The pathophysiological significance of receptor-binding cardiovascular protective molecule in aging-associated cardiovascular diseases

• Project/Area Number: 17K09313
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Yokohama City University
• Principal Investigator: Wakui Hiromichi 横浜市立大学, 医学部, 講師 (10587330)
• Co-Investigator(Kenkyū-buntansha): 山下 暁朗 横浜市立大学, 医学部, 准教授 (20405020) ; 田村 功一 横浜市立大学, 医学研究科, 教授 (40285143)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 心血管病 / 老化 / レニンアンジオテンシン系 / 腎線維化 / サーチュイン / レニン-アンジオテンシン系 / 循環器・腎臓内科 / トランスレーショナルリサーチ

Outline of Final Research Achievements

The AT1 receptor (AT1R)-associated protein (ATRAP) is a molecule specifically interacting with the carboxyl-terminal domain of AT1R. The results of in-vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R. Accumulating evidence indicates that a tissue-specific regulatory balancing of ATRAP and AT1R expression may be involved in the modulation of AT1R pathological signaling at local tissue sites and also in the pathophysiology of aging-associated cardiovascular diseases.
We herein report that ATRAP plays an important role in inhibiting kidney aging, possibly through sirtuin1-mediated mechanism independent of blocking AT1R signaling, and further protecting normal life span.

Academic Significance and Societal Importance of the Research Achievements

ATRAPが，AT1受容体結合性機能選択的制御作用とは異なる，腎臓近位尿細管細胞に及ぼす新規機能として，腎臓線維化抑制作用、抗加齢制御作用を発揮する可能性が高いことを明らかにした．ATRAPは腎老化および個体寿命に対して保護的に作用し，その機序はアンジオテンシン非依存性でSirt1を介している可能性が示唆された.

Research Products

• [Journal Article] Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice (2020)
  • Author(s): Wakui H, Yamaji T, Azushima K, Uneda K, Haruhara K, Nakamura A, Ohki K, Kinguchi S, Kobayashi R, Urate S, Suzuki T, Kamimura D, Minegishi S, Ishigami T, Kanaoka T, Matsuo K, Miyazaki T, Fujikawa T, Yamashita A, Tamura K.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1782-1782
  • DOI: 10.1038/s41598-020-58214-0
  • Peer Reviewed / Open Access
• [Journal Article] Preliminary Report: The Relevance of Tumor Necrosis Factor-α in Acquired Primary Lymphedema?A Histopathological Investigation (2019)
  • Author(s): Asano Saori、Mikami Taro、Matsubara Shinobu、Maegawa Jiro、Wakui Hiromichi、Tamura Kouichi、Yoshimi Ryusuke
  • Journal Title: Lymphatic Research and Biology Volume: 未定 Issue: 3 Pages: 232-238
  • DOI: 10.1089/lrb.2019.0046
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin II type 1 receptor-associated protein deficiency attenuates sirtuin1 expression in an immortalised human renal proximal tubule cell line (2019)
  • Author(s): Yamaji T, Yamashita A, Wakui H, Azushima K, Uneda K, Fujikawa Y, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Ishii T, Yamada T, Urate S, Suzuki T, Abe E, Tanaka S, Kamimura D, Ishigami T, Toya Y, Takahashi H, Tamura K.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 16550-16550
  • DOI: 10.1038/s41598-019-52566-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Native T1 time and extracellular volume fraction in differentiation of normal myocardium from non-ischemic dilated and hypertrophic cardiomyopathy myocardium: A systematic review and meta-analysis (2019)
  • Author(s): Minegishi Shintaro、Kato Shingo、Takase-Minegishi Kaoru、Horita Nobuyuki、Azushima Kengo、Wakui Hiromichi、Ishigami Tomoaki、Kosuge Masami、Kimura Kazuo、Tamura Kouichi
  • Journal Title: IJC Heart & Vasculature Volume: 25 Pages: 100422-100422
  • DOI: 10.1016/j.ijcha.2019.100422
  • Peer Reviewed / Open Access
• [Journal Article] Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study). (2019)
  • Author(s): Kinguchi S, Wakui H, Ito Y, Kondo Y, Azushima K, Osada U, Yamakawa T, Iwamoto T, Yutoh J, Misumi T, Aoki K, Yasuda G, Yoshii T, Yamada T, Ono S, Shibasaki-Kurita T, Hosokawa S, Orime K, Hanaoka M, Sasaki H, Inazumi K, Yamada T, Kobayashi R, Ohki K, Haruhara K, Kobayashi Y, Yamanaka T, Terauchi Y, Tamura K.
  • Journal Title: Cardiovasc Diabetol. Volume: 18 Issue: 1 Pages: 110-110
  • DOI: 10.1186/s12933-019-0912-3
  • Peer Reviewed / Open Access
• [Journal Article] Possible interesting link between dipping status and morning surge for subclinical target organ damage in hypertension. (2019)
  • Author(s): Tamura K, Waki K, Kawai Y, Ueda E, Ishii T, Wakui H.
  • Journal Title: J Clin Hypertens (Greenwich). Volume: 21 Issue: 9 Pages: 1295-1297
  • DOI: 10.1111/jch.13637
  • Peer Reviewed / Open Access
• [Journal Article] Effects of rikkunshito on renal fibrosis and inflammation in angiotensin II-infused mice (2019)
  • Author(s): Azushima Kengo、Uneda Kazushi、Wakui Hiromichi、Ohki Kohji、Haruhara Kotaro、Kobayashi Ryu、Haku Sona、Kinguchi Sho、Yamaji Takahiro、Minegishi Shintaro、Ishigami Tomoaki、Yamashita Akio、Tamura Kouichi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 6201-6201
  • DOI: 10.1038/s41598-019-42657-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of ATRAP in Renal Proximal Tubules on Angiotensin‐Dependent Hypertension (2019)
  • Author(s): Kinguchi Sho、Wakui Hiromichi、Azushima Kengo、Haruhara Kotaro、Koguchi Tomoyuki、Ohki Kohji、Uneda Kazushi、Matsuda Miyuki、Haku Sona、Yamaji Takahiro、Yamada Takayuki、Kobayashi Ryu、Minegishi Shintaro、Ishigami Tomoaki、Yamashita Akio、Fujikawa Tetsuya、Tamura Kouichi
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 8
  • DOI: 10.1161/jaha.119.012395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early Enhanced Leucine-Rich α-2-Glycoprotein-1 Expression in Glomerular Endothelial Cells of Type 2 Diabetic Nephropathy Model Mice (2018)
  • Author(s): haku Sona、Wakui Hiromichi、Azushima Kengo、Haruhara Kotaro、Kinguchi Sho、Ohki Kohji、Uneda Kazushi、Kobayashi Ryu、Matsuda Miyuki、Yamaji Takahiro、Yamada Takayuki、Minegishi Shintaro、Ishigami Tomoaki、Yamashita Akio、Ohashi Kenichi、Tamura Kouichi
  • Journal Title: BioMed Research International Volume: 2018 Pages: 1-9
  • DOI: 10.1155/2018/2817045
  • Peer Reviewed / Open Access
• [Journal Article] An interesting cross-talk between the glucagon-like peptide-1 receptor axis and angiotensin receptor pathway for modulation of renal sodium handling in obesity (2018)
  • Author(s): Tamura Kouichi、Yamaji Takahiro、Yamada Takayuki、Ohsawa Masato、Wakui Hiromichi
  • Journal Title: Hypertension Research Volume: 41 Issue: 10 Pages: 784-786
  • DOI: 10.1038/s41440-018-0085-6
  • Peer Reviewed
• [Journal Article] Possible interesting link between Janus kinase 2 mutation and renovascular hypertension (2018)
  • Author(s): Tamura Kouichi、Haruhara Kotaro、Azushima Kengo、Iwamoto Tamio、Wakui Hiromichi
  • Journal Title: The Journal of Clinical Hypertension Volume: 20 Issue: 4 Pages: 805-806
  • DOI: 10.1111/jch.13274
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin II Type 1 Receptor-associated Protein Inhibits Angiotensin II-induced Insulin Resistance with Suppression of Oxidative Stress in Skeletal Muscle Tissue (2018)
  • Author(s): Ohki Kohji、Wakui Hiromichi、Kishio Nozomu、Azushima Kengo、Uneda Kazushi、Haku Sona、Kobayashi Ryu、Haruhara Kotaro、Kinguchi Sho、Yamaji Takahiro、Yamada Takayuki、Minegishi Shintaro、Ishigami Tomoaki、Toya Yoshiyuki、Yamashita Akio、Imajo Kento、Nakajima Atsushi、Kato Ikuma、Ohashi Kenichi、Tamura Kouichi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2846-2846
  • DOI: 10.1038/s41598-018-21270-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiotensin receptor-binding molecule in leukocytes in association with the systemic and leukocyte inflammatory profile (2018)
  • Author(s): Haruhara Kotaro、Wakui Hiromichi、Azushima Kengo、Kurotaki Daisuke、Kawase Wataru、Uneda Kazushi、Haku Sona、Kobayashi Ryu、Ohki Kohji、Kinguchi Sho、Ohsawa Masato、Minegishi Shintaro、Ishigami Tomoaki、Matsuda Miyuki、Yamashita Akio、Nakajima Hideaki、Tamura Tomohiko、Tsuboi Nobuo、Yokoo Takashi、Tamura Kouichi
  • Journal Title: Atherosclerosis Volume: 269 Pages: 236-244
  • DOI: 10.1016/j.atherosclerosis.2018.01.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Possible combinatorial effects of current smoking and alcohol intake on chronic kidney disease in a Japanese nationwide cross-sectional survey (2017)
  • Author(s): Tamura Kouichi、Dejima Toru、Morita Yukiko、Hirade Satoshi、Wakui Hiromichi
  • Journal Title: Hypertension Research Volume: 40 Issue: 8 Pages: 730-731
  • DOI: 10.1038/hr.2017.62
  • Peer Reviewed
• [Journal Article] Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice (2017)
  • Author(s): Kino Tabito、Ishigami Tomoaki、Murata Tsumugi、Doi Hiroshi、Nakashima-Sasaki Rie、Chen Lin、Sugiyama Michiko、Azushima Kengo、Wakui Hiromichi、Minegishi Shintaro、Tamura Kouichi
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 6 Pages: 1250-1250
  • DOI: 10.3390/ijms18061250
  • Peer Reviewed / Open Access
• [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] An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities (2017)
  • Author(s): Minegishi Shintaro、Ishigami Tomoaki、Kawamura Hisho、Kino Tabito、Chen Lin、Nakashima-Sasaki Rie、Doi Hiroshi、Azushima Kengo、Wakui Hiromichi、Chiba Yumi、Tamura Kouichi
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 6 Pages: 1268-1268
  • DOI: 10.3390/ijms18061268
  • Peer Reviewed / Open Access
• [Journal Article] Within-visit blood pressure variability and cardiovascular risk factors in hypertensive patients with non-dialysis chronic kidney disease (2017)
  • Author(s): Azushima Kengo、Wakui Hiromichi、Uneda Kazushi、Haku Sona、Kobayashi Ryu、Ohki Kohji、Kinguchi Sho、Haruhara Kotaro、Fujikawa Tetsuya、Toya Yoshiyuki、Umemura Satoshi、Tamura Kouichi
  • Journal Title: Clinical and Experimental Hypertension Volume: 39 Issue: 7 Pages: 665-671
  • DOI: 10.1080/10641963.2017.1313850
  • Peer Reviewed
• [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] Possible impact of electronegative LDL on atherosclerosis in type 2 diabetes (2017)
  • Author(s): Tamura Kouichi、Haruhara Kotaro、Azushima Kengo、Tokita Yasuo、Wakui Hiromichi
  • Journal Title: Atherosclerosis Volume: 265 Pages: 253-255
  • DOI: 10.1016/j.atherosclerosis.2017.08.018
  • Peer Reviewed
• [Journal Article] L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor (2017)
  • Author(s): Masukawa Daiki、Koga Motokazu、Sezaki Anna、Nakao Yuka、Kamikubo Yuji、Hashimoto Tatsuo、Okuyama-Oki Yuki、Aladeokin Aderemi Caleb、Nakamura Fumio、Yokoyama Utako、Wakui Hiromichi、Ichinose Hiroshi、Sakurai Takashi、Umemura Satoshi、Tamura Koichi、Ishikawa Yoshihiro、Goshima Yoshio
  • Journal Title: JCI Insight Volume: 2 Issue: 18 Pages: 1-16
  • DOI: 10.1172/jci.insight.90903
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Intrarenal Enhancement of Leucine-Rich α-2-Glycoprotein-1 in the Early Stage of Diabetic Nephropathy (2019)
  • Author(s): Wakui Hiromichi
  • Organizer: ASN kidney week 2019
  • Int'l Joint Research
• [Presentation] 腎臓病に対する新しい治療ターゲット 糖尿病性腎臓病合併高血圧のトピックス (2019)
  • Author(s): 涌井広道
  • Organizer: 脳心血管抗加齢研究会2019
• [Presentation] The pathophysiological role of angiotensin receptor-binding protein in hypertension and kidney disease (2019)
  • Author(s): Wakui Hiromichi
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] アンジオテンシンII1型受容体直接結合因子ATRAPは慢性腎臓病における高血圧発症に決定的な役割を示す (2017)
  • Author(s): 小林 竜, 涌井 広道, 小豆島 健護, 畝田 一司, 白 善雅, 大城 光二, 春原 浩太郎, 金口 翔, 梅村 敏, 田村 功一
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] ストレプトゾトシン誘発糖尿病腎症モデルマウスにおけるAT1受容体直接結合因子ATRAPの意義 (2017)
  • Author(s): 春原 浩太郎, 涌井 広道, 小豆島 健護, 小林 竜, 大城 光二, 金口 翔, 坪井 伸夫, 横尾 隆, 田村 功一
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] ATRAPはアンジオテンシンII1型受容体非依存性の機序により腎老化および寿命を制御する (2017)
  • Author(s): 畝田 一司, 涌井 広道, 前田 晃延, 小豆島 健護, 白 善雅, 小林 竜, 大城 光二, 春原 浩太郎, 金口 翔, 山下 暁朗, 田村 功一
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] 局所RAAS活性化はどの様にして高血圧を引き起こすのか? 慢性腎臓病での高血圧における尿細管ATRAPの役割 (2017)
  • Author(s): 涌井 広道, 小林 竜, 大澤 正人, 小豆島 健護, 畝田 一司, 大城 光二, 春原 浩太郎, 金口 翔, 山地 孝拡, 山田 貴之, 田村 功一
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] アディポネクチンプロモーター制御下1型アンジオテンシンII受容体結合因子(ATRAP)高発現マウスにおける慢性アンジオテンシンII刺激によるインスリン抵抗性の検討 (2017)
  • Author(s): 大城 光二, 涌井 広道, 大澤 正人, 小豆島 健護, 白 善雅, 畝田 一司, 小林 竜, 春原 浩太郎, 金口 翔, 山田 貴之, 山地 孝拡, 岸尾 望, 田村 功一
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] 原発性アルドステロン症における24時間自由行動下血圧測定を含めた臨床的特徴の検討 (2017)
  • Author(s): 春原 須美玲, 小豆島 健護, 大上 尚仁, 毛利 史將, 川井 有紀, 畝田 一司, 小林 竜, 山内 淳司, 谷津 圭介, 涌井 広道, 戸谷 義幸, 田村 功一
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] 高口 知之, 金口 翔, 山田 貴之, 山地 孝拡, 春原 浩太朗, 大城 光二, 白 善雅, 小林 竜, 畝田 一司, 小豆島 健護, 涌井 広道, 戸谷 義幸, 田村 功一 (2017)
  • Author(s): 近位尿細管特異的ATRAPノックアウトマウスの作製とアンジオテンシン依存性高血圧への影響
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] アンジオテンシン依存性高血圧における中枢神経系でのATRAPの病態生理学的意義 (2017)
  • Author(s): 金口 翔, 山田 貴之, 山地 孝拡, 春原 浩太朗, 大城 光二, 白 善雅, 小林 竜, 畝田 一司, 小豆島 健護, 涌井 広道, 戸谷 義幸, 田村 功一
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] 六君子湯のグレリン活性化作用に着目した腎保護効果の検討 (2017)
  • Author(s): 高山 純佳, 鈴木 将太, 中野 雅友樹, 山田 貴之, 山地 孝拡, 金口 翔, 大城 光二, 春原 浩太郎, 小林 竜, 畝田 一司, 小豆島 健護, 橋本 達夫, 涌井 広道, 戸谷 義幸, 田村 功一
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] 食塩感受性の成因に迫る 食塩感受性血圧調節におけるアンジオテンシン受容体結合蛋白の病態生理学的意義 (2017)
  • Author(s): 涌井 広道, 畝田 一司, 出島 徹, 田村 功一
  • Organizer: 第40回日本高血圧学会総会
• [Remarks] 慢性腎臓病における高血圧発症のメカニズムを解明～疾患克服のための新たな高血圧治療の可能性～
  • URL: https://www.yokohama-cu.ac.jp/amedrc/news/d0md7n0000000569-att/wakui20170110a.pdf
• [Remarks] やせ型インスリン抵抗性と骨格筋との関わりを解明～糖尿病発症抑制の新たな可能性～
  • URL: https://www.yokohama-cu.ac.jp/amedrc/news/d0md7n0000002fpk-att/20180214_Wakui.pdf
• [Funded Workshop] American Society of Nephrology (ASN) kidney Week 2018 (2018)