The pathophysiological significance of receptor-binding molecule in cardiovascular diseases based on insulin resistance

• Project/Area Number: 19K21318
• Project/Area Number (Other): 18H06215 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Yokohama City University
• Principal Investigator: Kohji Ohki 横浜市立大学, 医学研究科, 客員研究員 (60828713)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 高血圧 / アンジオテンシン受容体 / 尿細管 / インスリン抵抗性 / レニン・アンジオテンシン系 / レニンーアンジオテンシン系

Outline of Research at the Start

1型アンジオテンシンII受容体(AT1受容体)の過剰活性化は、インスリン抵抗性を基盤とする高血圧・脂質異常症・糖尿病の発症・進展に関わる。AT1受容体への新規結合分子ATRAP(AT1 receptor-associated protein)について、組織局所での発現・活性化が、インスリン抵抗性を基盤とする高血圧・脂質異常症・糖尿病の発症・進展を制御できる、との仮説を検証するべく、病態モデル動物、組織特異的ATRAP発現制御動物などをもちいて、ATRAPの病態生理学的意義を生体レベルで明らかにし、ATRAPに着目した新規分子標的治療開発に向けた多面的な基礎的知見を得ることを目指す。

Outline of Final Research Achievements

The AT1 receptor (AT1R)-associated protein (ATRAP) is a molecule specifically interacting with the carboxyl-terminal domain of AT1R so as to inhibit hyperactivation of its downstream signaling.Although ATRAP expression is abundant in renal proximal tubules, little is known about the actual function of renal proximal tubule ATRAP in angiotensin II-mediated hypertension. We generated proximal tubule specific ATRAP knockout (PT-KO) mice using the Cre/loxP system with Pepck-Cre. ATRAP mRNA expression decreased by 80% in proximal regions of the nephron in PT-KO mice compared with wild-type (WT) mice. Blood pressure of PT-KO mice was comparable with that of WT mice at baseline. Moreover, no significant differences were noted in pressor response and cardiac hypertrophy to angiotensin II infusion between PT-KO and WT mice. The results indicate that renal proximal tubule ATRAP has a minor role in angiotensin II-mediated hypertension.

Academic Significance and Societal Importance of the Research Achievements

今回の実験結果と我々の過去の報告を総合すると、アンジオテンシン依存性高血圧の病態形成に腎近位尿細管ATRAPが果たす役割は小さく、腎ATRAPは主に腎遠位尿細管ATRAPを介したメカニズムによりアンジオテンシン依存性高血圧を抑制すると考えられた。

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] 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] 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] 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] 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
• [Presentation] 腎近位尿細管AT1受容体結合因子がアンジオテンシン依存性高血圧に及ぼす影響(Effects of AT1 Receptor-Associated Protein in Renal Proximal Tubules on Angiotensin II-Mediated Hypertension) (2019)
  • Author(s): 金口 翔, 涌井 広道, 小豆島 健護, 春原 浩太郎, 高口 知之, 大城 光二, 畝田 一司, 白 善雅, 山地 孝拡, 山田 貴之, 小林 竜, 石上 友章, 山下 暁朗, 藤川 哲也, 田村 功一
  • Organizer: 第42回日本高血圧学会総会
• [Presentation] 横浜市立大学附属病院腎臓・高血圧内科における入院患者データベース構築の取り組み (2019)
  • Author(s): 金岡 知彦, 大上 尚仁, 平塚 梨奈, 春原 須美玲, 角田 剛一朗, 花岡 正哲, 金口 翔, 大城 光二, 畝田 一司, 小林 竜, 涌井 広道, 戸谷 義幸, 田村 功一
  • Organizer: 第8回臨床高血圧フォーラム
• [Presentation] 漢方薬「六君子湯」による腎保護効果の検討 (2019)
  • Author(s): 畝田 一司, 小豆島 健護, 涌井 広道, 大城 光二, 春原 浩太郎, 小林 竜, 金口 翔, 山地 孝拡, 浦手 進吾, 田村 功一
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] 迅速ACTH負荷試験により診断に至った原発性アルドステロン症の1例 (2019)
  • Author(s): 竹之内 陽子, 大城 光二, 大上 尚仁, 平塚 梨奈, 春原 須美玲, 花岡 正哲, 小林 竜, 畝田 一司, 金岡 知彦, 涌井 広道, 戸谷 義幸, 田村 功一
  • Organizer: 第8回臨床高血圧フォーラム