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1996 Fiscal Year Final Research Report Summary

Analysis of Diabetic Complications Using Transgenic Mice

Research Project

Project/Area Number 07671144
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionThe University of Tokushima

Principal Investigator

YAMAOKA Takashi  The University of Tokushima, Otsuka Department of Clinical and Molecular Nutrition, Instructor, 医学部, 助手 (40263826)

Co-Investigator(Kenkyū-buntansha) II Setsuko  The University of Tokushima, Otsuka Department of Clinical and Molecular Nutriti, 医学部, 助手
ITAKURA Mitsuo  The University of Tokushima, Otsuka Department of Clinical and Molecular Nutriti, 医学部, 客員教授 (60134227)
Project Period (FY) 1995 – 1996
KeywordsTransgenic mouse / Aldose reductase / Sorbitol dehydrogenase / Polyol pathway / Diabetic complications / Diabetic retinopathy / Diabetic nephropathy
Research Abstract

To elucidate the mechanism of diabetic complications and establish a logical approach to their therapy, we have generated the transgenic mice expressing human aldose reductase (hAR) driven by mouse MHC class I molecule promoter (hAE-Tg). Northern and Western blot analyzes and immunoassay of hAR revealed that both hAR mRNA and hAR protein were expressed in all tissues tested. In the kidney of hAR-Tg, the level of hAR mRNA was 1.6 times as much as mouse AR (mAR) mRNA.Streptozotocin (STZ)-induced diabetes increased not only mAR mRNA by a factor of 3.9, but also hAR mRNA and hAR protein by a factor of 3.2 and 3.1, respectively. In STZ-induced diabetes, renal sorbitol content in hAR-Tg increased more than that in the littermates. In both hAR-Tg and the littermates, renal glutathione content was reduced by STZ-induced diabetes, but not by the galactose diet, whereas the ratio of lactate to pyruvate was increased by both STZ-induced diabetes and the galactose diet. Although the administration of AR inhibitor, epalrestat, improved the changes of renal sorbitol content, glutathione content, the lactate-to-pyruvate ratio, and polyuria in diabetic hAR-Tg, it had little effect on albuminuria. Retinal microaneurysms were observed in hAR-Tg with the galactose diet. The incidence and severity of the lesion were higher in hAR-Tg than those in the littermates, and suppressed by ARI.
Furthermore, to comprehensively investigate the association of the acceleration of polyol pathway with diabetic complications, we have obtained sorbitol dehydrogenase (SDH)-deficient mouse, cloned hSDH cDNA from HeLa cells by RT-PCR method, and generated hSDH-Tg. We are going to examine whether the diabetic complications observed in hAR-Tg improve or progress by crossbreeding hAR-Tg with SDH-deficient mice or hSDH-Tg.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Takashi Yamaoka: "Acute on set of diabetic pathological change in transgenic mice with human aldose reductase cDNA" Diabetologia. 38. 255-261 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mika Ohta: "Galactose-induced albuminuria in transgenic mice expressing human aldose reductase" Nutrition Research. 15. 1343-1353 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takashi Yamaoka: "The effect of non-enzymatic glycation on human aldose reductase" Diabetes Research and Clinical Practice. 27. 165-169 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kiyoshi Kunika: "Damage of charge-dependent renal tubular reabsorption causes diabetic micro albuminuria" Diabetes Research and Clinical Practice. in press.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maki Moritani: "Prevention of adoptively transferred diabetes in non-obese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes" J.Clin.Invest.98. 1851-1859 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akira Tomonari: "GGAAAT motifs play a major role in transcriptional activity of the human insulin gene in a pancreatic islet β cell line of MIN6" Diabetologia. 39. 1462-1468 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mitsuo Itakura: "Lessons from Animal Diabetes(ChapterII)" Birkhauser, 416 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takashi Yamaoka, Chihiro Nishimura, Kamejiro Yamashita, Taketo Yamada, Jun-ichiro Fujimoto, Mitsuo Itakura, and Yasuo Kokai: "Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA." Diabetologia. 38. 255-261 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mika Ohta, Setsuko Ii, Takashi Yamaoka, Kazuo Ono, Yasuo Kokai, Jun-ichiro Fujimoto, Hiroyuki Iwahana, Katsuhiko Yoshimoto, and Mitsuo Itakura: "Galactose-induced albuminuria in transgenic mice expressing human aldose reductase" Nutrition Research. 15. 1343-1353 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takashi Yamaoka, Ayako Oda, Chieko Bannai, Mitsuo Itakura, and Kamejiro Yamashita: "The effect of non-enzyme glycation on human aldose reductase" Diabetes Research and Clinical Practice. 27. 165-169 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kiyoshi Kunika, Takashi Yamaoka, and Mitsuo Itakura: "Diabetic damage of selective renal reabsorption assessed by albumin negative charge" Diabetes Research and Clinical Practice. 33. 181-189 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akira Tomonari, Katsuhiko Yoshimoto, Masaki Tanaka, Hiroyuki Iwahana, Jun-ichi Miyazaki, and Mitsuo Itakura: "GGAAAT Motifs Play a Major Role in Transcriptional Activity of the Human Insulin Gene in a Pancreatic Islet Beta Cell Line of MIN6." Diabetologia. 39. 1462-1468 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Maki Moritani, Katsuhiko Yoshimoto, Setsuko Ii, Maki Kondo, Hiroyuki Iwahana, Takashi Yamaoka, Toshiaki Sano, Naoko Nakano, Hitoshi Kikutani, and Mitsuo Itakura: "Prevention of adoptively transferred diabetes in non-obese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes : a gene therapy model for autoimmun diabetes." J Clin Invest. 98. 1851-1859 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mitsuo Itakura, Setsuko Ii, Mika Ohta, and Takashi Yamaoka: ""Polyol accumulation versus diabetic retinopathy and nephropathy in transgenic mice expressing human aldose reductase"" Lessons from Animal Diabetes, Ed.by E.Shafrir. 175-200 (1995)

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

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Published: 1999-03-09  

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