Comprehensive functional analysis and application of responses against hypoxia in the kidney

• Project/Area Number: 19390228
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: NANGAKU Masaomi The University of Tokyo, 医学部・附属病院, 特任講師 (90311620)
• Co-Investigator(Kenkyū-buntansha): INAGI Reiko 東京大学, 医学部・附属病院, 特任研究員 (50232509) ; WADA Takehiko 東京大学, 医学部・附属病院, 助教 (90447409) ; HANAFUSA Norio 東京大学, 医学部・附属病院, 講師 (90396739)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2007: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
• Keywords: 虚血 / 慢性腎臓病 / 低酸素 / 血管新生 / 腫瘍 / HIF / 腎不全

Research Abstract

低酸素状態において代償性の血管新生を司るVEGFの新たな調節因子として、MAP3K6が働いていることを、siRNA libraryをスクリーニングすることによって見出した。血管新生のアッセイや、MAP3K6をノックダウンした癌細胞株の移植実験により、MAP3K6によるVEGFの発現調節が生理的に重要であることを証明した。
並行して、慢性低酸素腎の網羅的遺伝子発現解析を行い、 metallothionein の新しい低酸素に対する防御機構を示した。同様の解析により、低酸素腎において腎臓に内因性にヘモグロビンが発現しており抗酸化能を持っていること、一方 Cu/Zn SOD の発現は減少しておりこれがTNF-alpha によることも見出し、腎臓の低酸素病態を理解するための知見を蓄積した。

Research Products

• [Journal Article] Nangaku M : Metallothionein is up-regulated by hypoxia and stabilizes HIF in the kidney (2009)
  • Author(s): Kojima I, Tanaka T, Inagi R, Nishi H, Aburatani H, Kato H, Miyata T, Fujita T
  • Journal Title: Kidney Int 75 Pages: 268-277
• [Journal Article] Glyoxalse I overexpression ameliorates renal ischemia-reperfusion injury in rats. (2009)
  • Author(s): Kumagai et al.
  • Journal Title: Am J Physiol Renal Physiol (In press)
  • Peer Reviewed
• [Journal Article] Suppression of MAP3 kinase 6 mediates anti-angiogenic and tumor-suppressive effects via VEGF repression (2009)
  • Author(s): Eto et al.
  • Journal Title: Am J Pathol (In press)
  • Peer Reviewed
• [Journal Article] Nangaku M : Hemoglobin is expressed as anti-oxidant factor by mesangial cell (2008)
  • Author(s): Nishi H, Inagi R, Kato H, Tanemoto M, Kojima I, Son D, Fujita T
  • Journal Title: J Am Soc Nephrol 19 Pages: 1500-1508
• [Journal Article] Nangaku M : Preconditioning of endoplasmic reticulum (ER) stress ameliorated anti-Thy1 glomerulonephritis of rats (2008)
  • Author(s): Inagi R, Kumagai T, Miyata T, Fujita T
  • Journal Title: J Am Soc Nephrol 19 Pages: 915-922
• [Journal Article] Nangaku M : Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD-a proteomic analysis (2008)
  • Author(s): Son D, Kojima I, Inagi R, Matsumoto M, Fujita T
  • Journal Title: Am J Physiol Renal Physiol 294
• [Journal Article] Nangaku M : Albumin suppresses vascular endothelial growth factor via alteration of hypoxia-inducible factor / hypoxia-responsive element pathway (2008)
  • Author(s): Katavetin P, Inagi R, Miyata T, Tanaka T, Sassa R, Ingelfinger JR, Fujita T
  • Journal Title: Biochem Biophys Res Commun 367 Pages: 305-310
• [Journal Article] Fujita T : HIF and renal disease (2008)
  • Author(s): Nangaku M, Inagi R, Miyata T
  • Journal Title: Nephron Exp Nephrol 110
• [Journal Article] Fujita T : Activation of the renin-angiotensin system and chronic hypoxia of the kidney (2008)
  • Author(s): Nangaku M
  • Journal Title: Hypertens Res 31 Pages: 175-184
• [Journal Article] Miyata T : The role of chronic hypoxia in kidney disease (2008)
  • Author(s): Nangaku M, Nishi H
  • Journal Title: Chin Med J 121 Pages: 257-264
• [Journal Article] Metallothionein is up-regulated by hypoxia and stabilizes HIF in the kidney. (2008)
  • Author(s): Kojima et al.
  • Journal Title: Kidney Int 75 Pages: 268-277
  • Peer Reviewed
• [Journal Article] Hemoglobin is expressed as anti-oxidant factor by mesangial cell. (2008)
  • Author(s): Nishi et al.
  • Journal Title: J Am Soc Nephrol 19 Pages: 1500-1508
  • Peer Reviewed
• [Journal Article] Preconditioning of endoplasmic reticulum (ER) stress ameliorated anti-Thyl glomerulonephritis of rats. (2008)
  • Author(s): Inagi et al.
  • Journal Title: J Am Soc Nephrol 19 Pages: 915-922
  • Peer Reviewed
• [Journal Article] Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD-aproteomic analysis. (2008)
  • Author(s): Son et al.
  • Journal Title: Am J Physiol Renal Physiol 294
  • Peer Reviewed
• [Journal Article] Albumin suppresses vascular endothelial growth factor via alteration of hypoxia-inducible factor/hypoxia-responsive element pathway. (2008)
  • Author(s): Katavetin et al.
  • Journal Title: Biochem Biophys Res Commun 367 Pages: 305-310
  • Peer Reviewed
• [Journal Article] The role of chronic hypoxia in kidney disease. (2008)
  • Author(s): Nangaku et al.
  • Journal Title: Chin Med J 121 Pages: 257-264
  • Peer Reviewed
• [Journal Article] Activation of the renin-angiotehsin system and chronic hypoxia of the kidney. (2008)
  • Author(s): Nangaku, Fujita
  • Journal Title: Hypertens Res 31 Pages: 175-184
  • Peer Reviewed
• [Journal Article] HIF and renal disease. (2008)
  • Author(s): Nangaku, et al.
  • Journal Title: Nephron Exp Nephrol 110
  • Peer Reviewed
• [Journal Article] The role of chronic hypoxia in kidney disease (2008)
  • Author(s): Nangaku M, Nishi H, Miyata T
  • Journal Title: Chin Med J 121 Pages: 257-264
  • Peer Reviewed
• [Journal Article] Activation of the renin-angiotensin system and chronic hypoxia of the kidney (2008)
  • Author(s): Nangaku M, Fujita T
  • Journal Title: Hypertens Res 31 Pages: 175-184
  • NAID: 10024359455
  • Peer Reviewed
• [Journal Article] Albumin suppresses vascular endothelial growth factor via alteration of hypoxia-inducible factor/hypoxia-responsive element pathway (2008)
  • Author(s): Katavetin P, et. al.
  • Journal Title: Biochem Biophys Res Commun 367 Pages: 305-310
  • Peer Reviewed
• [Journal Article] Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD-a proteomic analysis (2008)
  • Author(s): Son D, et. al.
  • Journal Title: Am J Physiol Renal Physiol 294
  • Peer Reviewed
• [Journal Article] van Ypersele de Strihou C, Miyata T : A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia (2007)
  • Author(s): Nangaku M, Izuhara Y, Takizawa S, Yamashita T, Fujii-Kuriyama Y, Ohneda O, Yamamoto M
  • Journal Title: Arterio Thromb Vasc Biol 27 Pages: 2548-2554
• [Journal Article] Nangaku M : Protective role of HIF-2 alpha against ischemic damage and oxidative stress in the kidney (2007)
  • Author(s): Kojima I, Tanaka T, Inagi R, Kato H, Yamashita T, Sakiyama A, Ohneda O, Takeda N, Sata M, Miyata T, Fujita T
  • Journal Title: J Am Soc Nephrol 18 Pages: 1218-1226
• [Journal Article] Nangaku M : Darbepoetin protects podocytes by preservation of the cytoskeleton and nephrin distribution (2007)
  • Author(s): Eto N, Wada T, Inagi R, Takano H, Shimizu A, Kato H, Kurihara H, Kawachi H, Shankland SJ, Fujita T
  • Journal Title: Kidney Int 72 Pages: 455-463
• [Journal Article] Nangaku M : Erythropoietin induces heme oxygenase-1 expression and attenuates oxidative stress (2007)
  • Author(s): Katavetin P, Inagi R, Miyata T, Sassa R, Adler S, Eto N, Kato H, Fujita T
  • Journal Title: Biochem Biophys Res Commun 359 Pages: 928-934
• [Journal Article] Fujita T : Receptor-independent intracellular radical scavenging activity of an angiotensin II receptor blocker (2007)
  • Author(s): Shao J, Nangaku M, Inagi R, Kato H, Miyata T, Matsusaka T, Noiri E
  • Journal Title: J Hypertens 25 Pages: 1643-1649
• [Journal Article] Eckardt KU : Hypoxia and the HIF system in kidney disease (2007)
  • Author(s): Nangaku M
  • Journal Title: J Mol Med 85 Pages: 1325-1330
• [Journal Article] Hypoxia and the HIF system in kidney disease (2007)
  • Author(s): Nangaku M, Eckardt KU
  • Journal Title: J Mol Med 85 Pages: 1325-1330
  • Peer Reviewed
• [Journal Article] A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia (2007)
  • Author(s): Nangaku M, et. al.
  • Journal Title: Arterio Thromb Vasc Biol 27 Pages: 2548-2554
  • Peer Reviewed
• [Journal Article] Protective role of HIF-2 alpha against ischemic damage and oxidative stress in the kidney (2007)
  • Author(s): Kojima I, et. al.
  • Journal Title: J Am Soc Nephrol 18 Pages: 1218-1226
  • Peer Reviewed
• [Journal Article] Darbepoetin protects podocytes by preservation of the cytoskeleton and nephrin distribution (2007)
  • Author(s): Eto N, et. al.
  • Journal Title: Kidney Int 72 Pages: 455-463
  • Peer Reviewed
• [Journal Article] Erythropoietin induces heme oxygenase-1 expression and attenuates oxidative stress (2007)
  • Author(s): Katavetin P, et. al.
  • Journal Title: Biochem Biophys Res Commun 359 Pages: 928-934
  • Peer Reviewed
• [Journal Article] Receptor-independent intracellular radical scavenging activity of an angiotensin II receptor blocker (2007)
  • Author(s): Shao J, et. al.
  • Journal Title: J Hypertens 25 Pages: 1643-1649
  • Peer Reviewed
• [Journal Article] Estabhshment of a sandwich ELISA for human megsin,a kidney-specific serine protease inhibitor (2007)
  • Author(s): Inagi R, et. al.
  • Journal Title: Nephrol Dial Transplant 22 Pages: 3311-7
  • Peer Reviewed
• [Journal Article] Angiotensin-induced hypoxia in the kidney:functional and structural changes of the renal circulation (2007)
  • Author(s): Nangaku M, et. al.
  • Journal Title: Adv Exp Med Biol 618 Pages: 85-99
  • Peer Reviewed
• [Journal Article] Inagi R : Glyoxalse I overexpression ameliorates renal ischemia-reperfusion injury in rats
  • Author(s): Kumagai T, Nangaku M, Kojima I, Nagai R, Ingelfinger JR, Miyata T, Fujita T
  • Journal Title: Am J Physiol Renal Physiol in press
• [Journal Article] Nangaku M : Suppression of MAP3 kinase 6 mediates anti-angiogenic and tumor-suppressive effects via VEGF repression
  • Author(s): Eto N, Miyagishi Y, Inagi R, Fujita T
  • Journal Title: Am J Pathol in press
• [Journal Article] Pathophysiological role of glyoxalase system in renal hypoxic injury
  • Author(s): Kumagai T, et. al.
  • Journal Title: Ann N Y Acad Sci.(review) (掲載確定)
• [Presentation] Transgenic Overexpression of Cytoglobin Improves the Kidney Ischemia/Reperfusion Injury Via Amelioration of Oxidative Stress. (2008)
  • Author(s): Nishi et al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2008-11-08
• [Presentation] Endoplasmic Reticulum Stress Induces Autophagy in Renal Proximal Tubular Cells. (2008)
  • Author(s): Kawakami et al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2008-11-06
• [Presentation] Glyoxalase I Relieves Endoplasmic Reticulum Stress Induced by Hypoxia. (2008)
  • Author(s): Inagi et al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2008-11-06
• [Presentation] Microarray Analysis of Chronic Hypoxia Kidney Revealed Activation of HIF by Metallothionein. (2008)
  • Author(s): Kojima et al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2008-11-06
• [Presentation] Glyoxalase I overexpression lowers hypoxia-induced oxidative stress and ameliorates renal ischemia-reperfusion injury in the rat (2008)
  • Author(s): Kumagai, et.al.
  • Organizer: International Society of Oxygen Transport to Tissues
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2008-08-04
• [Presentation] Glyoxalase I overexpression lowers hypoxia-induced oxidative stress and ameliorates renal ischemia-reerfusion injury in the rat. (2008)
  • Author(s): Kumagai et al.
  • Organizer: International Society of Oxygen Transport to Tissues
  • Place of Presentation: Sapporo,Japan
  • Year and Date: 2008-08-04
• [Presentation] Preconditioning with endoplasmic reticulum stress ameliorates anti-Thy1 glomerulonephritis in rats (2008)
  • Author(s): Inagi, et.al.
  • Organizer: Congress of ERA/EDTA
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2008-05-11
• [Presentation] Preconditioning with endoplasmic reticulum stress ameliorates anti-Thyl glomerulonephritis in rats. (2008)
  • Author(s): Inagi et al.
  • Organizer: Congress of ERA/EDTA
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2008-05-11
• [Presentation] Transgenic Overexpression of Cytoglobin Improves the Kidney Ischemia/Reperfusion Injury Via Amelioration of Oxidative Stress (2008)
  • Author(s): Nishi, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
• [Presentation] Endoplasmic Reticulum Stress Induces Autophagy in Renal Proximal Tubular Cells (2008)
  • Author(s): Kawakami, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
• [Presentation] Glyoxalase I Relieves Endoplasmic Reticulum Stress Induced by Hypoxia (2008)
  • Author(s): Inagi, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
• [Presentation] Microarray Analysis of Chronic Hypoxic Kidney Revealed Activation of HIF by Metallothionein (2008)
  • Author(s): Kojima, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: Philadelphia, USA
• [Presentation] Glyoxalase I overexpression lowers oxidative stress and ameliorates renal ischemia-reperfusion injury in the rat (2008)
  • Author(s): Kumagai, et.al.
  • Organizer: Keystone Symposium
  • Place of Presentation: Vancouver, Canada
• [Presentation] Microarray analysis of chronic hypoxic kidney revealed activation of HIF by metallothionein (2008)
  • Author(s): Kojima, et.al.
  • Organizer: Keystone Symposium
  • Place of Presentation: Vancouver, Canada
• [Presentation] A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia (2008)
  • Author(s): Nangaku, et.al.
  • Organizer: Keystone Symposium
  • Place of Presentation: Vancouver, Canada
• [Presentation] MAP3 kinase 6 mediates VEGF expression and participates in tumorigenesis and angiogenesis (2008)
  • Author(s): Eto, et.al.
  • Organizer: Keystone Symposium
  • Place of Presentation: Vancouver, Canada
• [Presentation] Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD-a proteomic analysis (2008)
  • Author(s): Son, et.al.
  • Organizer: Keystone Symposium
  • Place of Presentation: Vancouver, Canada
• [Presentation] Darbepoetin Ameliorates Urinary Protein Excretion by Preservation of the Cytoskeleton and Nephrin Distribution in the Podocytes (2007)
  • Author(s): Eto, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco, USA
• [Presentation] Suppression of MAP3 Kinase 6 Mediates Anti-Angiogenic and Tumor-Suppressive Effects Via VEGF Repression (2007)
  • Author(s): Eto, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco, USA
• [Presentation] A Novel Class of Prolyl Hydroxylase Inhibitors Induces Angiogenesis and Exerts Organ Protection Against Ischemia (2007)
  • Author(s): Nangaku, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco, USA
• [Presentation] Chronic Hypoxia Aggravates Renal Injury Via Suppression of Cu/Zn-SOD-A Proteomic Analysis (2007)
  • Author(s): Son, et.al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco, USA
• [Presentation] Cytoglobin, a Novel Me mber of the Globin Family, Protects the Kidney Against Oxidative Stres s under Ischemic Conditions (2007)
  • Author(s): Nishi, et.al.
  • Organizer: Americ an Society of Nephrology
  • Place of Presentation: San Francisco, USA
• [Presentation] Darbepoetin Amehorates Urinary Protein Excretion by Preservation of the Cytoskeleton and Nephrin Distribution in the Podocytes (2007)
  • Author(s): Eto N, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Suppression of MAP3 Kinase 6 Mediates Anti-Angiogenic and Tumor-Supressive Effects Via VEGF Repression (2007)
  • Author(s): Eto N, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] A Novel Class of Prolyl Hydroxylase Inhibitors Induces Angiogenesis and Exerts Organ Protection Against Ischemia (2007)
  • Author(s): Nangaku M, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Chronic Hypoxia Aggravates Renal Injury Via Suppression of Cu/Zn・SOD-A Proteomic Analysis (2007)
  • Author(s): Son D, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Cytoglobin, a Novel Member of the Globin Family, Protects the Kidney Against Oxidative Stress under Ischemic Conditions (2007)
  • Author(s): Nishi H, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Preconditioning of Endoplasmic Reticulum(ER)Stress Ameliorated Anti-Thy1 Glomerulonephritis of Rats (2007)
  • Author(s): Inagi R, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Indoxyl Sulfate Induces Endoplasmic Reticulum Stress-Mediated Cell Injury in Human Proximal Tubular Cells (2007)
  • Author(s): Kawakami T, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Glyoxalase I Overexpression Lowers Oxidative Stress and Ameliorates Renal Ischemia-Reperfusion Injury in the Rat (2007)
  • Author(s): Kumagai T, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Differential Effects of AIlgiotensin II Type la Receptor Activity in Bone Marrow-Derived Cells on End-Organ Injuries (2007)
  • Author(s): Kato H, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Cobalt Ameliorates Renal Injury in an Obese,Hypertensive Tyrpe 2 Diabetes Rat Model (2007)
  • Author(s): Izuhara Y, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Presentation] Cloning and Characterization of Novel Gene,PLEP,in Human Glomerular Cells (2007)
  • Author(s): Ohtomo S, et. al.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Francisco,USA
• [Book] 薬局:病気と薬の説明ガイド2007 (2007)
  • Author(s): 稲城 玲子、南学 正臣
  • Total Pages: 1327
  • Publisher: 南山堂