2010)
  • Author(s): Matsubara T, Abe H, Ueda O, Tominaga T, Mima A, Nagai K, Torikoshi K, Araki M, Goto C, Kinosaki M, Jishage K, Fukushima N, Iehara N, Fukatsu A, Arai H, Doi T
  • Organizer: 43^<rd> American Society of Nephrology(ASN) Annual Meeting
  • Place of Presentation: Denver, CO, U.S.A.
  • Year and Date: 2010-11-19
• [Presentation] Chondrogenic Potential of Mesangial Cells in Diabetic Nephropathy (2009)
  • Author(s): Kishi S, Abe H, Akiyama H, Doi T
  • Organizer: 49th The American Society for Cell Biology Annual Meeting
  • Place of Presentation: San Diego, U.S.A.
  • Year and Date: 20091205-09
• [Presentation] TCF7L2(Transcription factor 7-like 2) Regulates Activin Receptor-Like Kinase1(ALK1)/ Smad1 Pathway for Development of Diabetic Nephropathy.(Araoka T : Young Investigator Travel Grant Award) (2009)
  • Author(s): Araoka T, Abe H, Matsuura M, Murakami T, Kishi S, Tominaga T, Shigeta R, Yoshikawa K, Kishi F, Mima A, Takahashi T, Hirano T, Doi T
  • Organizer: American Diabetes Association 69th Scientific Session
  • Place of Presentation: New Orleans., U.S.A.
  • Year and Date: 20090605-09
• [Presentation] The Novel Function of Trophoblast Glycoprotein(Tpbg) on Actin Remodeling in Podocyte Injured in Experimental Glomerulonephritis (2009)
  • Author(s): Murakami T, Abe H, Matsuura M, Araoka T, Kishi S, Tominaga T, Shigeta R, Yoshikawa K, Kishi F, Takamatsu N, Takahashi T, Mima A, Nagai K, Takai Y, Doi T
  • Organizer: American Society of Nephrology(ASN) Annual Meeting
  • Place of Presentation: Pennsylvania, U.S.A.
  • Year and Date: 2009-10-30