Exploration of epigenome abnormalities involved in salt sensitive hypertension

• Project/Area Number: 26670426
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Fujita Toshiro 東京大学, 先端科学技術研究センター, 特任研究員、名誉教授 (10114125)
• Co-Investigator(Kenkyū-buntansha): MARUMO Takeshi 東京大学, 先端科学技術研究センター 臨床エピジェネティクス講座, 特任准教授 (70265817)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エピゲノム / 食塩感受性高血圧 / DNAメチル化 / エピジェネティクス / 高血圧 / 腎臓

Outline of Final Research Achievements

Aberrant epigenome may underlie the pathogenesis of salt sensitive hypertension. We analyzed changes in molecules involved in salt reabsorption in a cell-type specific manner. We found that the promoter region of angiotensinogen is aberrantly demethylated in the proximal tubules of diabetic mice, which develop hypertension (J Am Soc Nephrol 2015). Aberrant demethylation of angiotensinogen may lead to persistent activation of salt absorption and/or renal injury.
In addition, we observed that pendrin, a molecule involved in reabsorption of salt, is upregulated in hypertension induced by infusion of angiotensin II. We collected intercalated cells from Atp6v1b1-EGFP mice by sorting and now investigating the changes in epigenome.

Research Products

• [Journal Article] Rac1-Mediated Activation of Mineralocorticoid Receptor in Pressure Overload-Induced Cardiac Injury (2016)
  • Author(s): Nobuhiro Ayuzawa, Miki Nagase, Kohei Ueda, Mitsuhiro Nishimoto, Wakako Kawarazaki, Takeshi Marumo, Atsu Aiba, Takayuki Sakurai, Takayuki Shindo, Toshiro Fujita
  • Journal Title: Hypertension Volume: 67 Issue: 1 Pages: 99-106
  • DOI: 10.1161/hypertensionaha.115.06054
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diabetes Induces Aberrant DNA Methylation in the Proximal Tubules of the Kidney. (2015)
  • Author(s): Marumo T, Yagi S, Kawarazaki W, Nishimoto M, Ayuzawa N, Watanabe A, Ueda K, Hirahashi J, Hishikawa K, Sakurai H, Shiota K, Fujita T.
  • Journal Title: J Am Soc Nephrol. Volume: 印刷中 Issue: 10 Pages: 2333-2397
  • DOI: 10.1681/asn.2014070665
  • Peer Reviewed
• [Journal Article] Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways (2015)
  • Author(s): Nishimoto M, Fujita T
  • Journal Title: Am J Physiol Renal Physiol. Volume: in press Issue: 5 Pages: F377-F387
  • DOI: 10.1152/ajprenal.00477.2013
  • Peer Reviewed
• [Journal Article] Mechanism of Salt-Sensitive Hypertension: Focus on Adrenal and Sympathetic Nervous Systems (2014)
  • Author(s): Fujita, T
  • Journal Title: J Am Soc Nephrol Volume: in press Issue: 6 Pages: 1148-1155
  • DOI: 10.1681/asn.2013121258
  • Peer Reviewed
• [Presentation] Mechanism of Salt-sensitive hypertension (2015)
  • Author(s): 藤田敏郎
  • Organizer: American Heart Association
  • Place of Presentation: Orland
  • Year and Date: 2015-11-08
  • Int'l Joint Research / Invited
• [Presentation] Epigenetic abnormalities underlie increased expression of nuclear receptor PXR in diabetic kidney disease. (2015)
  • Author(s): Atsushi Watanabe, Takeshi Marumo, Wakako Kawarazaki, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Daigoro Hirohama, Kohei Ueda, Hiroo Kumagai, Toshiro Fujita
  • Organizer: Kidney Week 2015 ASN Annual Meeting
  • Place of Presentation: San Diego Convention Center, USA
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Mineralocorticoid receptor and salt-sensitive hypertension (2015)
  • Author(s): 藤田敏郎
  • Organizer: International Symposium and Annual ADMIRE Cost Meeting
  • Place of Presentation: Zermatt, Switzerland
  • Year and Date: 2015-10-09
  • Int'l Joint Research / Invited
• [Presentation] Activation of Mineralocorticoid Receptor in Salt-Sensitive Hypertension –From Bench to Clinic (2015)
  • Author(s): 藤田敏郎
  • Organizer: Oriental Congress of Cardiology
  • Place of Presentation: 上海
  • Year and Date: 2015-09-11
  • Int'l Joint Research / Invited
• [Presentation] 生活習慣病とエピジェネティクス (2015)
  • Author(s): 藤田敏郎
  • Organizer: DOHAD研究会
  • Place of Presentation: 東京 昭和大学
  • Year and Date: 2015-07-31
  • Invited
• [Presentation] Salt, Aldosterone and Hypertension (2015)
  • Author(s): 藤田敏郎
  • Organizer: Asian Pacific Society of Hypertension
  • Place of Presentation: Bali
  • Year and Date: 2015-06-06
  • Int'l Joint Research / Invited
• [Presentation] “IMPORTANCE OF DIETARY SALT INTAKE IN ANTI-ALBUMINURIC EFFECT OF AN ALDOSTERONE BLOCKER (2015)
  • Author(s): 藤田敏郎
  • Organizer: European Society of Hypertension
  • Place of Presentation: Milan, Italy
  • Year and Date: 2015-05-12
  • Int'l Joint Research / Invited
• [Presentation] 糖尿病性腎症にみられるエピジェネティック異常は血糖治療に抵抗性を示す (2015)
  • Author(s): 丸茂丈史、八木慎太郎、河原崎和歌子、西本光宏、鮎澤信宏、渡邉篤史、上田浩平、菱川慶一、櫻井裕之、藤田敏郎
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Presentation] Plenary lecture ”Renal Mechanisms of Salt-Sensitive Hypertension” (2014)
  • Author(s): 藤田敏郎
  • Organizer: International Society of Nephrology (ISN) NEXUS Symposium
  • Place of Presentation: Brisbane, Australia
  • Year and Date: 2014-09-25 – 2014-09-28
  • Invited
• [Presentation] 糖尿病性腎症にみられる治療抵抗性DNAメチル化異常 (2014)
  • Author(s): 丸茂丈史、八木慎太郎、河原崎和歌子、西本光宏、鮎澤信宏、上田浩平、渡邉篤史、藤田敏郎
  • Organizer: 第6回腎疾患と高血圧研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-12
• [Presentation] 糖尿病性腎症にみられる治療抵抗性エピジェネティック異常 (2014)
  • Author(s): 丸茂丈史、八木慎太郎、河原崎和歌子、西本光宏、鮎澤信宏、渡邉篤史、菱川慶一、櫻井裕之、藤田敏郎
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-04
• [Presentation] STIM1 regulates blood pressure via NO production in vascular endothelial cells (2014)
  • Author(s): Mitsuhiro Nishimoto, Masashi Isshiki, Risuke Mizuno, Toshiro Fujita
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-14 – 2014-04-17