エピジェネティックな低酸素応答の解析による腎臓病の病態生理の解明

• 研究課題/領域番号: 24390213
• 研究種目: 基盤研究(B)
• 配分区分: 一部基金
• 応募区分: 一般
• 研究分野: 腎臓内科学
• 研究機関: 東京大学
• 研究代表者: 南学 正臣 東京大学, 医学部附属病院, 教授 (90311620)
• 研究分担者: 稲城 玲子 東京大学, 医学部附属病院, 特任准教授 (50232509) ; 和田 健彦 東京大学, 医学部附属病院, 講師 (90447409) ; 田中 哲洋 東京大学, 医学部附属病院, 病院講師 (90508079) ; 大瀬 貴元 東京大学, 医学部附属病院, その他 (10568447)
• 連携研究者: 児玉 龍彦 東京大学, 先端科学技術センター, 教授 (90170266) ; 油谷 浩幸 東京大学, 先端科学技術センター, 教授 (10202657)
• 研究期間 (年度): 2012-04-01 – 2015-03-31
• 研究課題ステータス: 完了 (2014年度)
• 配分額: 18,070千円 (直接経費: 13,900千円、間接経費: 4,170千円); 2014年度: 3,510千円 (直接経費: 2,700千円、間接経費: 810千円); 2013年度: 5,980千円 (直接経費: 4,600千円、間接経費: 1,380千円); 2012年度: 8,580千円 (直接経費: 6,600千円、間接経費: 1,980千円)
• キーワード: 低酸素 / HIF / エピジェネティックス / エピゲノム / ヒストン修飾 / 慢性腎臓病 / 腎細胞癌 / エピジェネティクス

研究成果の概要

in vivo における腎臓でのエピジェネティックな変化の機能的意義を明らかにするため、臓器レベルでの ChIP-seq を行うための条件検討を行った。laser capture microdissection によるPAT-ChIP を検討したが、RNA の quality が ChIP に耐える十分良質な状態の採取ができず、最終的に臓器レベルで whole の ChIP を行い、腎臓の大半を占める尿細管を対象とすることにした。モデル動物としては、虚血再還流後急性腎障害の後で長期的に進展する腎線維化モデルを使用し、ヒストン修飾を調節する化合物を用いて線維化の状態に変化が起こることを見出した。

研究成果

• [雑誌論文] Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.. (2015)
  • 著者名/発表者名: Yamaguchi J, Tanaka T, Eto N, Nangaku M.
  • 雑誌名: Kidney Int 巻: x
  • 査読あり / 謝辞記載あり
• [雑誌論文] SIRT1 maintains actin cytoskeleton by deacetylation of cortactin in injured podocytes. (2015)
  • 著者名/発表者名: Motonishi S, Nangaku M, Wada T, Ishimoto Y, Ohse T, Matsusaka T, Kubota N, Shimizu A, Kadowaki T, Tobe K, Inagi R.
  • 雑誌名: J Am Soc Nephrol 巻: x
  • 査読あり / 謝辞記載あり
• [雑誌論文] Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation. (2014)
  • 著者名/発表者名: Jo-Watanabe A, Ohse T, Nishimatsu H, Takahashi M, Ikeda Y, Wada T, Shirakawa J, Nagai R, Miyata T, Nagano T, Hirata Y, Inagi R, Nangaku M.
  • 雑誌名: Aging Cell 巻: Epub ahead of print 号: 3 ページ: 519-28
  • DOI: 10.1111/acel.12204
  • 査読あり / オープンアクセス
• [雑誌論文] Cross-enhancement of ANGPTL4 transcription by HIF1 alpha and PPAR beta/delta is the result of the conformational proximity of two response elements. (2014)
  • 著者名/発表者名: Inoue T, Kohro T, Tanaka T, Kanki Y, Li G, Poh HM, Mimura I, Kobayashi M, Taguchi A, Maejima T, Suehiro JI, Sugiyama A, Kaneki K, Aruga H, Dong S, Stevens JF, Yamamoto S, Tsutsumi S, Fujita T, Ruan X, Aburatani H, Nangaku M, Ruan Y, Kodama T, Wada Y.
  • 雑誌名: Genome Biology 巻: 15 号: 4
  • DOI: 10.1186/gb-2014-15-4-r63
  • 査読あり / オープンアクセス
• [雑誌論文] Hypoxia as a key player in the AKI-to-CKD transition. (2014)
  • 著者名/発表者名: Tanaka S, Tanaka T, Nangaku M.
  • 雑誌名: Am J Phyisol Renal Physiol 巻: 307 号: 11 ページ: F1187-F1195
  • DOI: 10.1152/ajprenal.00425.2014
  • 査読あり / 謝辞記載あり
• [雑誌論文] Hypoxia and fibrosis in chronic kidney disease: crossing at pericytes. (2014)
  • 著者名/発表者名: Kawakami T, Mimura I, Shoji K, Tanaka T, Nangaku M.
  • 雑誌名: Kidney Int 巻: Suppl 4 ページ: 107-112
  • 査読あり / 謝辞記載あり
• [雑誌論文] Role of hypoxia in progressive chronic kidney disease and implications for therapy. (2014)
  • 著者名/発表者名: Shoji K, Tanaka T, Nangaku M.
  • 雑誌名: Curr Opin Nephrol Hypertens 巻: 23 号: 2 ページ: 161-8
  • DOI: 10.1097/01.mnh.0000441049.98664.6c
  • 査読あり / 謝辞記載あり
• [雑誌論文] Revolution of nephrology research by deep sequencing : ChIP-seq and RNA-seq. (2014)
  • 著者名/発表者名: Mimura I, Kanki Y, Kodama T, Nangaku M.
  • 雑誌名: Kidney International 巻: 85 号: 1 ページ: 31-38
  • DOI: 10.1038/ki.2013.321
  • 査読あり
• [雑誌論文] Indoxyl sulfate signals for rapid mRNA stabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) and suppresses the expression of hypoxia-inducible genes in experimental CKD and uremia (2013)
  • 著者名/発表者名: Tanaka T, Yamaguchi J, Higashijima Y, Nangaku M
  • 雑誌名: FASEB J 巻: 27 号: 10 ページ: 4059-4075
  • DOI: 10.1096/fj.13-231837
  • 査読あり
• [雑誌論文] Sperm-associated antigen 4, a novel hypoxia-inducible factor 1 target, regulates eytokinesis, and its expression correlates with the prognosis of renal cell earcinoma. (2013)
  • 著者名/発表者名: Shoji K, Mimura I, Murayama T, Wada T, Kume H, Goto A, Ohse T, Tanaka T, Inagi R, van der Hoorn FA, Manabe I, Homma Y, Fukayama M, Sakurai T, Hasegawa T, Aburatani H, Kodama T, Nangaku M.
  • 雑誌名: American Journal of Pathology 巻: 182 号: 6 ページ: 2191-2203
  • DOI: 10.1016/j.ajpath.2013.02.024
  • 査読あり
• [雑誌論文] Endoplasmic reticulum stress signal impairs erythropoietin production:a role for ATF4. (2013)
  • 著者名/発表者名: Chiang CK, Nangaku M, Tanaka T, IwawakiT, Inagi R.
  • 雑誌名: Am J Physiol Cell Physiol. 巻: 304(4) 号: 4 ページ: C342-C353
  • DOI: 10.1152/ajpcell.00153.2012
  • 査読あり
• [雑誌論文] Novel therapeutic strategy with hypoxia-inducible factors via reversible epigenetic regulation mechanisms in progressive tubulointerstitial fibrosis. (2013)
  • 著者名/発表者名: Mimura I, Tanaka T, Nangaku M.
  • 雑誌名: Seminars in Nephrology 巻: 33 号: 4 ページ: 375-382
  • DOI: 10.1016/j.semnephrol.2013.05.009
  • 査読あり
• [雑誌論文] Angiogenesis and hypoxia. (2013)
  • 著者名/発表者名: Tanaka T, Nangaku M
  • 雑誌名: Nature Rev Nephrol 巻: 9 号: 4 ページ: 211-22
  • DOI: 10.1038/nrneph.2013.35
  • 査読あり
• [雑誌論文] HIF regulation in kidney disease. (2013)
  • 著者名/発表者名: Nangaku M, Rosenberger C, Heyman SN, Eckardt KU
  • 雑誌名: Clin Exp Pharmacol Physiol 巻: 40 号: 2 ページ: 148-57
  • DOI: 10.1111/1440-1681.12005
  • 査読あり
• [雑誌論文] Novel roles of complement in renal diseases and their therapeutic consequences. (2013)
  • 著者名/発表者名: Wada T, Nangaku M.
  • 雑誌名: Kidney Int 巻: 84 号: 3 ページ: 441-50
  • DOI: 10.1038/ki.2013.134
  • 査読あり
• [雑誌論文] Sperm-associated antigen 4, a novel hypoxia-inducible factor l target, regulates cytokinesis and its expression correlates with the prognosis of renal cell carcinoma. (2013)
  • 著者名/発表者名: Shoji K, et al.
  • 雑誌名: Am J Pathol 巻: (in press)
  • 査読あり
• [雑誌論文] Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host (2012)
  • 著者名/発表者名: Tanaka T
  • 雑誌名: J Biol Chem 巻: 287 号: 42 ページ: 34866-34882
  • DOI: 10.1074/jbc.m112.374587
  • 査読あり
• [雑誌論文] Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. (2012)
  • 著者名/発表者名: Mimura I
  • 雑誌名: Mol Cell Biol. 巻: Aug;32(15) 号: 15 ページ: 3018-3032
  • DOI: 10.1128/mcb.06643-11
  • 査読あり
• [学会発表] Hypoxia and Renal Disease. (2015)
  • 著者名/発表者名: Masaomi Nangaku
  • 学会等名: 8th World Congress of Nephrology
  • 発表場所: Cape Town, South Africa
  • 年月日: 2015-03-15
  • 招待講演
• [学会発表] Diabetic nephropathy and metabolic memory: role of epigenetics. (2014)
  • 著者名/発表者名: Masaomi Nangaku
  • 学会等名: 45th Indian Society of Nephrology Conference.
  • 発表場所: Kolkata, India
  • 年月日: 2014-12-19
  • 招待講演
• [学会発表] Hypoxic HIF, Fibrosis, and CKD. (2014)
  • 著者名/発表者名: Masaomi Nangaku
  • 学会等名: The 47th Annual Meeting of the American Society of Nephrology.
  • 発表場所: Philadelphia, USA
  • 年月日: 2014-11-15
  • 招待講演
• [学会発表] Long-Chain Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress Suppresses Erythropoietin Production in Kidney. (2014)
  • 著者名/発表者名: Thitinun Anusornvongchai, Chih-Kang Chiang, Yu Ishimoto, Norio Suzuki, Masayuki Yamamoto, Masaomi Nangaku, Reiko Inagi.
  • 学会等名: The 47th Annual Meeting of the American Society of Nephrology.
  • 発表場所: Philadelphia, USA
  • 年月日: 2014-11-14
• [学会発表] SIRT1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Podocytes. (2014)
  • 著者名/発表者名: Shuta Motonishi, Masaomi Nangaku, Takehiko Wada, Yu Ishimoto, Taiji Matsusaka, Akira Shimizu, Reiko Inagi.
  • 学会等名: The 47th Annual Meeting of the American Society of Nephrology.
  • 発表場所: Philadelphia, USA
  • 年月日: 2014-11-14
• [学会発表] Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways. (2014)
  • 著者名/発表者名: Hideki Kato, Taiji Matsusaka, Masaomi Nangaku.
  • 学会等名: The 47th Annual Meeting of the American Society of Nephrology.
  • 発表場所: Philadelphia, USA
  • 年月日: 2014-11-13
• [学会発表] Epigenetic Induction of Kidney Lineages in Human Kidney Derived iPS Cells. (2014)
  • 著者名/発表者名: Osamu Takase, Masaomi Nangaku, Keiichi Hishikawa.
  • 学会等名: The 47th Annual Meeting of the American Society of Nephrology.
  • 発表場所: Philadelphia, USA
  • 年月日: 2014-11-13
• [学会発表] SIRT1 MAINTAINS ACTIN CYTOSKELETON BY DEACETYLATION OF CORTACTIN IN PODOCYTES (2014)
  • 著者名/発表者名: Reiko Inagi, Shuta Motonishi, Masaomi Nangaku
  • 学会等名: The 51st European Renal Association/European Dialysis and Transplantation Association
  • 発表場所: Amsterdam, the Netherlands
  • 年月日: 2014-06-03
• [学会発表] A NON-TRANSCRIPTIONAL ROLE OF HYPOXIA-INDUCIBLE FACTOR (HIF)-1 IN DEFENSE AGAINST DNA DOUBLE STRAND INJURY. (2014)
  • 著者名/発表者名: Tetsuhiro Tanaka, Yoshiki Higashijima, Shinji Tanaka, Junna Yamaguchi, Masaomi Nangaku
  • 学会等名: The 51st European Renal Association/European Dialysis and Transplantation Association
  • 発表場所: Amsterdam, the Netherlands
  • 年月日: 2014-06-02
• [学会発表] Histone modifications in kidney disease (2014)
  • 著者名/発表者名: Masaomi Nangaku
  • 学会等名: International Society of Nephrology, NEXUS-drug discovery
  • 発表場所: Belgamo, Italy
  • 年月日: 2014-04-06
  • 招待講演
• [学会発表] 生活習慣病と癌における低酸素とHIFの役割の解明. (2012)
  • 著者名/発表者名: 南学正臣
  • 学会等名: 第35回日本分子生物学会年会
  • 発表場所: 福岡国際会議場、福岡 Japan(招待講演)
  • 年月日: 2012-12-12
• [学会発表] Uremia and hypoxic organ damage: a long-term consequence. (2012)
  • 著者名/発表者名: Nangaku M
  • 学会等名: 30th International Society of Blood Purification.
  • 発表場所: パシフィコ横浜 Japan(招待講演)
  • 年月日: 2012-09-07
• [学会発表] Epigenetic modulation of renal ischemic response. (2012)
  • 著者名/発表者名: Nangaku M
  • 学会等名: ISN Forefront Systems Biology and the Kidney.
  • 発表場所: Michigan, USA(招待講演)
• [学会発表] ChIP-seq revealed dynamic change of the chromatin conformation of GL UT3 in response to hypoxia via epigenetic modification. (2012)
  • 著者名/発表者名: Mimura I, et al.
  • 学会等名: ISN Forefront Systems Biology and the Kidney.
  • 発表場所: Michigan, USA
• [学会発表] Activation of a HIF1 alpha-PPAR delta axis underlies the induction of ANGPTL4, a mediator of nephrotic syndrome, under hypoxia. (2012)
  • 著者名/発表者名: Inoue T, et al.
  • 学会等名: ISN Forefront Systems Biology and the Kidney.
  • 発表場所: Michigan, USA
• [学会発表] miR-205 modulates cellular senescence state caused by oxidative and endoplasmic reticulum (ER) stresses in renal tubular cells. (2012)
  • 著者名/発表者名: Muratsu S, et al.
  • 学会等名: Keystone Symposium: Aging and diseases of aging.
  • 発表場所: シェラトン都ホテル、東京
• [学会発表] Synchronous recruitment of two transcription complexes exist under synergistic induction of ANGPTL4 by two different stimuli. (2012)
  • 著者名/発表者名: Inoue T, et al.
  • 学会等名: Keystone Symposium: Aging and diseases of aging.
  • 発表場所: シェラトン都ホテル、東京
• [学会発表] Glyoxalase I ameliorates age-related endothelial dysfunction. (2012)
  • 著者名/発表者名: Jo A, et al.
  • 学会等名: Keystone Symposium: Aging and diseases of aging.
  • 発表場所: シェラトン都ホテル、東京
• [学会発表] GLUT3 expression is enhanced by chromatin conformational change in response to hypoxia via cooperative interaction of HIF1 and KDM3A. (2012)
  • 著者名/発表者名: Mimura I, et al.
  • 学会等名: Keystone Symposium: Aging and diseases of aging.
  • 発表場所: シェラトン都ホテル、東京
• [学会発表] Downregulation of miR-205 Modulates Cell Susceptibility to Oxidative and Endoplasmic Reticulum Stresses in Renal Tubular Cells. (2012)
  • 著者名/発表者名: Muratsu S, et al.
  • 学会等名: The 45^<th> Annual Meeting of the American Society of Nephrology.
  • 発表場所: California, USA
• [学会発表] Anthracycline Inhibits Recruitment of Hypoxia-Inducible Transcription Factors, Blunts the Induction of Lysyl Oxidase and Suppresses Migration of Renal Cell Carcinoma. (2012)
  • 著者名/発表者名: Tanaka T, et al.
  • 学会等名: The 45^<th> Annual Meeting of the American Society of Nephrology.
  • 発表場所: California, USA
• [学会発表] Identification and Characterization of a Novel HIF-1 Target that Regulates Cytokinesis as a Defensive Mechanism against Polyploidy. (2012)
  • 著者名/発表者名: Shoji K, et al.
  • 学会等名: The 45^<th> Annual Meeting of the American Society of Nephrology.
  • 発表場所: California, USA
• [学会発表] Dynamic Change of the Chromatin Conformation in Response to Hypoxia Enhances the Expression of GLUT3 (SLC2A3) by Cooperative Interaction of HIF1 and KDM3A. (2012)
  • 著者名/発表者名: Mimura l, et al.
  • 学会等名: The 45^<th> Annual Meeting of the American Society of Nephrology.
  • 発表場所: California, USA
• [学会発表] ANGPTL4, a Mediator of Nep!irotic Syndrome, Is Induced through a HIF1 alpha-PPAR beta/delta Axis under Hypoxia. (2012)
  • 著者名/発表者名: Inoue T, et al.
  • 学会等名: The 45^<th> Annual Meeting of the American Society of Nephrology.
  • 発表場所: California, USA
• [学会発表] Downregulation of miR-205 Modulates Cell Susceptibility t0 Oxidative and Endoplasmic Reticulum Stresses in Renal Tubular Cells. (2012)
  • 著者名/発表者名: Muratsu S, et al.
  • 学会等名: The 45^<th> Annual Meeting of the American Society of Nephrology.
  • 発表場所: California, USA
• [学会発表] Breathless: Dynamic Changes in Chromatin Conformation in Renal Hypoxia.
  • 著者名/発表者名: Nangaku M
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
  • 招待講演
• [学会発表] Indoxyl Sulfate Signals for Rapid mRNA Stabilization of Cbp/p300-Interacting Transactivator with Glu/Asp-Rich Carboxy-Terminal Domain 2 (CITED2) and Suppresses the Expression of Hypoxia-Inducible Genes in Experimental CKD and Uremia.
  • 著者名/発表者名: Tetsuhiro Tanaka, Junna Yamaguchi, Yoshiki Higashijima, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] Glyoxalase I Prevents Age-Related Endothelial Dysfunction through Modulation of eNOS Phosphorylation.
  • 著者名/発表者名: Airi Jo, Takamoto Ohse, Hiroaki Nishimatsu, Masao Takahashi, Satoshi Unuma, Takehiko Wada, Yoichiro Ikeda, Toshio Miyata, Yasunobu Hirata, Reiko Inagi, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] Optimal Hemoglobin Target Might Be Different between Elderly Hemodialysis Patients and Non-Elderly Patients.
  • 著者名/発表者名: Norio Hanafusa, Takanobu Nomura, Takeshi Hasegawa, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] SIRT1 Maintains Podocyte Homeostasis via Regulation of Actin Fiber Formation.
  • 著者名/発表者名: Shuta Motonishi, Reiko Inagi, Takehiko Wada, Takamoto Ohse, Akira Shimizu, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] An Antifibrotic Role of Hypoxia-Inducible Factor 3 in Renal Tubular Cells.
  • 著者名/発表者名: Tetsuhiro Tanaka, Kumi Shoji, Junna Yamaguchi, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] The Mechanism of ANGPTL4 Induction, a Mediator of Nephrotic Syndrome, through Its Chromatin Conformational Change.
  • 著者名/発表者名: Tsuyoshi Inoue, Imari Mimura, Takahide Kohro, Toshiya Tanaka, Hiroyuki Aburatani, Tatsuhiko Kodama, Youichiro Wada, Masaomi Nangaku
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] Galacto-Oligosaccharides Modified Gut Microbiota and Attenuated Renal Injury.
  • 著者名/発表者名: Satoshi Unuma, Takamoto Ohse, Airi Jo, Akira Shigehisa, Koji Kawakami, Takahiro Matsuki, Osamu Chonan, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] Induction of CCAAT/Enhancer-Binding Protein Delta (CEBPD) Links Inflammation and Hypoxia to Injury by Regulating Hypoxia-Inducible Factor 1 (HIF-1).
  • 著者名/発表者名: Junna Yamaguchi, Tetsuhiro Tanaka, Nobuaki Eto, Masaomi Nangaku.
  • 学会等名: The 46th Annual Meeting of the American Society of Nephrology
  • 発表場所: Atlanta, USA
• [学会発表] Toward the podocyte protection therapy.
  • 著者名/発表者名: Nangaku M.
  • 学会等名: 7th World Congress of Nephrology
  • 発表場所: Hong Kong
  • 招待講演
• [学会発表] Hypoxia as a converging pathway in renal fibrosis.
  • 著者名/発表者名: Nangaku M.
  • 学会等名: Satellite Symposium on renal fibrosis of 7th World Congress of Nephrology
  • 発表場所: Guangzhou, China
  • 招待講演
• [学会発表] combat with kidney disease: current and future
  • 著者名/発表者名: Nangaku M.
  • 学会等名: 50th Anniversary of Dialysis in Taiwan
  • 発表場所: Taipei, Taiwan
  • 招待講演
• [学会発表] Hypoxia and fibrosis of the kidney
  • 著者名/発表者名: Nangaku M.
  • 学会等名: International Symposium "Frontiers in Renal Disease Research”
  • 発表場所: Daejeon, Korea
  • 招待講演
• [学会発表] Role of Uremic Toxins in ESA Resistance in Dialysis Patients
  • 著者名/発表者名: Nangaku M.
  • 学会等名: 8th International Congress on Uremia Research and Toxicity
  • 発表場所: Okinawa, Japan
  • 招待講演