Research on receptor binding molecule in hypertension and organ injury

• Project/Area Number: 24591233
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Yokohama City University
• Principal Investigator: TAMURA KOUICHI 横浜市立大学, 医学部, 准教授 (40285143)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: シグナル伝達 / 生理活性 / 循環器・高血圧 / 生体分子 / トランスレーショナルリサーチ / 生体機能制御 / 動脈硬化 / 高血圧 / 慢性腎臓病 / 新規治療 / バイオマーカー

Outline of Final Research Achievements

In the course of an investigational search for a fine means to regulate AT1R signaling at the local tissue sites, we have focused our analysis on the AT1R-associated protein (ATRAP; Agtrap gene), which is a molecule that directly binds to the carboxyl‐terminal domain of AT1R. In contrast to the classical components of the renin-angiotensin system (i.e. angiotensinogen, renin and AT1R), alteration of ATRAP expression exerts no evident effects on baseline BP and renal morphology and function in vivo such as in ATRAP-transgenic mice and ATRAP-deficient mice in physiological condition. However, accumulating experimental results in these mice indicate that ATRAP exerts inhibitory effects on the exaggerated activation of tissue AT1R signaling in response to pathological stimuli, in order to protect cardiovascular and renal tissues under pathological conditions, in spite of no influence of ATRAP on physiological AT1R signaling.

Research Products

• [Journal Article] Therapeutic impact of the single fixed-dose combination with a high-dose angiotensin-receptor blocker and a low-dose thiazide diuretic in the management of hypertension: awaiting further accumulation of clinical evidence. (2014)
  • Author(s): Tamura K, Ohki K, Kobayashi R, Uneda K, Azushima K, Ohsawa M, Wakui H, Sakai M, Tokita Y, Umemura S.
  • Journal Title: Hypertens Res. Volume: 37 Issue: 12 Pages: 1032-1034
  • DOI: 10.1038/hr.2014.130
  • Peer Reviewed
• [Journal Article] Effects of the Angiotensin receptor blocker olmesartan on adipocyte hypertrophy and function in mice with metabolic disorders. (2014)
  • Author(s): Maeda A, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, Kanaoka T, Kobayashi R, Ohki K, Matsuda M, Tsurumi-Ikeya Y, Yamashita A, Tokita Y, Umemura S.
  • Journal Title: Biomed Res Int. Volume: 2014 Pages: 946492-946492
  • DOI: 10.1155/2014/946492
  • Peer Reviewed / Open Access
• [Journal Article] Fetal programming by high-sucrose diet during pregnancy affects the vascular angiotensin II receptor-PKC-L-type Ca(2+) channels (Cav1.2) axis to enhance pressor responses. (2014)
  • Author(s): Tamura K, Ohki K, Kobayashi R, Uneda K, Azushima K, Ohsawa M, Wakui H, Umemura S.
  • Journal Title: Hypertens Res. Volume: 37 Issue: 9 Pages: 796-798
  • DOI: 10.1038/hr.2014.105
  • Peer Reviewed
• [Journal Article] Effects of Ang II receptor blocker irbesartan on adipose tissue function in mice with metabolic disorders. (2014)
  • Author(s): Maeda A, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, Kobayashi R, Tsurumi-Ikeya Y, Kanaoka T, Dejima T, Ohki K, Haku S, Yamashita A, Umemura S.
  • Journal Title: Int J Med Sci. Volume: 11(6) Issue: 6 Pages: 646-51
  • DOI: 10.7150/ijms.8577
  • Peer Reviewed / Open Access
• [Journal Article] Effects of single pill-based combination therapy of amlodipine and atorvastatin on within-visit blood pressure variability and parameters of renal and vascular function in hypertensive patients with chronic kidney disease. (2014)
  • Author(s): Azushima K, Uneda K, Tamura K, Wakui H, Ohsawa M, Kobayashi R, Dejima T, Kanaoka T, Maeda A, Toya Y, Umemura S.
  • Journal Title: Biomed Res Int. Volume: 2014 Pages: 437087-437087
  • DOI: 10.1155/2014/437087
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of amino acids into dialysate during hemodialysis using hydrophilic and nonhydrophilic polyester-polymer alloy and polyacrylonitrile membrane dialyzers. (2014)
  • Author(s): Yokomatsu A, Fujikawa T, Toya Y, Shino-Kakimoto M, Itoh Y, Mitsuhashi H, Tamura K, Hirawa N, Yasuda G, Umemura S.
  • Journal Title: Ther Apher Dial. Volume: 18 Pages: 340-346
  • Peer Reviewed / Open Access
• [Journal Article] Endovascular treatment of renal artery stenosis improves contralateral renal hypertrophy with nephrotic syndrome. (2014)
  • Author(s): Wakui H, Hosokawa Y, Oshikawa J, Tamura K, Toya Y, Yabana M, Furihata S, Sugano T, Umemura S.
  • Journal Title: CEN Case Rep. Volume: 3 Issue: 1 Pages: 53-55
  • DOI: 10.1007/s13730-013-0085-y
  • Peer Reviewed
• [Journal Article] Deletion of the angiotensin II type 1 receptor-associated protein enhances renal sodium reabsorption and exacerbates angiotensin II-mediated hypertension. (2013)
  • Author(s): Ohsawa M, Tamura K, Wakui H, Maeda A, Dejima T, Kanaoka T, Azushima K, Uneda K, Tsurumi-Ikeya Y, Kobayashi R, Matsuda M, Uchida S, Toya Y, Kobori H, Nishiyama A, Yamashita A, Ishikawa Y, Umemura S.
  • Journal Title: Kidney Int. Volume: 86(3) Issue: 3 Pages: 570-81
  • DOI: 10.1038/ki.2014.95
  • Peer Reviewed / Open Access
• [Journal Article] Activation of angiotensin II type 1 receptor-associated protein exerts an inhibitory effect on vascular hypertrophy and oxidative stress in angiotensin II-mediated hypertension. (2013)
  • Author(s): Wakui H, Dejima T, Tamura K, Uneda K, Azuma K, Maeda A, Ohsawa M, Kanaoka T, Azushima K, Kobayashi R, Matsuda M, Yamashita A, Umemura S.
  • Journal Title: Cardiovasc Res. Volume: 100(3) Issue: 3 Pages: 511-9
  • DOI: 10.1093/cvr/cvt225
  • Peer Reviewed / Open Access
• [Journal Article] Bofu-tsu-shosan, an oriental herbal medicine, exerts a combinatorial favorable metabolic modulation including antihypertensive effect on a mouse model of human metabolic disorders with visceral obesity. (2013)
  • Author(s): Azushima K, Tamura K, Wakui H, Maeda A, Ohsawa M, Uneda K, Kobayashi R, Kanaoka T, Dejima T, Fujikawa T, Yamashita A, Toya Y, Umemura S.
  • Journal Title: PLoS One. Volume: 8(10) Issue: 10 Pages: e75560-e75560
  • DOI: 10.1371/journal.pone.0075560
  • Peer Reviewed / Open Access
• [Journal Article] What can we expect from the binding characteristics of azilsartan, a newly available angiotensin II blocker, in hypertension? (2013)
  • Author(s): Tamura K, Ohsawa M, Kanaoka T, Maeda A, Azushima K, Uneda K, Wakui H, Azuma K, Tsurumi-Ikeya Y, Umemura S
  • Journal Title: Hypertens Res Volume: 36 Pages: 107-108
  • Peer Reviewed
• [Journal Article] Enhanced angiotensin receptor-associated protein in renal tubule suppresses angiotensin-dependent hypertension. (2013)
  • Author(s): Wakui H, Tamura K, Masuda S, Tsurumi-Ikeya Y, Fujita M, Maeda A, Ohsawa M, Azushima K, Uneda K, Matsuda M, Kitamura K, Uchida S, Toya Y, Kobori H, Nagahama K, Yamashita A, Umemura S.
  • Journal Title: Hypertension. Volume: 61(6) Issue: 6 Pages: 1203-10
  • DOI: 10.1161/hypertensionaha.111.00572
  • Peer Reviewed / Open Access
• [Journal Article] Upstream stimulatory factors 1 and 2 mediate the transcription of angiotensin II binding and inhibitory protein. (2013)
  • Author(s): Matsuda M, Tamura K, Wakui H, Maeda A, Ohsawa M, Kanaoka T, Azushima K, Uneda K, Haku S, Tsurumi-Ikeya Y, Toya Y, Maeshima Y, Yamashita A, Umemura S.
  • Journal Title: J Biol Chem. Volume: 288(26) Issue: 26 Pages: 19238-49
  • DOI: 10.1074/jbc.m113.451054
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced angiotensin receptor-associated protein in renal tubule suppresses angiotensin dependent hypertension (2013)
  • Author(s): Wakui H, Tamura K, et al.
  • Journal Title: Hypertension Volume: ー
  • Peer Reviewed
• [Journal Article] UPSTREAM STIMULATORY FACTORS 1 AND 2 MEDIATE THE TRANSCRIPTION OF ANGIOTENSIN II BINDING AND INHIBITORY PROTEIN (2013)
  • Author(s): Matsuda M, Tamura K, et al.
  • Journal Title: Journal of Biological Chemistry Volume: ー
  • Peer Reviewed
• [Journal Article] The physiology and pathophysiology of a novel angiotensin receptor-binding protein ATRAP/Agtrap (2013)
  • Author(s): Tamura K, et al.
  • Journal Title: Current Pharmaceutical Design Volume: ー
  • Peer Reviewed
• [Journal Article] Effects of Aliskiren-Based Therapy on Ambulatory Blood Pressure Profile, Central Hemodynamics, and Arterial Stiffness in Nondiabetic Mild to Moderate Hypertensive Patients (2012)
  • Author(s): Kanaoka T, Tamura K, et al.
  • Journal Title: Journal of Clinical Hypertension Volume: 14 Issue: 8 Pages: 522-529
  • DOI: 10.1111/j.1751-7176.2012.00640.x
  • Peer Reviewed
• [Journal Article] Relationship of Ambulatory Blood Pressure and the Heart Rate Profile with Renal Function Parameters in Hypertensive Patients with Chronic Kidney Disease (2012)
  • Author(s): Kanaoka T, Tamura K, et al.
  • Journal Title: Clinical and Experimental Hypertension Volume: 34 Issue: 4 Pages: 264-269
  • DOI: 10.3109/10641963.2012.681082
  • Peer Reviewed
• [Presentation] Losartan and Ambulatory Blood Pressure Variability. (2014)
  • Author(s): Azuma K, Tamura K
  • Organizer: American Society of Nephrology (ASN) Kidney Week 2014
  • Place of Presentation: アトランタ，米国
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] Single Pill-Based Combination Therapy with Amlodipine and Atorvastatin Improves Renal and Vascular Function and Clinic Blood Pressure Variability in Hypertension with Chronic Kidney Disease. (2014)
  • Author(s): Tamura K, Azushima K, Uneda K, Wakui H, Ohsawa M, Kobayashi R, Ohki K, Azuma K, Dejima T, Kanaoka T, Toya Y, Umemura S.
  • Organizer: American Society of Nephrology (ASN) Kidney Week 2014
  • Place of Presentation: アトランタ，米国
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] 受容体結合因子ATRAP/Agtrapを介した 腎尿細管機能制御と血圧調節 (2014)
  • Author(s): 田村功一，涌井広道，大澤正人，小豆島健護，畝田一司，小林 竜， 大城光二，松田みゆき，大友優太，山下暁朗，戸谷義幸，梅村 敏
  • Organizer: 第37回日本高血圧学会総会 シンポジウム
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-10-17 – 2014-10-19
  • Invited
• [Presentation] CKDの降圧治療 - 尿蛋白と糖尿病の有無による層別化 - (2014)
  • Author(s): 田村功一，小井手裕一
  • Organizer: 第37回日本高血圧学会総会 日本高血圧学会・日本腎臓学会・日本糖尿病学会合同シンポジウム
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-10-17 – 2014-10-19
  • Invited
• [Presentation] ARB，ACE阻害薬，DRIの使い分け (2014)
  • Author(s): 田村功一
  • Organizer: 第37回日本高血圧学会総会 教育講演
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-10-17 – 2014-10-19
  • Invited
• [Presentation] Angiotensin II Receptor-Interacting Molecule, ATRAP, Exerts A Selective Inhibitory Modulation on Pathological Activation of Tissue Angiotensin II Receptor Signaling in Hypertension (2013)
  • Author(s): Kouichi Tamura, Hiromichi Wakui, Akinobu Maeda, Masato Ohsawa, Toru Dejima, Kengo Azushima, Tomohiko Kanaoka, Kazushi Uneda, Ryu Kobayashi, Sona Haku, Koichi Azuma, Yoshiyuki Toya, Akio Yamashita, Satoshi Umemura
  • Organizer: The 23rd European Meeting on Hypertension &Cardiovascular Protection
  • Place of Presentation: Milan, Italy
• [Presentation] Gene-Targeted Deletion of the Angiotensin II Type 1 Receptor-Interacting and Functionally Modulating Protein Enhances Renal Sodium Reabsorption and Exacerbates Angiotensin II-Mediated Hypertension (2013)
  • Author(s): Kouichi Tamura, Masato Ohsawa, Hiromichi Wakui, Akinobu Maeda, Toru Dejima, Tomohiko Kanaoka, Kengo Azushima, Kazushi Uneda, Ryu Kobayashi, Miyuki Matsuda, Yoshiyuki Toya, Satoshi Umemura
  • Organizer: American Society of Nephrology (ASN) Kidney Week 2013
  • Place of Presentation: Atlanta, USA
• [Presentation] Updates of JSN/JSH-related Guidelines for the Management of Hypertension (2013)
  • Author(s): Kouichi Tamura
  • Organizer: The 2013 Annual Conference of Taiwan Hypertension Society
  • Place of Presentation: Taipei, Taiwan
  • Invited
• [Presentation] Improvements in ambulatory blood pressure variability translate into inhibition of cardiovascular and renal injury in hypertensive patients with chronic kidney disease. (2012)
  • Author(s): Kouichi Tamura, et al.
  • Organizer: Scientific Sessions 2012 American Heart Association
  • Place of Presentation: Los Angeles, CA, USA
• [Presentation] Pro-functional intervention for diabetic foot: Position of LDL apheresis (2012)
  • Author(s): Kouichi Tamura, et al.
  • Organizer: 第80回欧州動脈硬化学会サテライトシンポジウム“7th LIPID CLUB & Therapeutic Apheresis”
  • Place of Presentation: SAN GEMINI (TR), Italy
  • Invited
• [Presentation] Ang II Type 1 Receptor-associated Protein, ATRAP/Agtrap, Functions as a Selective Inhibitory Molecule of Ang II Receptor Signaling in Hypertension (2012)
  • Author(s): Tamura K, et al.
  • Organizer: 第24回国際高血圧学会“24th Scientific Meeting of the International Society of Hypertension”
  • Place of Presentation: Sydney, Australia
• [Book] 高血圧治療ガイドライン2014(JSH2014) (2014)
  • Author(s): 日本高血圧学会高血圧治療ガイドライン作成委員会（執筆委員：田村功一，他）．
  • Total Pages: 248
  • Publisher: ライフサイエンス出版（東京）
• [Book] エビデンスに基づくCKD診療ガイドライン2013 (2013)
  • Author(s): 田村功一 他．日本腎臓学会エビデンスに基づく CKD 診療ガイドライン 2013 作成委員会
  • Total Pages: 259
  • Publisher: 東京医学社
• [Book] jmedmook No. 20『あなたも名医！ 高血圧，再整理』 (2012)
  • Author(s): 田村功一，前田晃延，金岡知彦．
  • Total Pages: 195
  • Publisher: 日本医事新報社出版局
• [Book] CKD診療ガイド2012 (2012)
  • Author(s): 日本腎臓学会CKD診療ガイド2012改訂委員会
  • Total Pages: 145
  • Publisher: 東京医学社
• [Remarks] 研究成果がKidney International誌に掲載されました
  • URL: http://www.yokohama-medicine.org/news/index.html#20140508093557
• [Remarks] 日本高血圧学会Young Investigator’s Award最優秀賞を受賞しました!
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/ohsawa_2014_10.html
• [Remarks] 『Banyu Foundation Research Grant』，『先進医薬研究財団』に決定
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/wakui_20141225.html
• [Remarks] 生活習慣病にかかるとタンパク質「ATRAP」が減少する - 横市大
  • URL: http://www.excite.co.jp/News/it_biz/20130801/Cobs_ie_201308_atrap--.html
• [Remarks] 横浜市大が肥満への漢方薬効果を解明
  • URL: http://www.kanaloco.jp/article/63595/cms_id/63386