Molecular genetics and clinical assessment of new high sensitive measurement system for soluble angiotensin IV receptor.

• Project/Area Number: 17K09726
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: University of Fukui
• Principal Investigator: Konoshita Tadashi 福井大学, 学術研究院医学系部門, 准教授 (40270954)
• 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: レニン－アンジオテンシン系 / アンジオテンシンIV受容体 / LNPEP / 遺伝子多型 / 高血圧 / 慢性腎臓病 / 糖尿病 / 妊娠高血圧腎症（子癇前症） / レニン-アンジオテンシン系 / IRAP / 高血圧学 / アンジオテンシン受容体

Outline of Final Research Achievements

We had identified Angiotensin IV (AT4) receptor as a hypertension/diabetes specific gene through genetic DNA chip analysis. It is a component of the renin angiotensin system. At the same time, it is the same protein as insulin regulated aminopeptidase (IRAP). Thus it could be presumed that AT4 is a key molecule that mediate the blood pressure abnormality and carbohydrate dysregulation.
Accordingly we have established a high sensitivity measurement system for the AT4 with a monoclonal antibody method after polyclonal system. Actual measurements on clinical subjects revealed that the sAT4 values tended to be lower on hypertensive cases, obesity cases and dyslipidemic cases and that the sAT4 values were significantly low on CKD cases. Furthermore we revealed that a genetic variant of the AT4 associate the plasma concentrations.

Academic Significance and Societal Importance of the Research Achievements

独自に開発したAT4の高感度測定システムにより、AT4が体質的に濃度が規定されていることや各種病態と関連のあることが明らかとなった。測定方法もその成績も全く独自でかつ新しい知見である点で学術的な意義は大きいと考えられる。
また、これにより生活習慣病や妊娠中毒症などの疾患のマーカー（疾患の程度の評価や発症の予測）となり、実際の臨床に役立つ可能性がある。さらに遺伝的体質との関係を明らかにしたので、体質に応じた個別化医療（いわゆるテーラーメイド医療）の開発にも役立つことが期待され、社会的意義もあると考えられる。

Research Products

• [Int'l Joint Research] クワズルナタール大学(南アフリカ)
• [Int'l Joint Research] University of KwaZulu-Natal(南アフリカ)
• [Journal Article] Soluble angiotensin IV receptor levels in preeclampsia: is there a variation? (2020)
  • Author(s): Khaliq OP, Konoshita T, Moodley J, Ramsuran V, Naicker T
  • Journal Title: J Matern Fetal Neonatal Med Volume: - Issue: 6 Pages: 1-6
  • DOI: 10.1080/14767058.2020.1743665
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene polymorphisms of uric acid are associated with pre-eclampsia in South Africans of African ancestry. (2020)
  • Author(s): Khaliq OP, Konoshita T, Moodley J, Ramsuran V, Naicker T
  • Journal Title: Hypertens Pregnancy Volume: 39 Issue: 2 Pages: 103-116
  • DOI: 10.1080/10641955.2020.1741608
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cardiac overexpression of perilipin 2 induces atrial steatosis, connexin 43 remodeling, and atrial fibrillation in aged mice. (2019)
  • Author(s): Sato S, Suzuki J, Hirose M, Yamada M, Zenimaru Y, Nakaya T, Ichikawa M, Imagawa M, Takahashi S, Ikuyama S, Konoshita T, Kraemer FB, Ishizuka T.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 317 Issue: 6 Pages: E1193-E1204
  • DOI: 10.1152/ajpendo.00227.2019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cutting Edge アンジオテンシンIV受容体（AT4）の 高感度測定系の確立． (2019)
  • Author(s): 此下忠志
  • Journal Title: Med Sci Digest Volume: 45 Pages: 43-46
• [Journal Article] 腎泌尿器領域における内分泌性高血圧. (2019)
  • Author(s): 此下忠志
  • Journal Title: 腎臓内科・泌尿器科 Volume: 10 Pages: 3-11
• [Journal Article] BIOLOGY TOPICS：新レニン-アンジオテンシン系因子AT4の新規高感度測定系． (2019)
  • Author(s): 此下忠志
  • Journal Title: BIO Clinica Volume: 34 Pages: 66-69
• [Journal Article] <b>Progression of glucose metabolism disorder and uric acid</b> (2018)
  • Author(s): 浦邊真知，帰山沙織，中屋隆裕，山田実夏，市川麻衣，佐藤さつき，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥，此下忠志
  • Journal Title: GOUT AND NUCLEIC ACID METABOLISM Volume: 42 Issue: 1 Pages: 7-14
  • DOI: 10.6032/gnam.42.7
  • NAID: 130007420069
  • ISSN: 1344-9796, 2186-6368
  • Year and Date: 2018-07-25
  • Peer Reviewed / Open Access
• [Journal Article] <b>SLC2A9（GLUT9）遺伝子多型とレニン−アンジオテンシン系活性化に関するメンデルランダム化法による関連解析</b> (2018)
  • Author(s): 此下忠志，浦邊真知，牧野耕和
  • Journal Title: GOUT AND NUCLEIC ACID METABOLISM Volume: 42 Issue: 1 Pages: 73-74
  • DOI: 10.6032/gnam.42.73
  • NAID: 130007419997
  • ISSN: 1344-9796, 2186-6368
  • Year and Date: 2018-07-25
  • Peer Reviewed / Open Access
• [Journal Article] The role of uric acid in preeclampsia: Is uric acid a causative factor or a sign of preeclampsia? (2018)
  • Author(s): Khaliq OP, Konoshita T, Moodley J, Naicker T
  • Journal Title: Curr Hypertens Rep Volume: 20 Issue: 9
  • DOI: 10.1007/s11906-018-0878-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship between screen time and nutrient intake in Japanese children and adolescents: a cross-sectional observational study. (2018)
  • Author(s): Tsujiguchi H, Hori D, Kambayashi Y, Hamagishi T, Asakura H, Mitoma J, Kitaoka M, Anyenda EO, Nguyen TT, Yamada Y, Hayashi K, Konoshita T, Sagara T, Shibata A, Sasaki S, Nakamura H
  • Journal Title: Environ Health Prev Med Volume: 23 Issue: 1
  • DOI: 10.1186/s12199-018-0725-0
  • NAID: 50012994944
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between the Use of Parabens and Allergic Diseases in Japanese Adults-A Cross-Sectional Study. (2018)
  • Author(s): Shimizu Y, Kambayashi Y, Tsujiguchi H, Hori D, Nguyen TT, Suzuki F, Hamagishi T, Yamada Y, Nakamura H, Yoshikawa T, Hayashi K, Hibino Y, Shibata A, Fukutomi Y, Ohya Y, Yamamoto-Hanada K, Muto G, Hirota R, Konoshita T, Nakamura H
  • Journal Title: J-Multidiciplin Sci J Volume: 1 Issue: 1 Pages: 148-158
  • DOI: 10.3390/j1010014
  • Peer Reviewed / Open Access
• [Journal Article] 病態とリスク因子対策 高血圧症における血漿レニン活性，レニン遺伝子と心腎血管疾患との関連. (2018)
  • Author(s): 此下忠志
  • Journal Title: 循環plus Volume: 18 Pages: 7-9
• [Journal Article] Association of gene polymorphisms of aldosterone synthase and angiotensin converting enzyme in pre-eclamptic South African black women (2018)
  • Author(s): Aung M, Konoshita T, Moodley J, Gathiram P
  • Journal Title: Pregnancy Hyperten Volume: 11 Pages: 38-43
  • DOI: 10.1016/j.preghy.2017.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Association of gene polymorphisms of four components of renin-angiotensin-aldosterone system and preeclampsia in South African black women. (2017)
  • Author(s): Aung M, Konoshita T, Moodley J, Gathiram P
  • Journal Title: Eur J Obst Gynecol Reprod Biol Volume: 215 Pages: 180-187
  • DOI: 10.1016/j.ejogrb.2017.05.011
  • Peer Reviewed
• [Journal Article] Cardiac overexpression of perilipin 2 induces dynamic steatosis: Prevention by hormone-sensitive lipase. (2017)
  • Author(s): Ueno M, Suzuki J, Hirose M, Sato S, Imagawa M, Zenimaru Y, Takahashi S, Ikuyama S, Koizumi T, Konoshita T, Kraemer F, Ishizuka T
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 313 Issue: 6 Pages: E699-E709
  • DOI: 10.1152/ajpendo.00098.2017
  • Peer Reviewed
• [Journal Article] Sex- and age-specific associations of social status and health-related behaviors with health check attendance: findings from the cross-sectional Kanazawa Study. (2017)
  • Author(s): Tsujiguchi H, Hori D, Kambayashi Y, Hamagishi T, Asakura H, Mitoma J, Kitaoka M, Olando AE, Thao NTT, Yamada Y, Hayashi K, Konoshita T, Sagara T, Shibata A, Nakamura H
  • Journal Title: Health Volume: 9 Issue: 09 Pages: 1285-1300
  • DOI: 10.4236/health.2017.99093
  • Peer Reviewed / Open Access
• [Journal Article] <b>メタボリックシンドローム進展の観点からみた血糖値と尿酸値との関係について</b> (2017)
  • Author(s): 浦邊真知，帰山沙織，中屋隆裕，山田実夏，市川麻衣，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥，此下忠志
  • Journal Title: GOUT AND NUCLEIC ACID METABOLISM Volume: 41 Issue: 1 Pages: 78-79
  • DOI: 10.6032/gnam.41.78
  • NAID: 130005859017
  • ISSN: 1344-9796, 2186-6368
  • Open Access
• [Journal Article] <b>高尿酸血症と高血圧・生活習慣病 </b> (2017)
  • Author(s): よく分かるシリーズ３ 高尿酸血症と高血圧・生活習慣病
  • Journal Title: GOUT AND NUCLEIC ACID METABOLISM Volume: 41 Issue: 2 Pages: 231-232
  • DOI: 10.6032/gnam.41.231
  • NAID: 130006258946
  • ISSN: 1344-9796, 2186-6368
  • Open Access
• [Journal Article] 心腎血管病予防のための生活習慣病診療 －人工血液透析患者さん増加の歯止めに向けて－ (2017)
  • Author(s): 此下忠志
  • Journal Title: 日本予防医学会雑誌 Volume: 11 Pages: 87-92
  • NAID: 40021326778
  • Peer Reviewed
• [Journal Article] 尿酸とメタボリックシンドローム・高血圧－レニン-アンジオテンシン系の関与－ (2017)
  • Author(s): 此下忠志，浦邊真知
  • Journal Title: 高尿酸血症と痛風 Volume: 25 Pages: 111-116
  • Peer Reviewed
• [Presentation] Genetic association study of uromodulin and serum uric acid concentration and blood pressure. (2019)
  • Author(s): Konoshita T, Azuma S, Kasahara M, Furutani M, Kaeriyama S, Nakaya T, Yamada M, Ichikawa M, Sato S, Imagawa M, Zenimaru Y, Suzuki J, Fujii M, Makino Y, Onoe T
  • Organizer: 29th European Meeting on Hypertension
  • Int'l Joint Research
• [Presentation] 生活習慣病症におけるウロモジュリン遺伝子の相関解析． (2019)
  • Author(s): 此下忠志，東 慎一郎，笠原美沙子，浦邊真知，帰山沙織，中屋隆裕，山田実夏，市川麻衣，山本勝司，佐藤さつき，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] 尿酸分泌調節関連分子PDZK1の遺伝子多型と糖尿病性腎症の関連解析． (2019)
  • Author(s): 笠原美佐子，此下忠志，鈴木仁弥，銭丸康夫，牧野耕和，藤井美紀，今川美智子，佐藤さつき，山本勝司，市川麻衣，山田実夏，中屋隆裕，浦邉真知，帰山沙織，東慎一郎
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] ウロモジュリン遺伝子多型による尿酸と血圧の関係に関するメンデルランダム化法による関連解析． (2019)
  • Author(s): 此下忠志，東慎一郎，杉山光寿，笠原美沙子，古谷真知，帰山沙織，中屋隆裕，山田実夏，市川麻衣，斉藤理恵，佐藤さつき，今川美智子，銭丸康夫，鈴木仁弥，藤井美紀，牧野耕和
  • Organizer: 第42回日本高血圧学会総会
• [Presentation] 尿酸代謝・血圧値に関するウロモジュリン遺伝子の相関解析． (2019)
  • Author(s): 此下忠志，浦邊真知，佐藤さつき，銭丸康夫，藤井美紀，牧野耕和
  • Organizer: 第52回日本痛風・核酸代謝学会
• [Presentation] Association study of uric acid transporter GLUT9 genotype with the renin-angiotensin system. (2018)
  • Author(s): Konoshita T, Urabe M, Kaeriyama S, Nakaya T, Yamada M, Ichikawa M, Sato S, Yamamoto K, Imagawa M, Fujii M, Makino Y, Zenimaru Y, Suzuki J
  • Organizer: 28th European Meeting on Hypertension
  • Int'l Joint Research
• [Presentation] Genetic variation in the renin-angiotensin-aldosterone system and renal survival in Japanese patients with diabetic nephropathy. (2018)
  • Author(s): Makino Y, Konoshita T, Fujii M
  • Organizer: 28th European Meeting on Hypertension
  • Int'l Joint Research
• [Presentation] Heart-specific overexpression of HMG-CoA synthase 2 induces mitochondrial stress-Adaptation via the ATF4 pathway. (2018)
  • Author(s): Zenimaru Y, Suzuki J, Nakaya T, Yamada M, Ichikawa M, Sato S, Imagawa M, Kramer FB, Konoshita T, Ishizuka T
  • Organizer: American Diabetes Association 78th scientific sessions
  • Int'l Joint Research
• [Presentation] Overexpression of perilipin 2 induces cardiac steatosis and atrial fibrillation via connexin 43 remodeling. (2018)
  • Author(s): Sato S, Suzuki J, Hirose M, Nakaya T, Yamada M, Ichikawa M, Imagawa M, Zenimaru Y, Takahashi S, Kramer FB, Konoshita T, Ishizuka T
  • Organizer: American Diabetes Association 78th scientific sessions
  • Int'l Joint Research
• [Presentation] Effects of hormone-sensitive lipase overexpression on lipotoxic cardiomyopathy in mice lacking adipose triglyceride lipase. (2018)
  • Author(s): Yamada M, Suzuki J, Hirose M, Nakaya T, Ichikawa M, Sato S, Imagawa M, Zenimaru Y, Kramer FB, Konoshita T, Ishizuka T
  • Organizer: American Diabetes Association 78th scientific sessions
  • Int'l Joint Research
• [Presentation] GLUT9（SLC2A9）遺伝子多型とレニン-アンジオテンシン系活性化に関するメンデルランダム化法による関連解析． (2018)
  • Author(s): 此下忠志，浦邊真知，帰山沙織，中屋隆裕，山田実夏，市川麻衣，山本勝司，佐藤さつき，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] SGLT2（SLC5A2）遺伝子多型と肥満度指数の相関解析． (2018)
  • Author(s): 浦邊真知，帰山沙織，中屋隆裕，山田実夏，市川麻衣，山本勝司，佐藤さつき，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥，此下忠志
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] ATP binding cassette subfamily G member 2（ABCG2）遺伝子多型と糖尿病性腎症の関連解析． (2018)
  • Author(s): 帰山沙織，浦邊真知，中屋隆裕，山田実夏，市川麻衣，山本勝司，佐藤さつき，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥，此下忠志
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] SLC2A9 (GLUT9)遺伝子多型とレニン-アンジオテンシン系活性化に関するメンデルランダム化法による関連解析 (2018)
  • Author(s): 此下忠志，浦邊真知，牧野耕和
  • Organizer: 第51回日本痛風・核酸代謝学会
• [Presentation] Genetic variant of angiotensin IV receptor (AT4) and plasma angiotensin II concentration. (2017)
  • Author(s): Konoshita T, Kaeriyama S, Urabe M, Nakaya T, Yamada M, Ichikawa M, Sato S, Yamamoto K, Imagawa M, Fujii M, Makino Y, Zenimaru Y, Suzuki J
  • Organizer: 27th European Meeting on Hypertension
  • Int'l Joint Research
• [Presentation] A genetic variant in the distal enhancer region of the human renin gene affects renin expression. (2017)
  • Author(s): Makino Y, Konoshita T, Nakaya T, Ichikawa M, Yamamoto K,Wakanhara S, Ishizuka T
  • Organizer: 27th European Meeting on Hypertension
  • Int'l Joint Research
• [Presentation] An association study between a novel component of the renin-angiotensin system, Chromosome 9 Open Reading Frame 3 (C9orf3) and prevalence of hypertension among subjects with type 2 diabetes mellitus. (2017)
  • Author(s): Ichikawa M, Konoshita T, Urabe M, Kaeriyama S, Nakaya T, Yamada M, Yamamoto K, Sato S, Imagawa M, Makino Y, Fujii M, Zenimaru Y, Suzuki J
  • Organizer: 27th European Meeting on Hypertension
  • Int'l Joint Research
• [Presentation] Insulin regulated aminopeptidase/Angiotensin IV receptor（IRAP/AT4）遺伝子多型と血中angiotensin II濃度 (2017)
  • Author(s): 此下忠志，帰山沙織，浦邊真知，中屋隆裕，山田実夏，市川麻衣，佐藤さつき，今川美智子，藤井美紀，牧野耕和，銭丸康夫，鈴木仁弥
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] アンジオテンシンIV 受容体（AT4）遺伝子多型と血漿アンジオテンシンII濃度 (2017)
  • Author(s): 此下忠志，帰山沙織，浦邊真知，中屋隆裕，山田実夏，市川麻衣，山本勝司，佐藤さつき，今川美智子，牧野耕和，銭丸康夫，鈴木仁弥
  • Organizer: 第40回日本高血圧学会総会
• [Book] 福井大学病院の得意な治療がわかる本―最高・最新の医療を安心と信頼の下で/生活習慣病のスペシャリストによる最高・最新の治療―特殊な高血圧が見逃されています (2017)
  • Author(s): 此下忠志
  • Total Pages: 160
  • Publisher: 株式会社バリューメディカル
• [Book] 福井大学病院の得意な治療がわかる本―最高・最新の医療を安心と信頼の下で/脂質異常症―動脈硬化を起こさない！最新の治療を (2017)
  • Author(s): 鈴木仁弥，此下忠志
  • Total Pages: 160
  • Publisher: 株式会社バリューメディカル
• [Book] 福井大学病院の得意な治療がわかる本―最高・最新の医療を安心と信頼の下で/糖尿病の最新の診療 (2017)
  • Author(s): 銭丸康夫，此下忠志
  • Total Pages: 160
  • Publisher: 株式会社バリューメディカル