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Tubulointerstitial injury is exacerbated in streptozotocin-induced diabetic matrix metalloproteinase-2 knockout mice

Research Project

Project/Area Number 19590970
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionKurume University

Principal Investigator

FUKAMI Kei  Kurume University, 医学部, 准教授 (80309781)

Co-Investigator(Kenkyū-buntansha) UEDA Seiji  久留米大学, 医学部, 講師 (80322593)
Project Period (FY) 2007 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords糖尿病性腎症 / 細胞外基質 / MMP-2 / 尿細管間質 / 尿蛋白 / Diabetic Nephropathy / AGE / podocyte
Research Abstract

Background and Aims : Matrix metalloproteinnase-2 (MMP-2) is one of the potent metalloproteinases which can degrade various types of extracellular matrix (ECM) such as collagen IV, V and laminin. It has been suggested that diabetes-induced accumulation of ECM are, at least in part, by down-regulation of MMP-2. However there is no data whether MMP-2 activity and expression affect diabetes-induced renal damage in vivo. Therefore, we investigated the effects of MMP-2 deficiency on tubulointerstitial injury in diabetic animals.
Materials and Methods : Diabetes was induced by streptozotocin (STZ)(50mg/kg) in male MMP-2 knockout mice (MMP-2 KO) and C57BL/6J mice (Ctrl). After 16 weeks, cortical MMP-2 expression and activity were measured by zymography and real-time PCR, respectively. Urinary albumin excretion (UAE) and N-acetyl-β-D-glucosaminidase (NAG) were measured by enzyme-linked immunosorbent assay (ELISA). Alfa-smooth muscle actin (α-SMA) was evaluated by western blots and immnohistoche … More mistry. Tubulointerstitial injury and fibrosis were evaluated by hematoxylin and eosin staining (HE) and Masson-trichrome staining, respectively.
Results : Plasma levels of glucose and HbA1c were increased by about 2-3-folds in 16-week diabetic mice compared with non-diabetic Ctrl mice (plasma glucose ; 490.3+/-7.5mg/dl, HbA1c ; 9.91+/-0.22% in 16-week diabetic mice). MMP-2 expression and activity in the total kidney cortex of diabetic mice were increased in zymography and RT-PCR analysis. Serum levels of BUN, creatinine (Cr) and UAE were significantly increased in MMP-2 KO DM mice compared with Ctrl DM mice (BUN ; 23.2+/-1.7 vs 39.8+/-6.0mg/dl, p<0.01, Cr ; 0.07+/-0.01 vs 0.17+/-0.04mg/dl, p<0.01, UAE ; 0.08+/-0.01 vs 0.16+/-0.03mg/mgCr, p<0.05). Further, tubulointerstitial injury and cortical α-SMA expression were enhanced in DM mice, which were further increased in MMP-2 KO DM mice.
Conclusions : We demonstrate for the first time that tubulointerstitial injury and fibrosis were exacerbated in diabetic MMP-2 knockout mice, even though MMP-2 levels were increased in diabetic mice. The present study suggests that the decrease in other matrix-degrading enzymes may be involved in the tubulointerstitial injury and fibrosis in diabetic nephropathy. Less

Report

(4 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (38 results)

All 2010 2009 2008 2007 Other

All Journal Article (28 results) (of which Peer Reviewed: 27 results) Presentation (7 results) Book (3 results)

  • [Journal Article] Development of enzyme-linked immunosorbent assay system for PEDF and its clinical utility2010

    • Author(s)
      Kei Fukami, Sho-ichi Yamagishi, Seiya Okuda
    • Journal Title

      Curr Mol Med. 10(3)

      Pages: 317-20

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Irbesartan inhibits advanced glycation end product(AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs(RAGE)expression2010

    • Author(s)
      Matsui T, Yamagishi SI, Takeuchi M, Ueda S, Fukami K
    • Journal Title

      Pharmacol Res 61

      Pages: 34-9

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy.2009

    • Author(s)
      Yoshida Y, Yamagishi S, Matsui T, Jinnouchi Y, Fukami K, Imaizumi T, Yamakawa R.
    • Journal Title

      Diabetes Metab Res Rev 25

      Pages: 678-86

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Circulating matrix metalloproteinase-2 is an independent correlate of proteinuria in patients with chronic kidney disease2009

    • Author(s)
      Nagano M, Fukami K, Yamagishi S, Ueda S, Kaida Y, Matsumoto T, Yoshimura J, Hazama T, Takamiya Y, Kusumoto T, Gohara S, Tanaka H, Adachi H, Okuda S.
    • Journal Title

      Am J Nephrol 29

      Pages: 109-15

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Irbesartan inhibits advanced glycation end product (AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs (RAGE) expression.2009

    • Author(s)
      Matsui T, Yamagishi SI, Takeuchi M, Ueda S, Fukami K, Okuda S.
    • Journal Title

      Pharmacol Res. 25

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Positive association of serum levels of advanced glycation end products and high mobility group box-1 with asymmetric dimethylarginine in nondiabetic chronic kidney disease patients.2009

    • Author(s)
      Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Ueda Y, Suzuki T, Yamada S, Takeuchi M, Fukami K, Ueda S, Adachi H, Matsui T, Okuda S
    • Journal Title

      Yamagishi SI. Metabolism. 3

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis2009

    • Author(s)
      Jones LK, O'Sullivan KM, Semple T, Kuligowski MP, Fukami K, Ma FY, Nikolic-Paterson DJ, Holdsworth SR
    • Journal Title

      Kitching AR. Nephrol Dial Transplant. 24

      Pages: 3024-32

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] RAGE-Induced Cytosolic ROS Promote Mitochondrial Superoxide Generation in Diabetes.2009

    • Author(s)
      Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC, Tan AL, Fukami K, Thallas-Bonke V, Nawroth PP, Brownlee M, Bierhaus A, Cooper ME
    • Journal Title

      Forbes JM. J Am Soc Nephrol. 20

      Pages: 742-52

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation2009

    • Author(s)
      Matsui T, Yamagishi S, Takeuchi M, Ueda S, Fukami K, Okuda S.
    • Journal Title

      Biochem Biophys Res Commun. 385

      Pages: 269-72

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD)2009

    • Author(s)
      Ueda S, Yamagishi SI, Matsumoto Y, Kaida Y, Fujimi-Hayashida A, Koike K, Tanaka H, Fukami K, Okuda S.
    • Journal Title

      Life Sci. 84

      Pages: 853-6

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] A case of acute kidney injury related to intravenous Zoledronic acid in a patient with multiple myeloma. Kiyomi Koike, Kei Fukami2009

    • Author(s)
      Satoshi Morishige, Takuma Hazama, Kensei Taguchi, Ryotaro Ando, Makio Nagano, Jyunko Yoshimura, Seiji Ueda, Michitoshi Hashiguchi, Kiyoshi Tamaki, Hidemi Nishida
    • Journal Title

      Seiya Okuda. Nippon Jinzo Gakkai Shi. 51

      Pages: 557-62

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Clinical Utility of Acarbose, an alpha-Glucosidase Inhibitor in Cardiometabolic Disorders2009

    • Author(s)
      Yamagishi S, Matsui T, Ueda S, Fukami K, Okuda S.
    • Journal Title

      Curr Drug Metab. 10

      Pages: 159-63

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats.2009

    • Author(s)
      Fujimura T, Yamagishi SI, Ueda S, Fukami K, Shibata R, Matsumoto Y, Kaida Y, Hayashida A, Koike K, Matsui T, Nakamura KI, Okuda S.
    • Journal Title

      Nephrol Dial Transplant. 24

      Pages: 1397-406

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy.2009

    • Author(s)
      Shibata R, Ueda S, Yamagishi SI, Kaida Y, Matsumoto Y, Fukami K, Hayashida A, Matsuoka H, Kato S, Kimoto M, Okuda S.
    • Journal Title

      Nephrol Dial Transplant. 24

      Pages: 1162-9

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Circulating matrix metalloproteinase-2 is an independent correlate of proteinuria in patients with chronic kidney disease2009

    • Author(s)
      Nagano M, Fukami K(2番)
    • Journal Title

      Am J Nephrol 29

      Pages: 109-15

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protective role of pigment epithelium-derived factor(PEDF)in early phase of experimental diabetic retinopathy2009

    • Author(s)
      Yoshida Y, Yamagishi S, Fukami K(5番)
    • Journal Title

      Diabetes Metab Res Rev 25

      Pages: 678-86

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Circulating matrix metalloproteinase-2 is an independent correlate of proteinuria in patients with chronic kidney disease.2009

    • Author(s)
      Nagano M, Fukami K
    • Journal Title

      American Journal of Nephrology 29

      Pages: 109-115

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RAGE-lnduced Cytosolic ROS Promote Mitochondrial Superoxide Generation in Diabetes.2009

    • Author(s)
      Coughlan MT, Fukami K
    • Journal Title

      J Am Soc Nephrol 20

      Pages: 742-52

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of AGEs in diabetic nephropathy2008

    • Author(s)
      Fukami K, Yamagishi S, Ueda S, Okuda S.
    • Journal Title

      Curr Pharm Des. 14

      Pages: 946-52

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complications2008

    • Author(s)
      Yamagishi S, Nakamura K, Matsui T, Ueda S, Fukami K, Okuda S.
    • Journal Title

      Expert Opin Investig Drugs. 17

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway.2008

    • Author(s)
      Thallas-Bonke V, Thorpe SR, Coughlan MT, Fukami K, Yap FY, Sourris KC, Penfold SA, Bach LA, Cooper ME
    • Journal Title

      Forbes JM. Diabetes. 57

      Pages: 460-9

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression2008

    • Author(s)
      Yamagishi S, Matsui T, Nakamura K, Inoue H, Takeuchi M, Ueda S, Fukami K, Okuda S, Imaizumi T.
    • Journal Title

      Microvasc Res. 75

      Pages: 130-4

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression.2008

    • Author(s)
      Yamagishi SI, Matsui T, Nakamura K, Inoue H, Takeuchi M, Ueda S, Fukami K, Okuda S, Imaizumi T.
    • Journal Title

      Microvasc Res. 75

      Pages: 130-4

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-iniected rats.2008

    • Author(s)
      Fujimura T, Fukami K
    • Journal Title

      Nephrol Dial Transplant. 24

      Pages: 1397-1406

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Plasminogen activator inhibitor-1 expression is pathogenetic in experimental murine diabetic renal disease Diabetologia2007

    • Author(s)
      M. Lassila, K. Fukami, Jandeleit-Dahm, T. Semple, P. Carmeliet, M.E. Cooper, A.R. Kitching
    • Journal Title

      50

      Pages: 1315-26

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Possible involvument of AGE and MMP-2 in podocyte detachment and loss2007

    • Author(s)
      Kei Fukami, Sho-ichi Yamagishi, Seiji Ueda, Hiroshi Kawachi, Masavoshi Takeuchi, Seiya Okuda
    • Journal Title

      Journal of the American Society of Nephrology 18

    • Related Report
      2007 Annual Research Report
  • [Journal Article] Role of AGEs in Diabetic Nephropathy2007

    • Author(s)
      Kei Fukami, Sho-ichi Yamagishi, Seiji Ueda, Seiya Okuda
    • Journal Title

      Current Pharmaceutical Design (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel therapeutic targets for diabetic nephropathy2007

    • Author(s)
      Kei Fukami, Sho-ichi Yamagishi, Seiji Ueda, Seiya Okuda
    • Journal Title

      Endocr Metab ImmuneDisord Drug Targets 7

      Pages: 83-92

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation]2009

    • Organizer
      第52回日本腎臓学会学術集会
    • Related Report
      2009 Final Research Report
  • [Presentation] Possible involvement of AGE and MMP-2 in podocyte detachment and loss.2008

    • Author(s)
      Fukami K
    • Organizer
      ヨーロッパ糖尿病学会
    • Place of Presentation
      Roma
    • Year and Date
      2008-09-10
    • Related Report
      2008 Annual Research Report
  • [Presentation]2008

    • Organizer
      第51回日本腎臓学会学術集会
    • Related Report
      2009 Final Research Report
  • [Presentation] Possible involvement of AGE and MMP-2 in podocyte detachment and loss. Roma.2008

    • Author(s)
      Fukami K, Takamiya Y, Yamagishi S, Ueda S, Takeuchi M, Okuda S
    • Organizer
      Diabetologia
    • Place of Presentation
      EASD
    • Related Report
      2009 Final Research Report
  • [Presentation] Possible involvement of AGE and MMP-2 in podocyte detachment and loss2007

    • Author(s)
      Kei Fukami, Sho-ichi Yamagishi, Seiji Ueda, Hiroshi Kawachi, Masayoshi Thkeuchi, Seiya Okuda
    • Organizer
      The European Association for the Study of Diabetes
    • Place of Presentation
      アムステルダム
    • Year and Date
      2007-09-19
    • Related Report
      2007 Annual Research Report
  • [Presentation]2007

    • Organizer
      第50回日本腎臓学会学術集会
    • Related Report
      2009 Final Research Report
  • [Presentation] Possible involvement of AGE and MMP-2 in podocyte detachment and loss.2007

    • Author(s)
      Fukami K, Takamiya Y, Yamagishi S, Ueda S, Takeuchi M, Okuda S
    • Organizer
      Amsterdam. Diabetologia
    • Place of Presentation
      EASD
    • Related Report
      2009 Final Research Report
  • [Book] エビデンスが不十分な年齢層への降圧目標と降圧薬選択のポイント2009

    • Author(s)
      深水圭、山岸昌一、奥田誠也薬局
    • Related Report
      2009 Final Research Report
  • [Book] 糖尿病合併高血圧におけるRA系の関わりとテルミサルタンの降圧効果とその有用性2008

    • Author(s)
      羽田勝計、山岸昌一、深水圭、Mark Cooper
    • Publisher
      Pharma Medica
    • Related Report
      2009 Final Research Report
  • [Book] 糖尿病と酸化ストレス糖尿病患者の酸化ストレスマーカー

    • Author(s)
      深水圭、山岸昌一、奥田誠也
    • Publisher
      AGEs/PEDF(in press)
    • Related Report
      2009 Final Research Report

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Published: 2007-04-01   Modified: 2018-02-02  

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