Research for expression mechanism of klotho in CKD model mice

• Project/Area Number: 17K09733
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Jichi Medical University
• Principal Investigator: Kurosu Hiroshi 自治医科大学, 医学部, 准教授 (40468690)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Klotho / 無機リン酸 / ビスホスホネート / リン酸カルシウム / pH / ステロイドホルモン / 慢性腎臓病 / リン

Outline of Final Research Achievements

Excessive intake of phosphate has been known to induce renal tubular damage and interstitial inflammation, leading to acute kidney injury or chronic kidney disease in rodents and humans. It has been known that Klotho-FGF23 endocrine system regulates homeostasis of phosphate in our body. It has been reported that and decreasing of the expression level of Klotho, which is mainly expressing in the kidney, is observed in the early stage of CKD. However, mechanism of regulation of Klotho expression remains unclear. In this research, we have found three new knowledge. 1) Renal Klotho expression is reduced in the mice fed 2.0% inorganic phosphate for 4 weeks. 2) Klotho expression is increasing in HKC-8 cells by the treatment of Sex steroid hormones. 3) Bisphosphonates, drug for treatment of osteoporosis also increase expression level of Klotho in HK-2 cells.

Academic Significance and Societal Importance of the Research Achievements

本研究課題の遂行により生体物質である性ホルモンと骨粗鬆症地治療薬であるビスホスホネート製剤に腎臓でのKlotho発現誘導活性を見出した。性ホルモンは慢性腎臓病患者において血中濃度が低下しているホルモンであり、慢性腎臓病発症の一因となるKlothoの発現低下が性ホルモン濃度の低下により誘発する可能性と性ホルモンの補充により抑制できる可能性が示された。またビスホスホネート製剤の作用に関しては、骨粗鬆症だけでなく慢性腎臓病への適応拡張につながる研究の橋渡しとなる根拠を見出せた。

Research Products

• [Journal Article] The Body-wide Transcriptome Landscape of Disease Models. (2018)
  • Author(s): Kozawa S, Ueda R, Urayama K, Sagawa F, Endo S, Shiizaki K, Kurosu H, Maria de Almeida G, Hasan SM, Nakazato K, Ozaki S, Yamashita Y, Kuro-O M, Sato TN.
  • Journal Title: iScience Volume: 2 Pages: 238-268
  • DOI: 10.1016/j.isci.2018.03.014
  • Peer Reviewed / Open Access
• [Journal Article] Identification and quantification of plasma calciprotein particles with distinct physical properties in patients with chronic kidney disease (2018)
  • Author(s): Miura Yutaka、Iwazu Yoshitaka、Shiizaki Kazuhiro、Akimoto Tetsu、Kotani Kazuhiko、Kurabayashi Masahiko、Kurosu Hiroshi、Kuro-o Makoto
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1256-1256
  • DOI: 10.1038/s41598-018-19677-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Klothoマウス (2018)
  • Author(s): 黒須 洋
  • Organizer: 第18回日本抗加齢医学会総会
  • Invited