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Inhibition of Chronic Renal Failure by HGF: Mechanistic Study on the HGF-mediated Therapeutic Effects

Research Project

Project/Area Number 14570187
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionOsaka University

Principal Investigator

MIZUNO Shinya  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (10219644)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Toshikazu  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (00049397)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsChrinic Renal Failure / HGF / Tissue Fibrosis / TGF-beta / Mesangial Cells / Glomerulosclerosis / Myofibroblasts / Diabetic Nephropathy / 慢性腎疾患 / 細胞外マトリックス / 再生医学
Research Abstract

It is now widely accepted that HGF is an essential intrinsic repair factor not only in liver but also in parenchymal organs (such as kidney, lung, stomach, skin and so on). Based on these backgrounds, we hypothesized that HGF plays an important role for inhibiting tissue fibrosis, which is characterized by a loss in parenchymal epithelial cells. Actually, we for the first time demonstrated that H GE-induced regeneration of renal epithelial cells leads to prevention of renal interstitial fibrosis, a histopathological hallmark of chronic renal failure. However, it is still unclear: 1) whether HGF reverses fibrotic lesions once the chronic renal injuries are established; and 2) how HGF produces the beneficial effect at a molecular level(s).
In the current study, we used streptozotocin-treated mice as a model of diabetic nephropathy to determine physiological and therapeutic effects of HGF on hyperglycemia-induced renal diseases. When the diabetic mice were treated with anti-rodent HGF IgG, … More there were rapid progressions of glomerular hypertrophy/fibrosis and renal dysfunction. Inversely, supplement of exogenous HGF led to improvement in renal function. In this process, HGF initially targeted glomerular mesangial cells and suppressed the high glucose-induced production of TGF-beta1 (a key molecule of renal fibrosis in diabetes), leading to preventions of glomerular fibrosis and proteinuria. Overall, HGF was found to be effective in attenuating diabetic glomerulopathy (characterized by tuft fibrosis, hypertrophy and urinary albumin excretion), even at an advanced stage of diabetes.
It is now clear that HGF directly targets glomerular mesangial cells, which are a key player of tuft fibrosis as collagen-producing cells. Thus, we next focused on effect of HGF on glomerular cell behavior. Using anti-Thy-1 IgG-injected rats as an animal model of mesangial proliferative glomerulonephritis, we addressed if HGF may alter proliferative activity in the glomerular mesangial cells. In the anti-Thy-1 IgG-injected rats, mesangial cells newly expressed c-Met/HGF receptor along with trans-differentiation to myofibroblasts. When we administered recombinant HGF protein in the rat model, mesangial cell (i.e., myofibroblast-like) proliferation became faint. ln a culture model, HGF was demonstrated to inhibit PDGF-mediated mesangial cell proliferation, accompanied with suppressed p42 MAPK (Erk) phosphorylation. Consistently with the suppressed myofibroblast proliferation, glomerular fibrotic lesions were suppressed by HGF.
Throughout the current experiments, we delineated a new function of HGF to antagonize progression of chronic renal failure: 1) HGF target interstitial myofibroblasts and suppresses TGF-beta1 production; and 2) HGF inhibits PDGF-mediated proliferation of the myofibroblasts, both of which contribute to HGF-mediated anti-fibrotic outcomes in chronic renal diseases. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy."Am.J.Physiol.. 286. F134-F143 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Mizuno, et al.: "Repeated streptozotocin injections cause early onset of glomerulosclerosis in mice."Exp.Anim.. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Mizuno, et al.: "Steroid therapy delays the progression of glomerular sclerosis but not nephrotic symptoms in the ICGN mouse strain."Vet.Biochem.. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospin al fluid can prevent and ameliorate hearing impairment in rats."FASEB J.. 18. 212-214 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism."Am.J.Pathol.. 164. 1091-1098 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis."Am.J.Physiol.. 284. F1171-F1180 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 水野信哉, 他: "医学のあゆみ"医歯薬出版. 3 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 水野信哉, 他: "臨床免疫"科学論評社. 9 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 水野信哉, 中村敏一: "The Lung"メディカルレビュー社. 11 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 水野信哉, 中村敏一: "Annual Review腎臓2003"中外医学社. 11 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 水野信哉, 中村敏一: "再生医学・再生医療"東京化学同人. 11 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizuno S, Nakarnura T: "Suppression of chronic glomerular injuries and TGF-beta1 production by HGF in attenuation of murine diabetic nephropathy."Am J Phsiol. 286. F134-F143 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizuno S, Wen JH, Kurosawa T: "Steroid therapy delays the progression of glomerular sclerosis but not nephrotic symptoms in the ICGN mouse strain."Vet Biochem. 40. 54-60 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori N, Mizuno S, Yoshida Y, Chin K, Mishima M, Sisson TH, Simon RH, Nakamura T, Miyake M: "The plasminogen activation system reduces fibrosis in the lung by a HGF-dependent mechanism."Am J Pathol. 164. 1091-1098 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Oshima K, Shimamura M, Mizuno S, Taniami K, Doi K, Morishita R, Nakamura T, Kubo T, Kaneda Y.: "HGF gene transfer in cerebrospinal fluid can prevent hearing impairment in rats."FASEB J. 18. 212-214 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Bessho K, Mizuno S, Matsumoto K, Nakamura T: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis."Am J Phsiol. 284. F1171-F1180 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakamaki Y, Matsumoto K, Mizuno S, Miyoshi S, Matsuda H, Nakamura T: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice."Am J Respir Cell Mol Biol. 26. 525-533 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawashima K, Mizuno S, Mizuno-Horikawa Y, Kurosawa T: "Protein restriction ameliorates renal tubulointerstitial nephritis and reduces renal transforming growth factor-beta expression in unilateral ureteral obstruction."Exp Nephrol. 10. 7-18 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy"Am.J.Physiol.. 286. F134-F143 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Mizuno, et al.: "Repeated streptozotocin injections cause early onset of glomerulosclerosis in mice"Exp.Anim.. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Mizuno, et al.: "Steroid therapy delays the progression of glomerular sclerosis but not nephrotic symptoms in the ICGN mouse strain"Vet.Biochem.. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats"FASEB J.. 18. 212-214 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism"Am.J.Pathol.. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis"Am.J.Physiol.. 284. F1171-F1180 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 水野信哉, 他: "医学のあゆみ"医歯薬出版(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 水野信哉, 他: "臨床免疫"科学論評社. 9 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 水野信哉, 中村敏一: "The Lung"メディカルレビュー社. 11 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 水野信哉, 中村敏一: "Annual Review 腎臓 2003"中外医学社. 11 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuno S, et al.: "Repeated streptozotocin injections cause early onset of glomerulosclerosis in mice"Exp Aninmal. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Bessho K, et al.: "Counteractive effects of HGF on PDGF-mediated mesangial cell proliferation in a rat model of glomerulonephritis"Am J. Physiol.. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sawashima K, et al.: "Protein restriction ameliorates renal tubulointerstitial nephritis and reduces renal transforming growth factor-beta expression in unilateral ureteral obstruction"Exp Nephrol. 10. 7-18 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakamaki Y, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice"Am J Respir Cell Mol. Biol.. 26. 525-533 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 水野信哉, 他: "HGFとTGF-βのバランスを介した組織線維化調節機構"臨床免疫. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 水野信哉, 他: "肺再生因子HGFによる呼吸器疾患での肺蘇生療法の可能性"The Lung Perspective. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 水野信哉, 他: "現代化学別冊41・再生医学・再生医療"東京化学同人. 12 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 水野信哉, 他: "Annual Review腎臓"中外医学社. 11 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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