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

• 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
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糖尿病性腎症 / Sox9 / Smad1 / BMP4 / 軟骨細胞様形質変化 / 不可逆的腎機能低下 / ALK3/6 / Scleraxis / HIF1 / ALK3 / 6

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 Volume: 287 Issue: 24 Pages: 20430-20442
  • 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) Issue: 37 Pages: 32162-9
  • 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
  • NAID: 10029427023
  • 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)
  • 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] Sox9 induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy (2011)
  • Author(s): Kishi S., et al
  • Journal Title: J Biol 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: 本腎臓学会誌 Volume: 53 Pages: 1000-1005
  • NAID: 10030343457
  • 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
• [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., et al.
  • Journal Title: Mol Cells. Volume: 30(3) Pages: 209-218
  • Peer Reviewed
• [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
  • Place of Presentation: あわぎんホール(徳島県郷土文化会館)(徳島市)(招待講演)
  • 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: New Orleans., 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: さっぽろ芸術文化の館・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(札幌市)
  • 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: 広島大学・広仁会館(広島市)
  • Year and Date: 2011-05-13
• [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.
• [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
• [Presentation] Chondrogenic phenotypic change contributes to the irreversible progression of the diabetic nephropathy. (2010)
  • Author(s): Kishi S., et al.
  • Organizer: 50th The American Society for Cell Biology Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2010-12-11
• [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] メサンギウム細胞(MCs)の軟骨細胞形質獲得と低酸素下での不可逆的な腎機能低下の関連 (2010)
  • Author(s): 岸誠司, 他
  • Organizer: 第53回 日本腎臓学会学術総会
  • Place of Presentation: 神戸
  • Year and Date: 2010-06-16
• [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.
• [Presentation] Chondrogenic Potential of Mesangial Cells in Diabetic Nephropathy (2009)
  • Author(s): Kishi S, et al.
  • Organizer: 49th The American Society for Cell Biology Annual Meeting
  • Place of Presentation: San Diego, U.S.A
  • Year and Date: 2009-12-08
• [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
• [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.
• [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.
• [Book] 腎疾患の病態形成におけるBMP4・Smad1の役割 (2011)
  • Author(s): 安部秀斉
  • Publisher: 中外医学社