Pathophysiology of vascular injury via Notch signaling and metabolic reprogramming by urea toxins.

• Project/Area Number: 18H02729
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Saitama Medical University
• Principal Investigator: Takeshita Kyosuke 埼玉医科大学, 医学部, 教授 (70444403)
• Co-Investigator(Kenkyū-buntansha): 片岡 浩巳 川崎医療福祉大学, 医療技術学部, 教授 (80398049) ; 中山 享之 愛知医科大学, 医学部, 教授 (00456659) ; 丹羽 利充 修文大学, 医療科学部, 教授 (20208268) ; 佐藤 稔 川崎医科大学, 医学部, 准教授 (70449891)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: インドキシル硫酸 / Notchシグナル / 尿毒症性心筋症 / インフラマソーム / 動脈石灰化 / 動脈硬化 / 尿毒素

Outline of Final Research Achievements

Abdominal aortic calcification is a determinant of cardiovascular events in patients with chronic kidney disease (CKD). In a rat model of indoxyl sulfate (IS) loading, the aorta exhibited Moenckeberg-type atherosclerosis and decreased Notch signaling. Metabolomic analysis of the aorta showed increased production of nitric oxide and free radicals and decreased responsiveness to hypoxia. In the same heart model, cardiac hypertrophy and inflammasome activation were observed. In Notch1 heterozygous deficient mice, decreased Notch signaling was associated with accelerated adipocyte differentiation and the development of metabolic syndrome. IS alters Notch signaling and inflammatory and metabolic signals to form cardiovascular lesions unique to CKD.

Academic Significance and Societal Importance of the Research Achievements

本研究の目的は、慢性腎臓病における心血管病の原因となるインドキシル硫酸による血管壁細胞のNotchシグナルへの影響と、それによって誘導される血管平滑筋細胞の代謝変化を詳細に解明し治療標的を明らかにすることであり臨床の面で重要である。
炎症、低酸素に関わる細胞内シグナルとこれに基づく代謝異常は、癌、そして糖尿病、非アルコール性肝障害などの代謝性疾患においても注目される分野である。インドキシル硫酸に起因する炎症と代謝の連関に関わるNotchシグナルの挙動を詳細に検討することは、学問的な観点からも重要と考えられる。

Research Products

• [Journal Article] Indoxyl Sulfate Activates NLRP3 Inflammasome to Induce Cardiac Contractile Dysfunction Accompanied by Myocardial Fibrosis and Hypertrophy (2022)
  • Author(s): Yamaguchi Kazutoshi、Yisireyili Maimaiti、Goto Sumie、Cheng Xian Wu、Nakayama Takayuki、Matsushita Tadashi、Niwa Toshimitsu、Murohara Toyoaki、Takeshita Kyosuke
  • Journal Title: Cardiovascular Toxicology Volume: 22 Issue: 4 Pages: 365-377
  • DOI: 10.1007/s12012-021-09718-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch1 haploinsufficiency in mice accelerates adipogenesis (2021)
  • Author(s): Yamaguchi Kazutoshi、Hayashi Motoharu、Uchida Yasuhiro、Cheng Xian Wu、Nakayama Takayuki、Matsushita Tadashi、Murohara Toyoaki、Takeshita Kyosuke
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 16761-16761
  • DOI: 10.1038/s41598-021-96017-z
  • Peer Reviewed / Open Access
• [Journal Article] Sharpening the Focus: Acupuncture Interrupts the Brain?Gut Vicious Cycle Underlying Functional Dyspepsia (2020)
  • Author(s): Takeshita Kyosuke
  • Journal Title: Digestive Diseases and Sciences Volume: 65 Issue: 6 Pages: 1578-1580
  • DOI: 10.1007/s10620-020-06080-1
  • Peer Reviewed / Open Access
• [Journal Article] Indoxyl Sulfate-induced Vascular Calcification is mediated through Altered Notch Signaling Pathway in Vascular Smooth Muscle Cells (2020)
  • Author(s): Yamaguchi Kazutoshi、Yisireyili Maimaiti、Goto Sumie、Kato Katsuhiro、Cheng Xian Wu、Nakayama Takayuki、Matsushita Tadashi、Niwa Toshimitsu、Murohara Toyoaki、Takeshita Kyosuke
  • Journal Title: International Journal of Medical Sciences Volume: 17 Issue: 17 Pages: 2703-2717
  • DOI: 10.7150/ijms.43184
  • Peer Reviewed / Open Access
• [Journal Article] A short perspective on a COVID-19 clinical study: ‘diagnosis of COVID-19 by RT-PCR using exhale breath condensate samples’ (2020)
  • Author(s): Sawano Makoto、Takeshita Kyousuke、Ohno Hideaki、Oka Hideaki
  • Journal Title: Journal of Breath Research Volume: 14 Issue: 4 Pages: 042003-042003
  • DOI: 10.1088/1752-7163/abb99b
  • Peer Reviewed
• [Journal Article] In vivo tracking of transplanted macrophages with near infrared fluorescent dye reveals temporal distribution and specific homing in the liver that can be perturbed by clodronate liposomes (2020)
  • Author(s): Nishiwaki Satoshi、Saito Shigeki、Takeshita Kyosuke、Kato Hidefumi、Ueda Ryuzo、Takami Akiyoshi、Naoe Tomoki、Ogawa Mika、Nakayama Takayuki
  • Journal Title: PLOS ONE Volume: 15 Issue: 12 Pages: e0242488-e0242488
  • DOI: 10.1371/journal.pone.0242488
  • Peer Reviewed / Open Access