Elucidation of the pathophysiology of chronic kidney disease by comprehensive analysis of the hypoxia-responsive transcriptional network

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390260
• 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 東京大学, 医学部附属病院, 特任講師 (90311620)
• Co-Investigator(Kenkyū-buntansha): WADA Takehiko 東京大学, 医学部附属病院, 助教 (90447409) ; INAGI Reiko 東京大学, 医学部附属病院, 特任研究員 (50232509) ; TANAKA Tetsuhiro 東京大学, 保健健康推進本部, 助教 (90508079)
• Co-Investigator(Renkei-kenkyūsha): KODAMA Tatsuhiko 東京大学, 先端科学技術センター, 教授 (90170266) ; ABURATANI Hiroyuki 東京大学, 先端科学技術センター, 教授 (10202657)
• Project Period (FY): 2009 – 2011
• Keywords: 腎臓学

Research Abstract

We performed analysis of the transcriptional and regulatory network of hypoxia-inducible factor(HIF) by siRNA library screening, ChIP-sequencing, and microarray analysis. Based on these findings, we identified novel HIF regulatory molecules and HIF-1 target genes. Gene A, a novel HIF-1 target gene, showed a good correlation with prognosis of renal cell carcinoma. We also found that gene A plays a crucial role in cytokinesis.

Research Products

• [Journal Article] Dysregulated oxygen metabolism of the kidney by uremic toxins (2012)
  • Author(s): Chiang CK, Tanaka T, Nangaku M
  • Journal Title: J Ren Nutr Volume: 22 Pages: 77-80
  • URL: http://www.sciencedirect.com/science/article/pii/S1051227611002184
  • Peer Reviewed
• [Journal Article] Glyoxalase I retards renal senescence (2011)
  • Author(s): Ikeda Y, Inagi R, Miyata T, Nagai R, Arai M, Miyashita M, Itokawa M, Fujita T, Nangaku M.
  • Journal Title: Am J Pathol Volume: 179 Pages: 2810-21
  • URL: http://linkinghub.elsevier.com/retrieve/pii/S0002-9440(11)00840-6
  • Peer Reviewed
• [Journal Article] Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner (2011)
  • Author(s): Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M
  • Journal Title: Lab Invest Volume: 91 Pages: 1564-71
  • DOI: doi:10.1038/labinvest.2011.114
  • Peer Reviewed
• [Journal Article] Cytoglobin, a novel member of the globin family, protects kidney fibroblasts against oxidative stress under ischemic conditions (2011)
  • Author(s): Nishi H, Inagi R, Kawada N, Yoshizato K, Mimura I, Fujita T, Nangaku M
  • Journal Title: Am J Pathol Volume: 178 Pages: 128-39
  • URL: http://linkinghub.elsevier.com/retrieve/pii/S0002-9440(10)00057-X
  • Peer Reviewed
• [Journal Article] Epigenetic regulation for hypoxic response via HIF and histone demethylase (2011)
  • Author(s): Mimura I, Tanaka T, Wada Y, Kodama T, Nangaku M.
  • Journal Title: J Pharmacol Sci Volume: 115 Pages: 453-8
  • URL: https://www.jstage.jst.go.jp/article/jphs/advpub/0/advpub_10R19FM/_article
  • Peer Reviewed
• [Journal Article] Cytoglobin, a novel globin, plays an anti-fibrotic role in the kidney (2010)
  • Author(s): Mimura I, Nangaku M, Nishi H, Inagi R, Tanaka T, Fujita T
  • Journal Title: Am J Physiol Renal Physiol Volume: 299 Pages: F1120-33
  • URL: http://ajprenal.physiology.org/cgi/pmidlookup?view=long & pmid=20719976
  • Peer Reviewed
• [Journal Article] Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress (2010)
  • Author(s): Palm F, Nangaku M, Fasching A, Tanaka T, Nordquist L, Hansell P, Kawakami T, Nishijima F, Fujita T
  • Journal Title: Am J Physiol Renal Physiol Volume: 299 Pages: F380-386
  • URL: http://ajprenal.physiology.org/cgi/pmidlookup?view=long & pmid=20519374
  • Peer Reviewed
• [Journal Article] Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress (2010)
  • Author(s): Kawakami T, Inagi R, Wada T, Tanaka T, Fujita T, Nangaku M.
  • Journal Title: Am J Physiol Renal Physiol Volume: 299 Pages: F568-76
  • URL: http://ajprenal.physiology.org/cgi/pmidlookup?view=long & pmid=20534867
  • Peer Reviewed
• [Journal Article] Body weight control by a high-carbohydrate/low-fat diet slows the progression of diabetic kidney damage in an obese, hypertensive, type 2 diabetic rat model (2010)
  • Author(s): Ohtomo S, Izuhara Y, Nangaku M, Dan T, Ito S, vanYpersele de Strihou C, Miyata T
  • Journal Title: J Obesity pii Pages: 136502
  • URL: http://dx.doi.org/10.1155/2010/136502
  • Peer Reviewed
• [Journal Article] The suffocating kidney : Tubulointerstitial hypoxia in the pathogenesis of end-stage kidney disease (2010)
  • Author(s): Mimura I, Nangaku M
  • Journal Title: Nat Rev Nephrol Volume: 6 Pages: 667-78
  • URL: http://www.nature.com/nrneph/journal/v6/n11/full/nrneph.2010.124.html
  • Peer Reviewed
• [Journal Article] The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1 alpha in progression of chronic kidney disease (2010)
  • Author(s): Tanaka T, Nangaku M
  • Journal Title: Curr Opin Nephrol Hypretens Volume: 19 Pages: 43-50
  • URL: http://pt.wkhealth.com/pt/re/lwwgateway/landingpage.htm;jsessionid=PnJVzRfCYTWVxT2Lss9z8dqlgJqjn5ymxltQ7RMcJGkdwsJwJKxf!1393764361!181195629!8091!-1?issn=1062-4821 & volume=20 & issue=5 & spage=476
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress induces autophagy in renal proximal tubular cells (2009)
  • Author(s): Kawakami T, Inagi R, Takano H, Sato S, Ingelfinger JR, Fujita T, Nangaku M
  • Journal Title: Nephrol Dial Transplant Volume: 24 Pages: 2665-72
  • URL: http://ndt.oxfordjournals.org/cgi/pmidlookup?view=long & pmid=19454529
  • Peer Reviewed
• [Journal Article] Glyoxalse I overexpression ameliorates renal ischemia-reperfusion injury in rats (2009)
  • Author(s): Kumagai T, Nangaku M, Kojima I, Nagai R, Ingelfinger JR, Miyata T, Fujita T, Inagi R
  • Journal Title: Am J Physiol Renal Physiol Volume: 296 Pages: F912-21
  • URL: http://ajprenal.physiology.org/cgi/pmidlookup?view=long & pmid=19211689
  • Peer Reviewed
• [Journal Article] Suppression of MAP3 kinase 6 mediates anti-angiogenic and tumor-suppressive effects via VEGF repression (2009)
  • Author(s): Eto N, Miyagishi Y, Inagi R, Fujita T, Nangaku M
  • Journal Title: Am J Pathol Volume: 174 Pages: 1553-63
  • URL: http://linkinghub.elsevier.com/retrieve/pii/S0002-9440(10)61011-5
  • Peer Reviewed
• [Journal Article] 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, Nangaku M
  • Journal Title: Kidney Int Volume: 75 Pages: 268-277
  • URL: http://dx.doi.org/10.1038/ki.2008.488
  • Peer Reviewed
• [Journal Article] Novel therapeutic approach targeting the HIF-HRE system in the kidney (2009)
  • Author(s): Nangaku M
  • Journal Title: Adv Exp Biol Med Volume: 645 Pages: 81-86
  • URL: http://dx.doi.org/10.1007/978-0-387-85998-9_13
  • Peer Reviewed
• [Journal Article] Prolyl hydroxylase inhibitors to active HIF as a novel therapeutic approach against CKD (2009)
  • Author(s): Tanaka T, Nangaku M
  • Journal Title: J Pharmacol Sci Volume: 109 Pages: 24-31
  • URL: http://joi.jlc.jst.go.jp/JST.JSTAGE/jphs/08R09FM?from=PubMed
  • Peer Reviewed
• [Presentation] Abnormal Oxygen Metabolism and Epigenetic changes in Diabetic Kidney Disease (2012)
  • Author(s): Nangaku M
  • Organizer: Keystone Symposium on Complications of Diabetes
  • Place of Presentation: Boston, U. S. A.
  • Year and Date: 2012-03-12
• [Presentation] Progression of CKD following AKI : Role of hypoxia (2011)
  • Author(s): Nangaku M
  • Organizer: The 44^<th> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia, U. S. A
  • Year and Date: 20111100
• [Presentation] Derangement of Oxygen Sensing for Erythropoietin(EPO) Production by Unfolded Protein Response(UPR) (2011)
  • Author(s): Inagi R, Chiang CK, Tanaka T, Fujita T, Nangaku M
  • Organizer: The 44^<th> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia, U. S. A
  • Year and Date: 2011-11-12
• [Presentation] Indoxyl Sulfate Induces Cbp/p300-Interacting Transactivator, with Glu/Asp-Rich Carboxy-Terminal Domain, 2, and Impairs Hypoxia Response in Proximal Tubular Cells (2011)
  • Author(s): Tanaka T, Fujita T, Nangaku M
  • Organizer: The 44^<th> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia, U. S. A
  • Year and Date: 2011-11-12
• [Presentation] Identification & Characterization of a Novel Oncogenic HIF-1 Target Involved in Renal Cell Carcinoma (2011)
  • Author(s): Shoji K, Mimura I, Ohse T, Murayama T, Inagi R, Wada T, Tanaka T, Kume H, Goto A, Fujita T, Aburatani H, Kodama T, Nangaku M
  • Organizer: The 44^<th> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia, U. S. A
  • Year and Date: 2011-11-12
• [Presentation] HIF1 Modulates Chromatin Conformational Change by Recruiting KDM3A and Enhances Regulation of Glucose Transporter 3 in Endothelial Cells (2011)
  • Author(s): Mimura I, Inoue T, Wada Y, Kanki Y, Fujita T, Aburatani H, Kodama T, Nangaku M
  • Organizer: The 44^<th> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia, U. S. A.
  • Year and Date: 2011-11-11
• [Presentation] Renal Ischemia Reperfusion Injury Promotes Mid-Term Tubular Senescence (2011)
  • Author(s): Ikeda T, Inagi R, Fujita T, Nangaku M
  • Organizer: The 44^<th> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia, U. S. A
  • Year and Date: 2011-11-10
• [Presentation] Mechanism of the development of renal anemia and its treatment (2011)
  • Author(s): Nangaku M
  • Organizer: International Forum of Chronic Kidney Disease of the Taiwan Society of Nephrology
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2011-07-10
• [Presentation] Dysregulated oxygen metabolism of the kidney by uremic toxins (2011)
  • Author(s): Nangaku M
  • Organizer: 7^<th> International Congress on Uremia Research and Toxicity
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2011-05-12
• [Presentation] Indoxyl sulfate impairs hypoxia response in cultured proximal tubular cells (2011)
  • Author(s): Tanaka T, Fujita T, Nangaku M
  • Organizer: 7^<th> International Congress on Uremia Research and Toxicity
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2011-05-12
• [Presentation] Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in HIF-dependent manner (2011)
  • Author(s): Chiang CK, Inagi R, Tanaka T, Fujita T, Nangaku M
  • Organizer: 7^<th> International Congress on Uremia Research and Toxicity
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2011-05-12
• [Presentation] Cellular Defense Systems in Hypoxia : Mechanisms for Renal Protection (2011)
  • Author(s): Nangaku M
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2011-04-11
• [Presentation] Glyoxalase I Prevent Age-Related Aortic Medial Thickening by Reducing TGF-βand CTGF Signals Independent of Blood Pressure (2010)
  • Author(s): Ikeda T, Inagi R, Jo A, Ohse T, Miyata T, Manabe I, Nagai R, Fujita T, Nangaku M
  • Organizer: The 43^<rd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Denver, U. S. A
  • Year and Date: 2010-11-20
• [Presentation] Endoplasmic Reticulum Stress Disturbs Erythropoietin Gene Expression in a HIF-Dependent Manner (2010)
  • Author(s): Chiang CK, Nangaku M, Tanaka T, Fujita T, Inagi R
  • Organizer: The 43^<rd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Denver, U. S. A
  • Year and Date: 2010-11-19
• [Presentation] Elucidation of the Anti-Fibrotic Mechanism of a Novel HIF-Regulated Globin, Cytoglobin, with Molecular Genetics (2010)
  • Author(s): Mimura I, Nishi H, Tanaka T, Inagi R, Fujita T, Nangaku M
  • Organizer: The 43^<rd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Denver, U. S. A
  • Year and Date: 2010-11-19
• [Presentation] Impact of Anthracyclines on Hypoxia Response in Tubular Epithelial Cells (2010)
  • Author(s): Tanaka T, Fujita T, Nangaku M
  • Organizer: The 43^<rd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Denver, U. S. A
  • Year and Date: 2010-11-19
• [Presentation] MicroRNA Profiles of Tubular Cells under Hypoxia-Reoxygenation and Endoplasmic Reticulum Stress (2010)
  • Author(s): Muratsu S, Nangaku M, Tanaka T, Chiang CK, Wada T, Fujita T, Inagi R
  • Organizer: The 43^<rd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Denver, U. S. A
  • Year and Date: 2010-11-19
• [Presentation] Role of carbonyl stress in renal senescence (2010)
  • Author(s): Nangaku M, Ikeda Y, Fujita T, Inagi R
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Otsu, Japan
  • Year and Date: 2010-10-06
• [Presentation] Defensive mechanisms against fibrosis in the hypoxic kidney (2010)
  • Author(s): Nangaku M
  • Organizer: ISN-NEXUS : fibrosis and the kidney
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2010-07-01
• [Presentation] Role of hypoxia in chronic kidney disease (2010)
  • Author(s): Nangaku M
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Saxton River, U. S. A
  • Year and Date: 2010-06-29
• [Presentation] HIF and Renal Disease (2010)
  • Author(s): Nangaku M
  • Organizer: 12^<th> Asian Pacific Congress of Nephrology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2010-06-06
• [Presentation] Identification of novel targets of hypoxia-responsive pathways (2010)
  • Author(s): Nangaku M
  • Organizer: ISN-NEXUS : the kidney and the vascular system
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-04-17
• [Presentation] Impaired glomerular healing with persistent glomerular inflammation in streptozotocin-induced diabetic nephropathy (2010)
  • Author(s): Takano H, Shimizu A, Wakamatsu K, Ishikawa A, Masuda Y, Ishizaki M, Nangaku M, Fukuda Y
  • Organizer: ISN-NEXUS : the kidney and the vascular system
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-04-17
• [Presentation] Genome-wide analysis of hypoxic inducible factor 1 binding sites in human endothelial cells under hypoxia (2010)
  • Author(s): Mimura I, Wada Y, Tsutsumi S, Aburatani H, Kodama T, Nangaku M
  • Organizer: ISN-NEXUS : the kidney and the vascular system
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-04-16
• [Presentation] The evaluation of renal senescence and its retardation by the reduction of carbonyl stress (2010)
  • Author(s): Ikeda Y, Nangaku M, Inagi R, Kumagai T, Miyata T, Fujita T
  • Organizer: ISN-NEXUS : the kidney and the vascular system
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-04-16
• [Presentation] Cytoglobin, a novel member of the globin family, protects the kidney fibroblasts against oxidative stress under ischemic conditions (2009)
  • Author(s): Nishi H, Inagi R, Kawada N, Yoshizato K, Mimura I, Miyata T, Fujita T, Nangaku M
  • Organizer: The 42^<nd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: San Diego, U. S. A
  • Year and Date: 2009-10-31
• [Presentation] Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress (2009)
  • Author(s): Kawakami T, Inagi R, Fujita T, Nangaku M
  • Organizer: The 42^<nd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: San Diego, U. S. A
  • Year and Date: 2009-10-31
• [Presentation] Genome-wide analysis of hypoxic inducible factor 1 binding sites in human endothelial cells under hypoxia (2009)
  • Author(s): Mimura I, Nishi H, Inagi R, Fujita T, Nangaku M
  • Organizer: The 42^<nd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: San Diego, U. S. A
  • Year and Date: 2009-10-30
• [Presentation] Glyoxalase1 attenuates the impact of renal aging (2009)
  • Author(s): Ikeda Y, Inagi R, Miyata T, Fujita T, Nangaku M
  • Organizer: The 42^<nd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: San Diego, U. S. A.
  • Year and Date: 2009-10-30
• [Presentation] Acute Administration of Indoxyl Sulfate Increases the Glomerular Filtration Rate and Reduces Kidney Oxygenation, but without Affecting Renal Blood Flow (2009)
  • Author(s): Palm F, Gutweiler A, Welch WJ, Wilcox CS, Nangaku M
  • Organizer: The 42^<nd> Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Diego, U. S. A
  • Year and Date: 2009-10-30
• [Presentation] Glyoxalase1 attenuates the impact of renal aging (2009)
  • Author(s): Ikeda Y, Nangaku M, Kumagai T, Miyata T, Inagi R
  • Organizer: 10th International Symposium on the Maillard Reaction
  • Place of Presentation: Cairns, Australia
  • Year and Date: 2009-08-30
• [Presentation] Hypoxia-induced endoplasmic reticulum stress is ameliorated by glyoxalase I via reduction of intraWorld Congress of Nephrologycellular oxidative stress (2009)
  • Author(s): Inagi R, Nishi H, Tanaka T, Miyata T, Fujita T, Nangaku M
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Milan, Italy
  • Year and Date: 2009-05-25
• [Presentation] Transgenic overexpression of cytoglobin, a novel globin protein, improves tubulointerstitial injury via amelioration of oxidative stress in the hypoxic kidney (2009)
  • Author(s): Nishi H, Inagi R, Kawada N, Yoshizato K, Miyata T, Mimura I, Fujita T, Nangaku M
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Milan, Italy
  • Year and Date: 2009-05-25
• [Presentation] The renin-angiotensin system as a cause of renal hypoxia (2009)
  • Author(s): Nangaku M
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Milan, Italy
  • Year and Date: 2009-05-24
• [Presentation] Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats (2009)
  • Author(s): Kumagai T, Nangaku M, Kojima I, Nishi H, Tanaka T, Miyata T, Fujita T, Inagi R
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Milan, Italy
  • Year and Date: 2009-05-24
• [Presentation] Endoplasmic reticulum stress induces autophagy in renal proximal tubular cells (2009)
  • Author(s): Kawakami T, Inagi R, Takano H, Sato S, Ingelfinger J, Miyata T, Fujita T, Nangaku M
  • Organizer: World Congress of Nephrology
  • Place of Presentation: Milan, Italy
  • Year and Date: 2009-05-23
• [Book] Oxidative Stress in Applied Basic Research and Clinical Practice : Studies on Renal Disorders (2010)
  • Author(s): Miyata T, Eckardt KU, Nangaku M
  • Total Pages: 783
  • Publisher: Humana Press