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MOLECULAR MECHANISM OF HUMAN RENIN AND C-MYC, GENES REGULATION THROUGH NUCLEAR RECEPTOR LXR

Research Project

Project/Area Number 15590983
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionYOKOHAMA CITY UNIVERSITY, SCHOOL OF MEDICINE

Principal Investigator

TAMURA Kouichi  YOKOHAMA CITY UNIVERSITY, SCHOOL OF MEDICINE, SECOND DEPARTMENT OF INTERNAL MEDICINE, ASSOCIATE PROFESSOR, 医学部附属病院, 講師 (40285143)

Co-Investigator(Kenkyū-buntansha) UMEMURA Satoshi  YOKOHAMA CITY UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, DEPARTMENT OF MEDICAL SCIENCE AND CARDIORENAL MEDICINE, CHAIRMAN & PROFESSOR CHAIRMAN, 医学研究科, 教授 (00128589)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsRenin / Nuclear receptor / Liver X receptor alpha (LXRα) / Promoter / Transcriptional regulation / Cyclic AMP / Oxidized cholesterol / c-myc
Research Abstract

The cAMP-signaling pathway plays a crucial role in the regulation of the renin gene, but the mechanism involved remains poorly understood. We have focused our studies of renin gene regulation on the unique cAMP responsive element (huREN/CNRE, -135 to -107) in the human renin promoter. We have cloned a protein that binds to this unique CNRE and demonstrated that this protein is liver X receptor-α (LXRα), a transcriptional factor of the nuclear receptor family. Transient expression of LXRα in human renin-producing Calu-6 cells increased cAMP inducibility of human renin promoter. Similarly, LXRα-stably transfected Calu-6 cells exhibited increased cAMP inducibility of renin promoter as well as the endogenous renin gene. Site-directed mutation of huREN/CNRE, which disrupted LXRα binding, decreased cAMP-induced transcriptional activity of human renin promoter. Furthermore, we demonstrated that the binding of LXRa derived from human juxtaglomerular cells, the main production site of renin in the kidney, to the huREN/CNRE in vivo. These results suggest that LXRα plays an important role in the cAMP-mediated regulation of human renin gene transcription by binding to CNRE. In parallel experiments, we demonstrated that LXRα can also bind to the homologous CNRE in the c-myc promoter. cAMP promotes transcription through c-myc/CNRE : LXRa interaction in LXRα-transiently transfected cells and increases c-myc mRNA expression in stably transfected cells. Identification of LXRα as a novel cAMP responsive nuclear modulator of renin and c-myc expression not only has cardiovascular significance but may have generalized implication in the regulation of gene transcription.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (30 results)

All 2005 2004 2003 Other

All Journal Article (22 results) Book (1 results) Publications (7 results)

  • [Journal Article] The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardio myocyte hypertrophy2005

    • Author(s)
      Tanaka, Y., Tamura, K., Koide, Y., Sakai, M., Tsurumi, Y., Noda, Y., Umemura, M., Ishigami, T., Uchino, K., Kimura, K., Horiuchi, M., Umemura, S.
    • Journal Title

      FEBS Lett. 579

      Pages: 1579-1586

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Analysis of Factors that Affect Short-Term Blood Pressure Variability in Patients with Chronic Renal Failure2005

    • Author(s)
      Sakai, M., Tamura, K., Tanaka, Y., Tsurumi, Y., Okano, Y., Koide, Y., Endoh, T., Matsushita, K., Kihara, M., Hirawa, N., Toya, Y., Tokita, Y., Ohnishi, T., Umemura, S.
    • Journal Title

      Clin Exp Hypertens. 27

      Pages: 139-147

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Heparin recovers AT1 receptor and its intracellular signal transduction in cultured vascular smooth muscle cells2005

    • Author(s)
      Hashimoto, T., Kihara, M., Sato, K., Imai, N., Tanaka, Y., Sakai, M., Tamura, K., Hirawa, N., Toya, Y., Kitamura, H., Umemura, S.
    • Journal Title

      FEBS Lett. 579

      Pages: 281-284

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nuclear receptor LXRα is involved in cAMP-mediated human renin gene2004

    • Author(s)
      Tamura K, et al.
    • Journal Title

      Mol Cell Endocrinol 224

      Pages: 11-20

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1a receptor gene knockout mice2004

    • Author(s)
      Sato K, et al.
    • Journal Title

      J Am Soc Nephrol 15

      Pages: 1756-1763

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II2004

    • Author(s)
      Zou Y, et al.
    • Journal Title

      Nature Cell Biology 6

      Pages: 499-506

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression2004

    • Author(s)
      Tamura, K., Chen, Y.E., Tanaka, Y., Sakai, M., Tsurumi, Y., Koide, Y., Kihara, M., Pratt, R.E., Horiuchi, M., Umemura, S., Dzau, V.J.
    • Journal Title

      Mol Cell Endocrinol. 224

      Pages: 11-20

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1 a receptor gene-knockout mice2004

    • Author(s)
      Sato, K., Kihara, M., Hashimoto, T., Matsushita, K., Koide, Y., Tamura, K., Hirawa, N., Toya, Y., Fukamizu, A., Umemura, S.
    • Journal Title

      J Am Soc Nephrol. 15

      Pages: 1756-17663

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II2004

    • Author(s)
      Zou, Y., Akazawa, H., Qin, Y., Sano, M., Takano, H., Minamino, T., Makita, N., Iwanaga, K., Zhu, W., Kudoh, S., Toko, H., Tamura, K., Kihara, M., Nagai, T., Fukamizu, A., Umemura, S., Iiri, T., Fujita, T., Komuro, I.
    • Journal Title

      Nature Cell Biology 6

      Pages: 499-506

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nuclear receptor LXRα is involved in cAMP-mediated human renin gene expression2004

    • Author(s)
      Tamura K, et al.
    • Journal Title

      Molecular and Cellular Endocrinology 224

      Pages: 11-20

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1a receptor gene knockout mice2004

    • Author(s)
      Sato K, et al.
    • Journal Title

      Journal of American Society of Nephrology 15

      Pages: 1756-1763

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 高血圧合併CAPD患者に対するアンジオテンシンII受容体拮抗薬の効果についての検討2004

    • Author(s)
      田村 功一, 他
    • Journal Title

      腎と透析-臨時増刊号 特集名:腹膜透析2004 57

      Pages: 412-415

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 遺伝性高血圧症における尿細管レニン・アンジオテンシン系の意義に関する検討2004

    • Author(s)
      石上 友章, 他
    • Journal Title

      血圧 11

      Pages: 228-231

    • Related Report
      2004 Annual Research Report
  • [Journal Article] カルシウム拮抗薬2004

    • Author(s)
      田村 功一, 他
    • Journal Title

      医学のあゆみ-臨時増刊号 特集名:糖尿病・代謝症候群-state of arts 2004-2006 263

      Pages: 804-806

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin II signaling.2003

    • Author(s)
      Lopez-Ilasaca M, et al.
    • Journal Title

      Mol Biol Cell 14

      Pages: 5038-5050

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Different induction of PKC isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats.2003

    • Author(s)
      Koide Y, et al.
    • Journal Title

      Hypertens Res 26

      Pages: 421-426

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lipoxygenase products regulate nitric oxide and inducible nitric oxide synthase production in interleukin-1beta stimulated vascular smooth muscle cells.2003

    • Author(s)
      Hashimoto T, et al.
    • Journal Title

      Hypertens Res 26

      Pages: 177-184

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lipoxygenase products regulate nitric oxide and inducible nitric oxide synthase production in interleukin-1 beta stimulated vascular smooth muscle cells2003

    • Author(s)
      Hashimoto, T., Kihara, M., Yokoyama, K., Fujita, T., Kobayashi, S., Matsushita, K., Tamura, K., Hirawa, N., Toya, Y., Umemura, S.
    • Journal Title

      Hypertens Res. 6

      Pages: 177-184

    • NAID

      130004437036

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A case of acute renal failure due to cholesterol crystal embolism treated with LDL apheresis followed by corticosteroid and candesartan2003

    • Author(s)
      Tamura, K., Umemura, M., Yano, H., Sakai, M., Sakurai, Y., Tsurumi, Y., Koide, Y., Usui, T., Yabana, M., Toya, Y., Tokita, Y., Umemura, S.
    • Journal Title

      Clin Exp Nephrol. 7

      Pages: 67-71

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Different induction of PKC isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats2003

    • Author(s)
      Koide, Y., Tamura, K., Suzuki, A., Kitamura, K., Yokoyama, K., Hashimoto, T., Hirawa, N., Kihara, M., Ohno, S., Umemura, S.
    • Journal Title

      Hypertens Res. 26

      Pages: 421-426

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular pathophysiology of renin-angiotensin system2003

    • Author(s)
      Tamura, K.
    • Journal Title

      Yokohama Med Bull. 50

      Pages: 1-14

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and amodulator of angiotensin II signaling2003

    • Author(s)
      Lopez-liasaca, M., Liu, X., Tamura, K., Dzau, V.J.
    • Journal Title

      Moll Bloll Cell. 14

      Pages: 5038-5050

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] アンジオテンシノーゲン.第2章,レニン-アンギオテンシン系の分子生物学.The Renin-Angiotensin System.(堀内正嗣, 伊藤 裕, 竹内和久, 楽木宏美編)2003

    • Author(s)
      田村功一, 他
    • Publisher
      メデイカルレビュー社(東京)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Lopez-Ilasaca M, et al.: "The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin II signaling"Mol Biol Cell. 14. 5038-5050 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tamura K.: "Molecular pathophysiology of renin-angiotensin system"Yokohama Med Bull. 50. 1-14 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hashimoto T, et al.: "Lipoxygenase products regulate nitric oxide and inducible nitric oxide synthase production in interleukin-1beta stimulated vascular smooth muscle cells"Hypertens Res. 26. 177-184 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tamura K, et al.: "A case of acute renal failure due to cholesterol crystal embolism treated with LDL aphere sis followed by corticosteroid and candesartan"Clin Exp Nephrol. 7. 67-71 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koide Y, et al.: "Different induction of PKC isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats"Hypertens Res. 26. 421-426 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 田村 功一, 他: "Information Up-to-Date.脳卒中急性期の血圧管理-ISH statement"血圧. 10. 974-975 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 田村功一, 他: "アンジオテンシノーゲン.第2章,レニン-アンギオテンシン系の分子生物学.The Renin-Angiotensin System.(堀内正嗣, 伊藤 裕, 竹内和久, 楽木宏美編)"メデイカルレビュー社(東京). 55-62 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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