Metallothionein 3: A New Player in Diabetic Nephropathy

• Project/Area Number: 15K09372
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Asahikawa Medical College
• Principal Investigator: TAKIYAMA YUMI 旭川医科大学, 医学部, 准教授 (00396350)
• Co-Investigator(Kenkyū-buntansha): 世良 俊博 九州大学, 工学研究院, 准教授 (40373526) ; 中村 匡徳 名古屋工業大学, 工学(系)研究科(研究院), 教授 (20448046) ; 高橋 賢治 旭川医科大学, 大学病院, 医員 (00736332)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: メタロチオネイン3 / 糖尿病腎症 / HIF-1 / 酸化ストレス / 低酸素 / 腎症バイオマーカー / in vivo imaging / 結節性病変電顕所見

Outline of Final Research Achievements

We hypothesized that metallothionein 3 (MT3), a novel target gene of hypoxia inducible factor-1 (HIF-1), could be involved in the diabetic glomerular injury in a retrograde fashion, via hyperglycemia-induced hypoxia in renal proximal tubules accompanied with overexpression of MT3. To clarify the role of MT3 in diabetic kidney, we generated transgenic mice, harboring a 40-kb bacterial artificial chromosome (BAC) expressing human MT3 mRNA and protein to generate humanized BAC transgenic mice (BACTGMT3). Aging-, diabetes- and high fat-induced hypoxia induced overexpression of MT3 in tubular cells in BACTGMT3 mice, resulting in narrowing the vascular lumen of peritubular capillaries by the endothelial swelling, which could retrogradely cause glomerular hypertension, leading to the glomerular injury.

Research Products

• [Journal Article] Dipeptidyl peptidase-4 inhibitor treatment induces a greater increase in plasma levels of bioactive GIP than GLP-1 in non-diabetic subjects. (2017)
  • Author(s): Yanagimachi T, Fujita Y, Takeda Y, Honjo J, Sakagami H, Kitsunai H, Takiyama Y, Abiko A, Makino Y, Kieffer TJ, Haneda M.
  • Journal Title: Mol Metab Volume: 6 Issue: 2 Pages: 226-231
  • DOI: 10.1016/j.molmet.2016.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of IGFBP7 in Diabetic Nephropathy: TGF-β1 Induces IGFBP7 via Smad2/4 in Human Renal Proximal Tubular Epithelial Cells. (2016)
  • Author(s): Takiyama Y, Watanabe J, Honjyo J, Makino Y, Fujita Y, Tateno M, Haneda M.
  • Journal Title: PLOS ONE Volume: 14 Issue: 3 Pages: 1-20
  • DOI: 10.1371/journal.pone.0150897
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pancreatic glucose-dependent insulinotropic polypeptide (GIP) (1-30) expression is upregulated in diabetes and PEGylated GIP(1-30) can suppress the progression of low-dose-STZ-induced hyperglycaemia in mice. (2016)
  • Author(s): Yanagimachi T, Fujita Y, Takeda Y, Honjo J, Atageldiyeva KK, Takiyama Y, Abiko A, Makino Y, Kieffer TJ, Haneda M.
  • Journal Title: Diabetologia Volume: 59 Issue: 3 Pages: 5330541-5330541
  • DOI: 10.1007/s00125-015-3842-y
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High glucose induces platelet-derived growth factor-C via carbohydrate response element-binding protein in glomerular mesangial cells. (2016)
  • Author(s): Kitsunai H, Makino Y, Sakagami H, Mizumoto K, Yanagimachi T, Atageldiyeva K, Takeda Y, Fujita Y, Abiko A, Takiyama Y, Haneda M.
  • Journal Title: Physiol Rep Volume: 4 Issue: 6 Pages: 1-13
  • DOI: 10.14814/phy2.12730
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 新規腎糸球体イメージング法の検討：腎糸球体に及ぼす糖尿病の影響。 (2016)
  • Author(s): 滝山 由美、世良 俊博、中村 匡徳、上杉 健太朗、星野 正人、八木 直人、西條 泰明、羽田 勝計。
  • Organizer: 第 28回日本糖尿病性腎症研究会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-03
• [Presentation] A New Model for Diabetic Nephropathy: A Hypoxia-Induced Antioxidant Metallothionein-3 BACTG mice. (2016)
  • Author(s): Yumi Takiyama, Ryoichi Bessho, Takahiko Nakagawa, Masakazu Haneda.
  • Organizer: The American Society of Nephrology Annual Meeting & Scientific Exposition.
  • Place of Presentation: Chicago, USA.
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] A novel approach for estimating glomerular number and volume using synchrotron radiation micro-CT in SPring-8: The impacts of Diabetes on glomeruli. (2016)
  • Author(s): Yumi Takiyama
  • Organizer: The 15th Japan-Korea Diabetic Nephropathy Seminar.
  • Place of Presentation: Asahikawa, Japan.
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] 新規糖尿病腎症モデル：低酸素誘導抗酸化物質Metallothionein3トランスジェニックマウス。 (2016)
  • Author(s): 滝山 由美、別所 瞭一、藤田 征弘、安孫子 亜津子、立野 正敏、仲川 孝彦、羽田 勝計。
  • Organizer: 第31回日本糖尿病合併症学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-10-07
• [Presentation] Zinc; HIF-1 mimetic in Human Renal Proximal Tubular Cells. (2016)
  • Author(s): Ryoichi Bessho, Yumi Takiyama, Manami Maeda, Kuralay K. Atageldiyeva, Yukihiro Fujita, Atsuko Abiko, Masakazu Haneda.
  • Organizer: American Diabetes Association, 76th Scientific Sessions.
  • Place of Presentation: New Orleans, USA.
  • Year and Date: 2016-06-10
  • Int'l Joint Research
• [Presentation] ヒト近位尿細管細胞において、亜鉛はTGF-β1誘導線維化を抑制しHIF-1 target遺伝子発現を増強する。 (2016)
  • Author(s): 別所 瞭一, 前田 愛実, 滝山 由美, Kuralay. K. Atageldiyeva, 柳町 剛司、長南 茉欧, 高橋 耕平, 酒井 健太郎, 中村 知伸, 永島 優樹, 竹田 安孝、辻 賢, 本庄 潤, 藤田 征弘, 安孫子 亜津子, 羽田 勝計。
  • Organizer: 第 59 回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] SGLT2阻害剤治療1年後造血亢進を呈した一症例。 (2016)
  • Author(s): 滝山 由美、酒井 健太郎、阿部 智恵、中村 知伸、竹田 安孝、辻 賢, 坂上 英充、本庄 潤、藤田 征弘, 安孫子 亜津子, 羽田 勝計
  • Organizer: 第50回日本糖尿病学会北海道地方会。
  • Place of Presentation: 札幌
• [Presentation] 中枢性甲状腺機能低下症に対するT3,T4併用療法の一例 (2016)
  • Author(s): 1.滝山由美、滝山義之、江口耕平、牧野雄一
  • Organizer: 日本内分泌学会第16回北海道支部学術集会
  • Place of Presentation: 札幌
• [Presentation] Metallothionein3 トランスジェニックマウスは、高血糖無しに糖尿病性腎症類似病変を呈する (2015)
  • Author(s): 滝山 由美、別所 瞭一、柳町 剛司、藤田 征弘、立野 正敏、仲川 孝彦、羽田 勝計.
  • Organizer: 第 27 回日本糖尿病性腎症研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-12-05
• [Presentation] ヒト糖尿病性腎症近位尿細管における抗酸化物質Metallothionein3の発現制御機構の検討. (2015)
  • Author(s): 滝山 由美、別所 瞭一、柳町 剛司、本庄 潤、藤田 征弘、羽田 勝計.
  • Organizer: 第30回日本糖尿病合併症学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-27
• [Presentation] The impact of Diabetes on Total Glomerular Numbers and Size in Kidney Estimated by Synchrotron Radiation Micro-CT in SPring-8. (2015)
  • Author(s): Yumi Takiyama, Toshihiro Sera, Masanori Nakamura, Manami Maeda, Tsuyoshi Yanagimachi, Ryoichi Bessho, Kentaro Uesugi, Naoto Yagi, Masakazu Haneda.
  • Organizer: The American Society of Nephrology Annual Meeting & Scientific Exposition.
  • Place of Presentation: San Diego, CA.
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] Upregulated Metallothionein (MT) 3 Expression in Human Diabetic Kidney: Hypoxia Induced MT3 Expression via HIF-1a In Human Renal Proximal Tubular Epithelial Cells. (2015)
  • Author(s): Yumi Takiyama, Masakazu Haneda.
  • Organizer: The 14th Japan-Korea Diabetic Nephropathy Seminar.
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2015-10-30
  • Int'l Joint Research
• [Presentation] A New Player in Diabetic Nephropathy: Metallothionein 3 Is A Target For Hypoxia Inducible Factor-1. (2015)
  • Author(s): Yumi Takiyama, Manami Kobayashi, Kuralay Atageldiyeva, Tsuyoshi Yanagimachi, Jun Honjo, Yukihiro Fujita, Masakazu Haneda.
  • Organizer: American Diabetes Association, 75th Scientific Sessions.
  • Place of Presentation: Boston, MA.
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] 新規HIF-1標的遺伝子Metallothionein-3の糖尿病性腎症病態関与についての検討． (2015)
  • Author(s): 滝山 由美、前田 愛実、Kuralay K. Atageldiyeva、 柳町 剛司、本庄 潤、藤田 征弘、羽田 勝計.
  • Organizer: 第58回日本糖尿病学会年次学術集会.
  • Place of Presentation: 下関
  • Year and Date: 2015-05-21
• [Book] Current Therapy (2017)
  • Author(s): 滝山 由美
  • Total Pages: 1
  • Publisher: 株式会社ラフメディコム
• [Book] 日本臨床 (2016)
  • Author(s): 滝山 由美、羽田 勝計
  • Total Pages: 6
  • Publisher: 日本臨床社
• [Book] 新時代の臨床糖尿病学（下）－より良い血糖管理をめざしてー (2016)
  • Author(s): 滝山 由美、羽田 勝計
  • Total Pages: 6
  • Publisher: 日本臨床
• [Book] 糖尿病性腎症エキスパートブック: state of the art (2016)
  • Author(s): 滝山 由美
  • Total Pages: 7
  • Publisher: 南江堂
• [Book] 糖尿病 (2015)
  • Author(s): 滝山 由美
  • Total Pages: 10
  • Publisher: 医学出版
• [Book] 糖尿病学 (2015)
  • Author(s): 滝山 由美、羽田 勝計
  • Total Pages: 8
  • Publisher: 西村書店