New therapeutic strategy of hypertension in chronic kidney disease by functionally selective modulation of inflammatory signaling via receptor binding molecule

• Project/Area Number: 15K09293
• 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, 医学研究科, 教授 (40285143)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 慢性腎臓病 / 高血圧 / 受容体結合因子 / 上皮性ナトリウムチャネル / 炎症性サイトカイン / 分子機序 / 新規受容体結合因子 / 血管作動物質 / 遺伝子発現 / 情報伝達系制御

Outline of Final Research Achievements

We provided evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease (CKD). While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that down-regulation of renal ATRAP expression is involved in pathogenesis of hypertension in CKD. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on hypertension-resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel and tumor necrosis factor-α was significantly enhanced. Thus, renal ATRAP down-regulation is involved in the onset and progression of BP elevation in CKD, and it implicates ATRAP as a therapeutic target for hypertension in CKD.

Research Products

• [Journal Article] An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model. (2017)
  • Author(s): Kobayashi R, Wakui H, Azushima K, Uneda K, Haku S, Ohki K, Haruhara K, Kinguchi S, Matsuda M, Ohsawa M, Toya Y, Nishiyama A, Yamashita A, Tanabe K, Maeshima Y, Umemura S, Tamura K.
  • Journal Title: Kidney Int. Volume: 91 Issue: 5 Pages: 1115-1125
  • DOI: 10.1016/j.kint.2016.10.035
  • Peer Reviewed
• [Journal Article] Adipocyte-Specific Enhancement of Angiotensin II Type 1 Receptor-Associated Protein Ameliorates Diet-Induced Visceral Obesity and Insulin Resistance. (2017)
  • Author(s): Azushima K, Ohki K, Wakui H, Uneda K, Haku S, Kobayashi R, Haruhara K, Kinguchi S, Matsuda M, Maeda A, Toya Y, Yamashita A, Umemura S, Tamura K.
  • Journal Title: J Am Heart Assoc. Volume: 6 Issue: 3
  • DOI: 10.1161/jaha.116.004488
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice (2017)
  • Author(s): Wakui H, Ohki K, Azushima K, Uneda K, Haku S, Kobayashi R, Haruhara K, Kinguchi S, Matsuda M, Ohsawa M, Maeda A, Minegishi S, Ishigami T, Toya Y, Yamashita A, Umemura S, Tamura K
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 3 Pages: 676-676
  • DOI: 10.3390/ijms18030676
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancement of intrarenal plasma membrane calcium pump isoform 1 expression in chronic angiotensin II-infused mice (2017)
  • Author(s): Wakui Hiromichi、Sumida Koichiro、Fujita Megumi、Ohtomo Yuta、Ohsawa Masato、Kobayashi Ryu、Uneda Kazushi、Azushima Kengo、Haruhara Kotaro、Yatsu Keisuke、Hirawa Nobuhito、Minegishi Shintaro、Ishigami Tomoaki、Umemura Satoshi、Tamura Kouichi
  • Journal Title: Physiological Reports Volume: 5 Issue: 11 Pages: e13316-e13316
  • DOI: 10.14814/phy2.13316
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiotensin II Type 1 Receptor‐Associated Protein Regulates Kidney Aging and Lifespan Independent of Angiotensin (2017)
  • Author(s): Uneda Kazushi、Wakui Hiromichi、Maeda Akinobu、Azushima Kengo、Kobayashi Ryu、Haku Sona、Ohki Kohji、Haruhara Kotaro、Kinguchi Sho、Matsuda Miyuki、Ohsawa Masato、Minegishi Shintaro、Ishigami Tomoaki、Toya Yoshiyuki、Atobe Yoshitoshi、Yamashita Akio、Umemura Satoshi、Tamura Kouichi
  • Journal Title: Journal of the American Heart Association Volume: 6 Issue: 8
  • DOI: 10.1161/jaha.117.006120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 36.Effect of Single-pill Irbesartan/Amlodipine Combination-Based Therapy on Clinic and Home Blood Pressure Profiles in Hypertension with Chronic Kidney Disease (2016)
  • Author(s): Kobayashi R, Tamura K, Wakui H, Ohsawa M, Azushima K, Haku S, Uneda K, Ohki K, Haruhara K, Kinguchi S, Umemura S
  • Journal Title: Clinical and experimental hypertension Volume: 38 Issue: 8 Pages: 744-750
  • DOI: 10.1080/10641963.2016.1200063
  • Peer Reviewed / Open Access
• [Journal Article] 37.Comparison of Direct Renin inhibitor and Angiotensin II Receptor Blocker on Clinic and Ambulatory Blood Pressure Profiles in Hypertension with Chronic Kidney Disease (2016)
  • Author(s): Uneda K, Tamura K, Wakui H, Azushima K, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Ohsawa M, Fujikawa T, Umemura S
  • Journal Title: Clinical and experimental hypertension Volume: 38 Issue: 8 Pages: 738-743
  • DOI: 10.1080/10641963.2016.1200064
  • Peer Reviewed / Open Access
• [Journal Article] Dual inhibitory action on aldosterone by combined angiotensin receptor antagonism and neprilysin inhibition. (2016)
  • Author(s): Tamura K, Kobayashi R, Haku S, Azushima K, Wakui H.
  • Journal Title: Hypertens Res. Volume: 39 Issue: 11 Pages: 753-755
  • DOI: 10.1038/hr.2016.71
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Potential beneficial impact of angiotensin receptor blockers on arterial stiffness in hypertension. (2016)
  • Author(s): Tamura K, Kishio N, Haruhara K, Uneda K, Azushima K, Wakui H.
  • Journal Title: J Thorac Dis. Volume: 8 Issue: 7 Pages: E564-E566
  • DOI: 10.21037/jtd.2016.05.10
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The lesson of ankle-brachial index for long-term clinical outcomes: Time is not a line, but a series of now-points. (2016)
  • Author(s): Trovato GM, Tamura K.
  • Journal Title: Atherosclerosis. Volume: 250 Pages: 186-188
  • DOI: 10.1016/j.atherosclerosis.2016.05.013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Circadian blood pressure rhythm as a possible key target of SGLT2 inhibitors used for the treatment of Type 2 diabetes. (2016)
  • Author(s): Tamura K, Wakui H, Azushima K, Uneda K, Umemura S.
  • Journal Title: Hypertens Res. Volume: 39 Issue: 6 Pages: 396-398
  • DOI: 10.1038/hr.2016.1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TLR4 as a possible key regulator of pathological vascular remodeling by Ang II receptor activation. (2016)
  • Author(s): Tamura K, Kanaoka T, Kobayashi R, Ohki K, Ohsawa M.
  • Journal Title: Hypertens Res. Volume: 38 Issue: 10 Pages: 642-643
  • DOI: 10.1038/hr.2015.65
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of pitavastatin add-on therapy on chronic kidney disease with albuminuria and dyslipidemia. (2015)
  • Author(s): Ohsawa M, Tamura K, Wakui H, Kanaoka T, Azushima K, Uneda K, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Toya Y, Umemura S.
  • Journal Title: Lipids Health Dis. Volume: 14 Issue: 1 Pages: 161-161
  • DOI: 10.1186/s12944-015-0164-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Possible therapeutic impact of the iron chelation on renal fibrosis. (2015)
  • Author(s): Tamura K, Uneda K, Azushima K, Wakui H, Haruhara K.
  • Journal Title: Hypertens Res. Volume: 38 Issue: 7 Pages: 455-456
  • DOI: 10.1038/hr.2015.60
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: a multicenter, randomized, parallel-group controlled trial. (2015)
  • Author(s): Azushima K, Tamura K, Haku S, Wakui H, Kanaoka T, Ohsawa M, Uneda K, Kobayashi R, Ohki K, Dejima T, Maeda A, Hashimoto T, Oshikawa J, Kobayashi Y, Nomura K, Azushima C, Takeshita Y, Fujino R, Uchida K, Shibuya K, Ando D, Tokita Y, Fujikawa T, Toya Y, Umemura S.
  • Journal Title: Atherosclerosis. Volume: 240 Issue: 1 Pages: 297-304
  • DOI: 10.1016/j.atherosclerosis.2015.01.025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Renal Tubule Angiotensin II Type 1 Receptor-Associated Protein Promotes Natriuresis and Inhibits Salt-Sensitive Blood Pressure Elevation. (2015)
  • Author(s): Wakui H, Uneda K, Tamura K, Ohsawa M, Azushima K, Kobayashi R, Ohki K, Dejima T, Kanaoka T, Tsurumi-Ikeya Y, Matsuda M, Haruhara K, Nishiyama A, Yabana M, Fujikawa T, Yamashita A, Umemura S.
  • Journal Title: J Am Heart Assoc. Volume: 19;4(3) Issue: 3 Pages: 1-14
  • DOI: 10.1161/jaha.114.001594
  • Peer Reviewed / Open Access
• [Presentation] Angiotensin II Type 1 Receptor Interacting Molecule ATRAP Plays a Role in Renal Sodium Handling and Blood Pressure Regulation (2016)
  • Author(s): Kouichi Tamura
  • Organizer: The 26th Scientific Meeting of the International Society of Hypertension (ISH 2016)
  • Place of Presentation: ソウル、韓国
  • Year and Date: 2016-09-24
  • Int'l Joint Research
• [Presentation] Potential novel approach via functionally selective modulation of angiotensin receptor signaling : Focus on angiotensin receptor-binding molecule ATRAP (2016)
  • Author(s): Kouichi Tamura
  • Organizer: The ISH 2016 satellite symposium, Renin-angiotensin-aldosterone system (RAAS)
  • Place of Presentation: コングレスクエア日本橋（東京都）
  • Year and Date: 2016-09-23
  • Int'l Joint Research / Invited
• [Presentation] 後期高齢者の降圧目標:何をターゲットにどこまで下げるか：積極的な降圧を推奨する立場から (2016)
  • Author(s): 田村功一
  • Organizer: 第58回日本老年医学会（シンポジウム）
  • Place of Presentation: ANAクラウンプラザホテル金沢他（石川県金沢市）
  • Year and Date: 2016-06-08
  • Invited
• [Presentation] Effects of systemic deletion of angiotensin receptor-binding molecule on the aging kidney. (2015)
  • Author(s): Uneda K, Tamura K, Wakui H, Maeda A, Azushima K, Haku S, Kobayashi R, Ohsawa M, Toya Y, Umemura S.
  • Organizer: ASN Kidney Week 2015, American Society of Nephrology．
  • Place of Presentation: San Diego, 米国
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] Effects of systemic deletion of angiotensin receptor-binding molecule on the aging kidney. (2015)
  • Author(s): Uneda K, Tamura K, Wakui H, Maeda A, Azushima K, Haku S, Kobayashi R, Ohsawa M, Toya Y, Umemura S.
  • Organizer: ASN Kidney Week 2015, American Society of Nephrology
  • Place of Presentation: San Diego, 米国
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] Leucine-rich glycoprotein 1: A candidate biomarker for early renal function decline in type 2 diabetes. (2015)
  • Author(s): Haku S, Tamura K, Xu JW, Cavallin C, Wakui H, Azushima K, Uneda K, Kobayashi R, Haruhara K, Simonson MS, Umemura S.
  • Organizer: ASN Kidney Week 2015, American Society of Nephrology
  • Place of Presentation: San Diego, 米国
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] Toward development of novel therapeutic approach via functionally selective modulation of angiotensin receptor signaling: Focus on angiotensin receptor-binding protein ATRAP． (2015)
  • Author(s): 田村功一，涌井広道，小豆島健護，畝田一司，白 善雅，小林 竜，大城光二，春原浩太郎，金口 翔，大澤正人，前田晃延，金岡知彦，松田みゆき，山下暁朗，梅村 敏．
  • Organizer: 第38回日本高血圧学会総会
  • Place of Presentation: ひめぎんホール，愛媛県，松山市
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] Angiotensin receptor-binding protein ATRAP as a possible candidate for therapeutic strategy of functionally selective modulation of angiotensin receptor signaling. (2015)
  • Author(s): Tamura K, Wakui H, Azushima K, Uneda K, Kobayashi R, Ohki K, Haku S, Haruhara K, Kinguchi S, Ohsawa M, Maeda A, Kanaoka T, Umemura S.
  • Organizer: American Heart Association and American Stroke Association Council on Hypertension 2015 Scientific Sessions .
  • Place of Presentation: Washington DC, 米国
  • Year and Date: 2015-09-16
  • Int'l Joint Research
• [Book] 血圧変動 エビデンス＆プラクティス (2016)
  • Author(s): 田村功一
  • Total Pages: 215
  • Publisher: 先端医学社
• [Book] 日本内科学会雑誌：特集 慢性腎臓病と心血管系疾患 (2016)
  • Author(s): 田村功一
  • Total Pages: 150
  • Publisher: 日本内科学会
• [Book] 循環器内科：閉塞性動脈硬化症に対するLDL吸着療法：正コレステロール血症を呈する従来治療抵抗性閉塞性動脈硬化症に対するデキストラン硫酸カラムを用いたLDLアフェレシス療法(先進医療B: LETS-PAD 研究) (2016)
  • Author(s): 田村功一，植田瑛子，大澤正人，菅野晃靖，戸谷義幸
  • Total Pages: 98
  • Publisher: 科学評論社
• [Remarks] 慢性腎臓病悪化の主役である高血圧発症の鍵となるメカニズムを解明！
  • URL: http://www.yokohama-cu.ac.jp/amedrc/news/2017011_wakui.html
• [Remarks] 日本腎臓学会平成29年度若手研究者賞（YIA）を受賞しました
  • URL: https://www.jsn.or.jp/topics/notice/_3269.php
• [Remarks] 日本高血圧学会総会（松山）において，YIA優秀賞を受賞し表彰されました
  • URL: http://www.congre.co.jp/40jsh/
• [Remarks] 脂肪細胞機能制御による生活習慣病の新規治療の可能性を発表
  • URL: http://www.yokohama-medicine.org/news/
• [Remarks] 循環器・腎臓内科学田村功一准教授ら研究グループが肥満・動脈硬化症の原因を改善することを発見
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/tamura_2015_03.html
• [Patent(Industrial Property Rights)] 寿命短縮化モデル非ヒト哺乳動物 (2015)
  • Inventor(s): 田村功一，涌井広道，畝田一司，前田晃延
  • Industrial Property Rights Holder: 田村功一，涌井広道，畝田一司，前田晃延
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-103747
  • Filing Date: 2015-05-21