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1996 Fiscal Year Final Research Report Summary

Study for model of diabetic nephropathy and prevention of disease progress

Research Project

Project/Area Number 06557064
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field Kidney internal medicine
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

DOI Toshio  Kyoto University, Faculty of Medicine, Assisiant Professor, 医学研究科, 講師 (60183498)

Co-Investigator(Kenkyū-buntansha) HARA Seijiro  Shionogi Research Laboratones, Researcher, 研究員
HAKAMATA Yasuhiro  Kyoto University, Faculty of Medicine, Instructor, 医学研究科, 助手 (30261233)
YOKODE Masayuki  Kyoto University, Faculty of Medicine, Assistant Professor, 医学研究科, 講師 (20252447)
FUKATSU Atsushi  Aichi Medical University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (90247685)
Project Period (FY) 1994 – 1996
Keywordsdiabetic nephropathy / glomerulonephritis / advanced glycation endproducts / type IV collagen / DNA binding protein / chaperone / HSP 47 / ribozyme
Research Abstract

Diabetic nephropathy is one of the most important diseases for cause of endstage kidney disease. The pathogenesis and treatment of the disease are critical for medical and social problems. Diabetic complications are mediated by advanced glycation endproducts (AGE) which produced by long-term reaction between proteins and high glucose condition. This study was designed to establish the model of diabetic nephropathy and to study the mechanism and the prevention of disease progress. We analyzed knockout mice for apolipoprotein E that developed the progressive glomerulosclerosis in association with glomerular hypertrophy. Mesangial cells had a low affinity receptor for AGE (RAGE) and increased the synthesis of extracellular matrix including type IV collagen. This reaction was mediated by specific DNA binding protein for promoter of type IV collagen (Alp145), which had multifunctions including DNA replication factor C and DNA binding proteins for promoter of angiotensinogen. The expression … More of Alp145 was correlated with glomerular sclerosis and cell proliferation in vivo model. Furthermore, we applied the hammerhead ribozyme for targeting RAGE and established a stable cell line that produced RAGE-specific ribozyme. The induction of type IV mRNA by AGE on mesangial cell was inhibited by RAGE-specific ribozyme. Heat shock protein 47 (HSP47) is a collagen-specific chaperone that has a major role during the biosynthesis and secretion of procollagen molecules. The expression of HSP47 increased in parallel with the expression of collagens during the progression of glomerulosclerosis in renal ablation rats. The administration of antisense oligonucleotides against HSP47 at the induction of anti-thy-1 glomerulonephritis markedly suppressed the increased production of collagens and attenuated the histological manifestations of desease. This study provides to establish the model for typical glomerulosclerosis, to determine the mechanisms of disease progression, and to further develop new strategy for prevention of disease progression. Less

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] 家原 典之: "Differentiation of smooth muscle phemotypes in mouse mesangial cells" Kidney International. 49. 1330-1341 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 家原 典之: "Advanced glycation endproducts modulate transcriptional regulation in mesangial cells" Kidney International. 50. 1166-1172 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小松 武生: "Demorstration of DNA replication factor Cin human glomerular lesions" clinical nephrology. 49. 69-73 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 辻 博子: "Ribozyme targetting of receptor for advanced glycation end products in mesangial cells" Biochemical and Biophysical Research Communications. 245. 583-588 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 砂本 正明: "Expression of heat shock protein 47 is increased in remnant kidney and correlates with disease progression" in press.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 砂本 正明: "Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis" Laboratory Investigation. in press.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Iehara N.et.al.: "Differentiation of smooth muscle phemotyoes in mouse mesangial cells." Kidney International. 49. 1330-1341 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Iehara N.et.al.: "Advanced glycation endproducts modulate transcriptional regulation in mesangial cells." Kidney International. 50. 1166-1172 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Komatsu T.et.al.: "Demonstration of DNA replication factor C in human glomerular lesions." clinical nephrology. 49. 69-73 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuji H.et.al.: "Ribozyme targetting of receptor for advanced glycation end products in mesangial cells." Biochemical and Biophysical Research Communications. 245. 583-588 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sunamoto M,et.al.: "Expression of heat shock protein 47 is increased in remnant kidney and correlates with disease progression." International Journal of Experimental Pathology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sunamoto M,et.al.: "Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis." Laboratory Investigation. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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