Moleular Basis for HGF-mediated Self-defense System During sepsis

• Project/Area Number: 20590398
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Osaka University
• Principal Investigator: MIZUNO Shinya Osaka University, 医学系研究科, 助教 (10219644)
• Co-Investigator(Renkei-kenkyūsha): NAKAMURA Toshikazu 大阪大学, 先端科学イノベーションセンター, 特任教授 (00049397)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HGF / c-Met / 多臓器不全 / 敗血症 / 炎症性サイトカイン / マクロファージ / 肝細胞増殖因子 / 腎傷害 / 蛋白尿 / ポドサイト / 炎症性サイトカイ / スリット蛋白 / ネフリン / 高サイトカイン血症 / 分子機構 / 血栓形成 / 多臟器不全 / HO-1

Research Abstract

We demonstrated that direct effects of HGF on macrophages during leads to inhibition of the NF-?b activation and subsequent transcription of pro-inflammatory cytokines. Furthermore, we found, using a mouse model of sepsis, that HGF-mediated up-regulation of hemeoxygenese-1 is required for HGF to inhibit the onset of septic acute renal failure, lung injury and hepatitis. Based on the present data, we conclude that enhancement of the HGF-hemeoxygenase-1 pathway in macrophages can be a reasonable strategy to improve the sepsis-related pathological conditions.

Research Products

• [Journal Article] Recombinant human HGF, but not rat HGF, elicits glomerular injury and albuminuria in normal rats via an immune complex-dependent mechanism. (2011)
  • Author(s): Mizuno S, Ikebuch F, Fukuta K, Kato T. Matsumoto K, Adachi K, Abe. Nakamura.
  • Journal Title: Clin Exp Pharmacol Physiol 38 Pages: 192-201
  • Peer Reviewed
• [Journal Article] Preser.ations of nephrin and synaptopodin by HGF in podocytes for the attenuations of foot process injury and albuminuria in nephritic mice. (2011)
  • Author(s): Kato Y., Mizuno S, Nakamura T.
  • Journal Title: Nephrology 16 Pages: 310-318
  • Peer Reviewed
• [Journal Article] Preservations of nephrin and synaptopodin by recombinant hepatocyte growth factor in podocytes for the attenuations of foot process injury and alburninuria in nephritic mice. (2011)
  • Author(s): Kato T, Mizuno S, Nakamura T.
  • Journal Title: Nephrology Volume: 16 Pages: 310-318
  • Peer Reviewed
• [Journal Article] Recombinant human HGF, but not rat HGF, elicits glomerular injury and albuminuria in normal rats via an immunecomplex-dependent mechanism. (2011)
  • Author(s): Mizuno S, Ikebuchi F, Fukuta K, Kato T, Matsumoto K, Adachi K, Abe T, Nakamura T.
  • Journal Title: Clin Exp Pharmacol Physiol Volume: 38 Pages: 192-201
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor (HGF), an endogenous pulmotrophic regulator, for the rescue of acute and chronic lung diseases. (2011)
  • Author(s): Mizuno S, Ohnishi H, Nakamura T
  • Journal Title: Cell Signaling Transduction Therapy Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor (HGF) for a cell-signal-based therapy during acute and chronic liver diseases. (2011)
  • Author(s): Oka K, Fukuta K, Mizuno S.
  • Journal Title: Cell Signaling Transduction Therapy Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Disco.ery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. (2010)
  • Author(s): Nakamura T, Mizuno S.
  • Journal Title: Proc. Japan Acad. Series-B 86 Pages: 588-610
  • Peer Reviewed
• [Journal Article] The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice. (2010)
  • Author(s): Kato T., Mizuno S, Kamimoto M.
  • Journal Title: Biomed Res 1 Pages: 363-369
  • NAID: 130004470763
  • Peer Reviewed
• [Journal Article] Attenuation of ischemic myocardial injury and dysfunction by cardiac fibroblast-derived factor(s). (2010)
  • Author(s): Nakazato K, Naganuma W, Ogawa K, Yaoita H, Mizuno S, Nakamura T, Maruyama Y.
  • Journal Title: Fukushima J Med Sci 56 Pages: 1-16
  • NAID: 10030915998
  • Peer Reviewed
• [Journal Article] The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice. (2010)
  • Author(s): Kato T, Mizuno S, Kamimoto M.
  • Journal Title: Biomed Res Volume: 31 Pages: 363-369
  • NAID: 130004470763
  • Peer Reviewed
• [Journal Article] Attenuation of ischemic myocardial injury and dysfunction by cardiac fibroblast-derived factor(s). (2010)
  • Author(s): Nakazato K, Naganuma W, Ogawa K, Yaoita H, Mizuno S, Nakamura T, Maruyama Y
  • Journal Title: Fukushima J Med Sci Volume: 56 Pages: 1-16
  • NAID: 10030915998
  • Peer Reviewed
• [Journal Article] The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. (2010)
  • Author(s): Nakamura T, Mizuno S.
  • Journal Title: Proc Jpn Acad Ser B Volume: 86 Pages: 588-610
  • NAID: 130000258751
  • Peer Reviewed
• [Journal Article] Type 2a sodium-phosphate co-transporter serves as a histological predictor of renal dysfunction and tubular apical damage in the kidneys of septic mice (2010)
  • Author(s): Kamimoto-M, Mizuno-S, Ohnishi-H, Mizuno-Horikawa-Y
  • Journal Title: Biomedical Research 30 Pages: 251-258
  • NAID: 130004903759
  • Peer Reviewed
• [Journal Article] Type 2a sodium-phosphate co-transporter serves as a histological predictor of renal dysfunction and tubular apical damage in the kidneys of septic mice. (2009)
  • Author(s): Kamimoto M, Mizuno S, Ohnishi H, Mizuno-Horikawa Y.
  • Journal Title: Biomed Res 30 Pages: 251-258
  • NAID: 130004903759
  • Peer Reviewed
• [Journal Article] Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models. (2009)
  • Author(s): Kishi Y, Kuba K, Nakamura T, Wen J, Suzuki Y, Mizuno S, Nukiwa T, Matsumoto K, Nakamura T.
  • Journal Title: Cancer Sci 100 Pages: 1351-1358
  • NAID: 10027192650
  • Peer Reviewed
• [Journal Article] Tryptophan 2,3-dioxygenase is a key modulator of physiological neugenesis and anxiety-related behavior in mice. (2009)
  • Author(s): Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S, Matsumoto K, Nakamura T.
  • Journal Title: Mol Brain 2 Pages: 8-23
  • Peer Reviewed
• [Journal Article] Reciprocal regulation of IL-6 and Il-10 balance by HGF via recruitment of HO-1 in macrophages for attenuation of hepatic injury in a mouse model of endotoxemia. (2009)
  • Author(s): Kamimoto M, Mizuno S, Nakamura T.
  • Journal Title: Int J Mol Med 24 Pages: 161-170
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor prevents multiple organ injuries in endotoxemic mice through a heme oxygenase-dependent mechanism. (2009)
  • Author(s): Kamimoto M, Mizuno S, Matsumoto K, Nakamura T.
  • Journal Title: Biochem Biophys Res Communs 380 Pages: 333-337
  • Peer Reviewed
• [Journal Article] Reciprocal regulation of IL-6 and II-10 balance by HGF via recruitment of HO-1 in macrophages for attenuation of hepatic injury in a mouse model of endotoxemia (2009)
  • Author(s): Kamimoto-M, Mizuno-S, Nakamura-T
  • Journal Title: Internal Journal of Molecular Medicine 24 Pages: 161-170
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor prevents multiple organ injuries in endotoxemic mice through a heme oxygenase-dependent mechanism (2009)
  • Author(s): Kamimoto-M, Mizuno-S, Matsumoto-K, Nakamura-T
  • Journal Title: Biochem Biophys Res Communs 380 Pages: 333-337
  • Peer Reviewed
• [Journal Article] Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models (2009)
  • Author(s): Kishi Y, Kuba K, Nakamura T, Wen J, Suzuki Y, Mizuno S, Nukiwa T, Matsumoto K, Nakamura T.
  • Journal Title: Cancer Science 100 Pages: 1351-1358
  • NAID: 10027192650
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor prevents multiple organ injuries in endotoxemicmice through a heme oxygenase-dependent mechanism. (2009)
  • Author(s): Kamimoto-M, Mizuno-S, Matsumoto-K, Nakamura-T
  • Journal Title: Biochem Biophys Res Communs 380 Pages: 333-337
  • Peer Reviewed
• [Journal Article] Kamimoto M, Mizuno S and Nakamura T : Reciprocal regulation of IL-6and Il-10 balance by HGF via recruitment of HO-1 in raacrophages forattenuation of hepatic injury in a mouse model of endotoxemia. (2009)
  • Author(s): Kamimoto-M, Mizuno-S, Nakamura-T
  • Journal Title: Int J Mol Med (In press)
  • Peer Reviewed
• [Journal Article] HGF, as a renotrophic and anti-fibrotic regulator in chronic renal disease. (2008)
  • Author(s): Mizuno S, Matsumoto K, Nakamura T.
  • Journal Title: Front Biosci 13 Pages: 7072-7086
  • Peer Reviewed
• [Journal Article] The possible involvement of tensin2 in the expression and extension of nephrin by glomerular podocytes in mice. (2008)
  • Author(s): Kato T, Mizuno-S, Taketo MM, Kurosawa T.
  • Journal Title: Biomed Res 29 Pages: 279-287
  • NAID: 130004470727
  • Peer Reviewed
• [Journal Article] Intranasal HGF administration ameriorates the physiological and morphological changes in lung emphysema, (2008)
  • Author(s): Hegab-AE, Kubo-H, Hayama-M, Asada-M, He-M, Mizuno-S, Nakamura-T.
  • Journal Title: Mol Therapy 16 Pages: 1417-1426
  • Peer Reviewed
• [Journal Article] Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in renal failure of mice. (2008)
  • Author(s): Ohnishi H, Mizuno S, Nakamura T.
  • Journal Title: Am J Physiol 294
  • Peer Reviewed
• [Journal Article] Gelfand EW and Kanehiro A : Growth factors temporally associate with airway responsiveness and inflammation in allergen-exposed mice. (2008)
  • Author(s): Ito W, Tanimoto M, Ono K, Mizuno S, Yoshida A, Koga H, Fuchimoto Y, Kondo N, Tanimoto Y, Kiura K, Matsumoto K, Kataoka M, Nakamura T.
  • Journal Title: Int Arch Allergy Immunol 145 Pages: 324-339
  • Peer Reviewed
• [Journal Article] HGF, as a renotrophic and anti-fibrotic regulator in chronic renal disease. (2008)
  • Author(s): Mizuno s, Matsumoto-K, Nakamura-T
  • Journal Title: Front Biosci 13 Pages: 7072-7086
  • Peer Reviewed
• [Journal Article] The possible involvement of tensin2 in the expression and extension of nephrinby glomerular podocytes in mice. (2008)
  • Author(s): Kato-T, Mizuno-S, Taketo-MM, Kurosawa-T
  • Journal Title: Biomed Res 29 Pages: 279-287
  • Peer Reviewed
• [Journal Article] Intranasal HGF administration ameriorates the physiological andmorphological changes in lung emphysema. (2008)
  • Author(s): Hegab-AE, Kubo-H, Yamaya-M, Asada-M, He-M, Fujino-N, Mizuno-S, Nakamura T
  • Journal Title: Mol Therapy 16 Pages: 1417-1426
  • Peer Reviewed
• [Journal Article] Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acuterenal failure (2008)
  • Author(s): Ohnishi-H, Mizuno-S, dNakamura-T
  • Journal Title: Am J Physiol 294
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor (HGF), an endogenous pulmotrophic regulator, for the rescue of acute and chronic lung diseases.
  • Author(s): Mizuno S, Ohnishi H, Nakamura T.
  • Journal Title: Cell Signaling Transduction Therapy in press
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor (HGF) for a cell-signal-based therapy during acute and chronic liver diseases.
  • Author(s): Oka K, Fukuta K, Mizuno S.
  • Journal Title: Cell Signaling Transduction Therapy. in press
  • Peer Reviewed
• [Presentation] 骨髄由来DCの遊走およびサイトカイン産生に対するHGFの調節作用 (2010)
  • Author(s): 大西浩之, 岡清政, 水野信哉, 中村敏一
  • Organizer: 第83回日本生化学学会
  • Place of Presentation: 神戸市
  • Year and Date: 2010-12-08
• [Presentation] 急性腎不全マウスモデルでの病態進展に伴うHGF標的細胞の変遷とその意義 (2010)
  • Author(s): 水野信哉, 大西浩之, 神元幸, 中村敏一
  • Organizer: 第83回日本生化学学会
  • Place of Presentation: 神戸市
  • Year and Date: 2010-12-07
• [Presentation] リコビナントヒトHGFは免疫複合体の沈着を介して健常ラットに蛋白尿を惹起する (2010)
  • Author(s): 水野信哉, 池渕文彩, 福田一弘, 加藤貴史, 安達喜一, 松本邦夫, 中村敏一
  • Organizer: 第9回日本再生医療学会総会
  • Place of Presentation: 広島市
  • Year and Date: 2010-03-18
• [Presentation] 内因性HGFによる胆管上皮細胞の代償性成長を介した胆管硬化症の進展制御機構の解析 (2009)
  • Author(s): 水野信哉、中村敏一
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] 培養マクロファージを用いたHGFによるHMGB1放出抑制とその分子機構の解析 (2009)
  • Author(s): 神元幸、水野信哉、中村敏一
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] HGFによるカテプシンLの誘導抑制とその意義:糸球体傷害モデルを用いた解析 (2009)
  • Author(s): 加藤貴史、水野信哉、中村敏一
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] HGFによるカテプシンLの誘導抑制とその意義 : 糸球体傷害モデルを用いた解析 (2009)
  • Author(s): 加藤貴史, 水野信哉, 中村敏一
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸市
  • Year and Date: 2009-10-23
• [Presentation] 敗血症マウスにおけるHGFによる急性肺傷害の発症阻止とその分子基盤 (2009)
  • Author(s): 神元幸、水野信哉、中村敏一
  • Organizer: 第8回日本再生医療学会
  • Place of Presentation: 東京都
  • Year and Date: 2009-03-05
• [Presentation] HGFによるポドサイトでのネフリン発現増強を介した蛋白尿発症制御 (2009)
  • Author(s): 加藤貴史、水野信哉、中村敏一
  • Organizer: 第8回日本再生医療学会
  • Place of Presentation: 東京都
  • Year and Date: 2009-03-05
• [Presentation] HGFによるポドサイトの機能促進を介した蛋白尿制御機構 (2008)
  • Author(s): 加藤貴史、水野信哉、中村敏一
  • Organizer: 第81回日本生化学会大会.第31回日本分子生物学会年会合同大会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-12-10
• [Presentation] HGFによるポドサイトの機能促進を介した蛋白尿制御機構 (2008)
  • Author(s): 加藤貴史, 水野信哉, 中村敏一
  • Organizer: 第81回日本生化学会大会・第31回日本分子生物学会年会合同大会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-12-10
• [Presentation] HGFによるマクロファージでの翻訳後修飾を介したHO-1誘導促進とその生理的意義 (2008)
  • Author(s): 神元幸、水野信哉、中村敏一
  • Organizer: 第81回日本生化学会大会.第31回日本分子生物学会年会合同大会
  • Place of Presentation: 神戸市
• [Presentation] HGFによるマクロファージでの翻訳後修飾を介したHO-1誘導促進とその生理的意義 (2008)
  • Author(s): 神元幸, 水野信哉, 中村敏一
  • Organizer: 第81回日本生化学会大会・第31回日本分子生物学会年会合同大会
  • Place of Presentation: 神戸市
• [Book] Gene Therapy : Types, Vectors and Developments (2011)
  • Author(s): Mizuno S, Nakamura T
  • Publisher: NOVA Science Publisher(印刷中)
• [Book] Coronary Stent Restenosis (2011)
  • Author(s): Mizuno S, Nakamura T
  • Publisher: The University of Carol Davila Bucharest(印刷中)
• [Book] Gene Therapy : Types, Vectors and Developments (2010)
  • Author(s): Mizuno-S, Nakamura-T
  • Publisher: Nova Science Publisher(In press)
• [Book] Gene Therapy for HGF Supplementation in the Rescue of Intractable Diseases. In "Gene Therapy : Types, Vectors and Developments".
  • Author(s): Mizuno-S, Nakamura-T.
  • Publisher: NOVA Science Publisher, Hauppauge.(New York)(in press)
• [Book] Hepatocyte growth factor (HGF) : Cardiotrophic roles and potential therapeutics for cardio.ascular disease. In : "Coronary Stent Restenosis".
  • Author(s): Mizuno S, Nakamura T.
  • Publisher: Edited Ion Tintoiuin(in press)