The role of PAR2 and autophagy in CKD-related atherosclerosis

• Project/Area Number: 18K15993
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tohoku University
• Principal Investigator: Oe Yuji 東北大学, 東北メディカル・メガバンク機構, 助教 (00791980)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 血液凝固 / 血管石灰化 / ウレミックトキシン / 酸化ストレス / 炎症 / 慢性腎臓病 / 動脈硬化 / 内皮障害 / 動脈硬化症 / 慢性腎臓病関連

Outline of Final Research Achievements

The aim of this study was to clarify the roles of coagulation factors and protease-activated receptor 2 (PAR2) in chronic kidney disease-related atherosclerosis, and the analysis was conducted using animal models. We combined adenine-induced nephropathy with a high phosphorus diet and found no changes in aortic calcification, inflammatory cytokines or autophagy markers due to PAR2 deficiency. Endothelial damage increases coagulation abnormality. To create a model of severe vascular calcification with a background of endothelial dysfunction, endothelial nitric oxide synthase deficient (eNOS) mice were fed with an adenine plus high phosphorus diet. eNOS deficiency exacerbated calcium deposition in the aorta and kidney, which was associated with inflammation, coagulation, and oxidative stress.

Academic Significance and Societal Importance of the Research Achievements

当初予定していた実験ツールでは、血液凝固やPAR2が動脈硬化に与える影響を証明できなかったが、内皮障害を背景に血管石灰化や凝固や炎症が増悪する実験モデルを新たに構築した。今後このモデルを応用して、血液凝固関連因子やPAR, Autophagyの役割を検討することを予定している。

Research Products

• [Journal Article] Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet (2021)
  • Author(s): Oe Yuji、Mitsui Shohei、Sato Emiko、Shibata Naoko、Kisu Kiyomi、Sekimoto Akiyo、Miyazaki Mariko、Sato Hiroshi、Ito Sadayoshi、Takahashi Nobuyuki
  • Journal Title: The American Journal of Pathology Volume: 191 Issue: 2 Pages: 283-293
  • DOI: 10.1016/j.ajpath.2020.10.012
  • Peer Reviewed
• [Journal Article] Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease (2020)
  • Author(s): Mitsui Shohei、Oe Yuji、Sekimoto Akiyo、Sato Emiko、Hashizume Yamato、Yamakage Shu、Kumakura Satoshi、Sato Hiroshi、Ito Sadayoshi、Takahashi Nobuyuki
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 4 Issue: 5 Pages: 318-318
  • DOI: 10.1152/ajprenal.00595.2019
  • Peer Reviewed
• [Presentation] 内皮型ＮＯ合成酵素欠損はＣＫＤ関連異所性石灰化を誘導する (2020)
  • Author(s): 大江佑治、佐藤恵美子、宮崎真理子、岡本好司、佐藤博、伊藤貞嘉、高橋信行
  • Organizer: 第63回日本腎臓学会総会