Significance for epigenomic regulation of renal gene expressions in the onset of salt-induced hypertension.

• Project/Area Number: 17K09735
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Keio University
• Principal Investigator: MIYASHITA Kazutoshi 慶應義塾大学, 医学部(信濃町), 特任准教授 (50378759)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 高血圧 / 塩分負荷 / 高血圧自然発症ラット / 記憶現象 / エピゲノム / ヒストンアセチル化 / 腎細動脈 / MMP2 / Sirt3 / 腸管塩分吸収 / 加齢 / NHE3 / 腸管 / ナトリウム吸収 / 循環器・高血圧

Outline of Final Research Achievements

We found a salt memory phenomenon in which spontaneously hypertensive rats (SHR) were subjected to transient salt loading and the systolic blood pressure was persistently increased even after discontinuation of the salt loading. In the present study, we investigated the significance for epigenetic modification of chromatin in persistent increase in the blood pressure after salt loading. Following transient salt loading, renal arteriole-specific epigenetic alterations persist, and histone acetylation-mediated MMP2 upregulation in the renal arterioles might promote medial hypertrophy which lead to renin hypersecretion and persistent elevation in the blood pressure.

Academic Significance and Societal Importance of the Research Achievements

申請者の研究室では、高血圧自然発症ラット(SHR)に一過性の塩分負荷を与えると、塩分負荷中止後も血圧が持続的に上昇することを見出し、腎細動脈の中膜肥厚に伴うレニン分泌の亢進が、血圧上昇の本態となる可能性を指摘した[Oguchi Hypertension. 2014]。本研究では腎臓のエピゲノム変容について解析し、塩分負荷に伴う腎細動脈リモデリングや、Na輸送の変容に関与するクロマチンエピゲノム修飾を同定した。この知見は、腎のエピゲノム変容を治療標的とした、新しい高血圧治療戦略の開発につながるものである。

Research Products

• [Journal Article] Effects of exercise on residual renal function in patients undergoing peritoneal dialysis: A post‐hoc analysis of a randomized controlled trial (2020)
  • Author(s): Uchiyama Kiyotaka、Washida Naoki、Morimoto Kohkichi、Muraoka Kaori、Nakayama Takashin、Adachi Keika、Kasai Takahiro、Miyashita Kazutoshi、Wakino Shu、Itoh Hiroshi
  • Journal Title: Therapeutic Apheresis and Dialysis Volume: . Issue: 6 Pages: 668-676
  • DOI: 10.1111/1744-9987.13481
  • Peer Reviewed
• [Journal Article] Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides. (2019)
  • Author(s): Fujii K, Kubo A, Miyashita K, Sato M, Hagiwara A, Inoue H, Ryuzaki M, Tamaki M, Hishiki T, Hayakawa N, Kabe Y, Itoh H, Suematsu M.
  • Journal Title: JCI insight Volume: 4 Issue: 22 Pages: 124816-124816
  • DOI: 10.1172/jci.insight.124816
  • Peer Reviewed / Open Access
• [Journal Article] Home-based Aerobic Exercise and Resistance Training in Peritoneal Dialysis Patients: A Randomized Controlled Trial (2019)
  • Author(s): Uchiyama Kiyotaka、Washida Naoki、Morimoto Kohkichi、Muraoka Kaori、Kasai Takahiro、Yamaki Kentaro、Miyashita Kazutoshi、Wakino Shu、Itoh Hiroshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2632-2632
  • DOI: 10.1038/s41598-019-39074-9
  • Peer Reviewed / Open Access
• [Journal Article] Pre-emptive medicine for hypertension and its prospects (2018)
  • Author(s): Itoh Hiroshi、Hayashi Kaori、Miyashita Kazutoshi
  • Journal Title: Hypertension Research Volume: 42 Issue: 3 Pages: 301-305
  • DOI: 10.1038/s41440-018-0177-3
  • Peer Reviewed
• [Journal Article] Exercise Capacity and Association with Quality of Life in Peritoneal Dialysis Patients (2018)
  • Author(s): Uchiyama Kiyotaka、Washida Naoki、Muraoka Kaori、Morimoto Kohkichi、Kasai Takahiro、Yamaki Kentaro、Miyashita Kazutoshi、Wakino Shu、Itoh Hiroshi
  • Journal Title: Peritoneal Dialysis International Volume: 39 Issue: 1 Pages: 66-73
  • DOI: 10.3747/pdi.2018.00075
  • Peer Reviewed
• [Journal Article] Organ memory: a key principle for understanding the pathophysiology of hypertension and other non-communicable diseases (2018)
  • Author(s): Itoh Hiroshi、Kurihara Isao、Miyashita Kazutoshi
  • Journal Title: Hypertension Research Volume: 41 Issue: 10 Pages: 771-779
  • DOI: 10.1038/s41440-018-0081-x
  • Peer Reviewed
• [Journal Article] Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid (2017)
  • Author(s): Fujii Chikako、Miyashita Kazutoshi、Mitsuishi Masanori、Sato Masaaki、Fujii Kentaro、Inoue Hiroyuki、Hagiwara Aika、Endo Sho、Uto Asuka、Ryuzaki Masaki、Nakajima Motowo、Tanaka Tohru、Tamaki Masanori、Muraki Ayako、Kawai Toshihide、Itoh Hiroshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-017-03917-0
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation (2017)
  • Author(s): Tamaki M, Miyashita K, Hagiwara A, Wakino S, Inoue H, Fujii K, Fujii C, Endo S, Uto A, Mitsuishi M, Sato M, Doi T, Itoh H.
  • Journal Title: Endocrine Journal Volume: 64 Issue: Suppl. Pages: S47-S51
  • DOI: 10.1507/endocrj.64.S47
  • NAID: 130007307942
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials. (2017)
  • Author(s): Itoh H, Kurihara I, Miyashita K, Tanaka M.
  • Journal Title: Hypertens Res. Volume: 40 Issue: 6 Pages: 526-534
  • DOI: 10.1038/hr.2016.192
  • Peer Reviewed / Open Access
• [Presentation] HYPERTENSION-RELATED PROTEIN DEACETYLASE SIRT3 AFFECTS BLOOD PRESSURE THROUGH REGULATION OF INTESTINAL SALT ABSORPTION IN MICE. (2019)
  • Author(s): Ryuzaki M, Miyashita K, Sato M, Uto A, Endo S, Fujii K, Inoue H, Kinouchi K, Itoh H.
  • Organizer: 56th ERA-EDTA congress
  • Int'l Joint Research
• [Presentation] SIGNIFICANCE OF EPIGENETIC MODIFICATION IN THE KIDNEY FOR THE ONSET AND PERSISTENCE OF HYPERTENSION AFTER TRANSIENT SALT LOADING IN MICE. (2019)
  • Author(s): Inoue H, Miyashita K, Fujii K, Kubo A, Sato M, Hagiwara A, Itoh H
  • Organizer: 56th ERA-EDTA congress
  • Int'l Joint Research
• [Presentation] Protective role of adenosine in the renal corticomedullary boundary zone against acute ischemia. (2019)
  • Author(s): Miyashita K, Fujii K, Kubo A, Sato M, Hagiwara A, Inoue H, Suematsu M, Itoh H
  • Organizer: 50th Scientific Meeting of Korean Society of Hypertension
  • Int'l Joint Research / Invited
• [Presentation] REGULATION OF INTESTINAL SALT ABSORPTION BY PROTEIN DEACETYLASE SIRT3 IN MICE AFFECTS BLOOD PRESSURE. (2019)
  • Author(s): Ryuzaki M, Miyashita K, Sato M, Uto A, Endo S, Fujii K, Inoue H, Kinouchi K, Itoh H.
  • Organizer: Premium Hypertension Conference 2019
  • Int'l Joint Research
• [Presentation] 長寿関連分子Sirt3が腸管塩分吸収と血圧制御に与える影響 (2019)
  • Author(s): 竜崎 正毅, 宮下 和季, 宇都 飛鳥, 押田卓磨, 木内 謙一郎, 伊藤 裕
  • Organizer: 第23回日本心血管内分泌代謝学会総会
• [Presentation] イメージングメタボロミクス：マウス虚血再灌流腎各部位でのエネルギー代謝とキサンチンオキシダーゼ阻害薬の腎保護効果 (2019)
  • Author(s): 宮下 和季, 藤井 健太郎, 久保 亜紀子, 佐藤 正明, 末松 誠, 伊藤 裕
  • Organizer: 第29回日本臨床薬理学会
• [Presentation] 内科の観点からみたサルコペニアと骨格筋ミトコンドリア代謝の改善に基づくサルコペニア治療 (2019)
  • Author(s): 宮下 和季, 藤井 千華子, 伊藤 裕
  • Organizer: 第5回日本筋学会学術集会
• [Presentation] 急性虚血性腎障害におけるフェブキスソタットによるATPブーストを介した腎保護メカニズムのマスイメージングを用いた可視化解析 (2018)
  • Author(s): 藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
  • Organizer: 第41回日本高血圧学会総会
• [Presentation] A semi-quantitative mass imaging technique revealed region-specific alteration of adenylates in the murine kidney after transient ischemia and reno-protective effect of febuxostat by ameliorating ATP levels in the cortex. (2018)
  • Author(s): 藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
  • Organizer: 第61回日本腎臓学会総会
• [Presentation] キサンチンオキシダーゼ阻害による虚血腎保護メカニズムのマスイメージングを用いた可視化解析 (2018)
  • Author(s): 藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
  • Organizer: 第91回日本内分泌学会総会
• [Presentation] Febuxostat exerted reno-protective effects after transient ischemia by promoting ATP recovery in the cortex: visualization of renal adenine nucleotides by an imaging mass-spectrometry technique (2018)
  • Author(s): K. Miyashita, K. Fujii, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 27th Scientific Meeting of International Society of Hypertension
  • Int'l Joint Research
• [Presentation] A mass imaging technique revealed a reno-protective effect of the xanthine oxidase inhibitor febuxostat in the ischemic kidney by promoting ATP recovery in the cortex (2018)
  • Author(s): K. Miyashita, K. Fujii, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 28th Scientific Meeting of European Society of Hypertension
  • Int'l Joint Research
• [Presentation] A SEMI-QUANTITAIVE IMAGING MASS SPECTROMETRY REVEALED THE RENO-PROTECTIVE EFFECT OF FEBUXOSTAT IN THE ISCHEMIC KIDNEY BY PROMOTING ATP RECOVERY IN THE CORTEX. (2018)
  • Author(s): K. Miyashita, K. Fujii, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 55th ERA-EDTA congress
  • Int'l Joint Research
• [Presentation] 一過性のDOCA-salt負荷による腎細動脈ヒストンアセチル化の亢進が高血圧発症に与える意義の解析 (2017)
  • Author(s): 2.宮下 和季, 井上 博之, 佐藤 正明, 萩原 あいか, 藤井 健太郎, 遠藤 翔, 宇都 飛鳥, 竜崎 正毅, 伊藤 裕
  • Organizer: 第25回ステロイドホルモン学会学術集会
• [Presentation] DOCA-salt高血圧マウスにおける血管シアーストレスの腎細動脈ヒストンアセチル化における意義 (2017)
  • Author(s): 5.井上 博之, 宮下 和季, 佐藤 正明, 萩原 あいか, 藤井 健太郎, 遠藤 翔, 宇都 飛鳥, 竜崎 正毅, 伊藤 裕
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] 塩分負荷に伴う腎臓各部位におけるヒストンアセチル化の高血圧発症における意義 (2017)
  • Author(s): 12.井上 博之, 宮下 和季, 佐藤 正明, 萩原 あいか, 藤井 健太郎, 竜崎 正毅, 伊藤 裕
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] HISTONE ACETYLATION IN EACH SEGMENT OF THE KIDNEY AFTER TRANSIENT SALT LOADING IN MICE AND THE SIGNIFICANCE FOR THE ONSET OF PERSISTENT HYPERTENSION. (2017)
  • Author(s): H. Inoue, K. Miyashita, M Sato, A. Hagiwara, K. Fujii, H. Itoh
  • Organizer: 54th ERA-EDTA congress
  • Int'l Joint Research