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

• 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
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥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)
• 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] Nuclear receptor LXRα is involved in cAMP-mediated human renin gene expression (2004)
  • Author(s): Tamura K, et al.
  • Journal Title: Molecular and Cellular Endocrinology 224 Pages: 11-20
• [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: Journal of American Society of Nephrology 15 Pages: 1756-1763
• [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
• [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
• [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
• [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
  • NAID: 130004437036
  • 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
  • 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
• [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)
• [Publications] Tamura K.: "Molecular pathophysiology of renin-angiotensin system"Yokohama Med Bull. 50. 1-14 (2003)
• [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)
• [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)
• [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)
• [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)
• [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)