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

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15590983
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: YOKOHAMA 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
• Keywords: Renin / 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.

Research Products

• [Journal Article] The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardio myocyte hypertrophy (2005)
  • 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
• [Journal Article] Analysis of Factors that Affect Short-Term Blood Pressure Variability in Patients with Chronic Renal Failure (2005)
  • 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
• [Journal Article] Heparin recovers AT1 receptor and its intracellular signal transduction in cultured vascular smooth muscle cells (2005)
  • 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
• [Journal Article] Nuclear receptor LXRα is involved in cAMP-mediated human renin gene (2004)
  • 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
• [Journal Article] Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1a receptor gene knockout mice (2004)
  • 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
• [Journal Article] Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II (2004)
  • 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
• [Journal Article] Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression (2004)
  • 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
• [Journal Article] Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1 a receptor gene-knockout mice (2004)
  • 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
• [Journal Article] Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II (2004)
  • 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
• [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
• [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
• [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
• [Journal Article] Lipoxygenase products regulate nitric oxide and inducible nitric oxide synthase production in interleukin-1 beta stimulated vascular smooth muscle cells (2003)
  • 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
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A case of acute renal failure due to cholesterol crystal embolism treated with LDL apheresis followed by corticosteroid and candesartan (2003)
  • 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
• [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., 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
• [Journal Article] Molecular pathophysiology of renin-angiotensin system (2003)
  • 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
• [Journal Article] The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and amodulator of angiotensin II signaling (2003)
  • 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
• [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
  • Total Pages: 55-62
  • 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