Angiotensinogen originating from liver by glomerular filtration pressure is involved in circadian rhythm of intrarenal renin-angiotensin system.

• Project/Area Number: 17K09693
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Ohashi Naro 浜松医科大学, 医学部附属病院, 特任講師 (50397387)
• Co-Investigator(Kenkyū-buntansha): 加藤 明彦 浜松医科大学, 医学部附属病院, 准教授 (60324357)
• 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: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 腎臓内レニン-アンジオテンシン系 / アンジオテンシノーゲン / 糸球体濾過圧 / 日内変動 / in vivo imaging / 糸球体濾過値 / 糸球体過剰濾過

Outline of Final Research Achievements

Intrarenal renin-angiotensin system (RAS) activation is associated with hypertension and renal damage. In addition, abnormal circadian rhythm of blood pressure (BP) and organ damage including kidney correlates with circadian rhythm of intrarenal RAS activation. However, the reasons why circadian rhythm of intrarenal RAS activation is caused has not been known.
We have used in vivo imaging and clarified that the mechanism depends on leakage by glomerular filtration pressure of AGT originating from liver in the situation where glomerular capillaries are destroyed diffusely.

Academic Significance and Societal Importance of the Research Achievements

糸球体濾過圧上昇の腎臓障害への関与は知られているが、糸球体濾過圧上昇により腎臓内RAS活性の基質であるAGTの漏出が増加し、腎臓障害や、臓器障害の原因となる日内変動異常の機序となることを明らかに出来た学術的意義は大きい。加えて、糸球体濾過圧を減弱することで腎保護効果がある新規糖尿病治療薬sodium glucose cotransporter (SGLT) 2阻害薬の腎保護の原因に、今回と同様の腎臓内AGTの濾過減少による腎臓内RAS活性抑制が提唱される可能性を有する。更にはSGLT2阻害薬が全ての慢性腎臓病への適応拡大につながる可能性も秘めている。以上より社会的意義も大きい成果と言える。

Research Products

• [Journal Article] The Urinary Angiotensinogen to Urinary Albumin Ratio Reflects Whether the Renin-angiotensin System in the Kidney Is Activated due to Filtration of Plasma Angiotensinogen through the Damaged Glomeruli or the Production of Angiotensinogen in the Proximal Tubules (2020)
  • Author(s): Ohashi N, Aoki T, Matsuyama T, Ishigaki S, Isobe S, Katahashi N, Sato T, Fujikura T, Kato A, Yasuda H.
  • Journal Title: Intern. Med. Volume: 59 Issue: 3 Pages: 357-364
  • DOI: 10.2169/internalmedicine.3624-19
  • NAID: 130007793871
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Increased heart rate is associated with intrarenal renin-angiotensin system activation in chronic kidney disease patients. (2019)
  • Author(s): Ohashi N, Isobe S, Ishigaki S, Aoki T, Matsuyama T, Sato T, Fujikura T, Kato A, Yasuda H.
  • Journal Title: Clin Exp Nephrol Volume: 23 Pages: 1109-1118
  • DOI: 10.1007/s10157-019-01746-1
  • Peer Reviewed
• [Journal Article] Salt Loading Aggravates the Relationship between Melatonin and Proteinuria in Patients with Chronic Kidney Disease (2019)
  • Author(s): Ohashi N, Ishigaki S, Isobe S, Matsuyama T, Sato T, Fujikura T, Tsuji T, Kato A, Yasuda H.
  • Journal Title: Intern. Med. Volume: 58 Issue: 11 Pages: 1557-1564
  • DOI: 10.2169/internalmedicine.1929-18
  • NAID: 130007658135
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] The Intrarenal Renin-angiotensin System Is Activated Immediately after Kidney Donation in Kidney Transplant Donors (2019)
  • Author(s): Ohashi N, Isobe S, Matsuyama T, Ishigaki S, Suzuki T, Tsuji T, Otsuka A, Kato A, Miyake H, Yasuda H.
  • Journal Title: Intern. Med. Volume: 58 Issue: 5 Pages: 643-648
  • DOI: 10.2169/internalmedicine.1756-18
  • NAID: 130007605865
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Presentation] Chronotherapy of renin-angiotensin system (RAS) inhibitor ameliorates renal damage via suppression of intrarenal RAS activity. (2019)
  • Author(s): Aoki T, Ohashi N, Isobe S, Ishigaki S, Matsuyama T, Fujikura T, Kato A, Yasuda H.
  • Organizer: Kidney Week 2019
  • Int'l Joint Research
• [Presentation] Increased heart rate reflects intrarenal renin-angiotensin system activation in chronic kidney disease patients but not in subjects without chronic kidney disease. (2019)
  • Author(s): Ohashi N, Isobe S, Ishigaki S, Aoki T, Matsuyama T, Sato T, Fujikura T, Kato A,
  • Organizer: Kidney Week 2019
  • Int'l Joint Research
• [Presentation] CKDにおける尿中アンジオテンシノーゲン排泄量と腎機能低下の関係 (2019)
  • Author(s): 石垣 さやか, 大橋 温, 青木 太郎, 田代 傑, 後藤 大樹, 松山 貴司, 永田 総一郎, 佐藤 太一, 内藤 善隆, 藤倉 知行, 加藤 明彦, 安田 日出夫
  • Organizer: 日本腎臓学会