Roles of endotoxin derived from gut microbiota in vascular calcification associated with chronic kidney disease

• Project/Area Number: 17K09731
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Osaka City University
• Principal Investigator: SHIOI ATSUSHI 大阪市立大学, 大学院看護学研究科, 教授 (90260801)
• Co-Investigator(Kenkyū-buntansha): 森岡 与明 大阪市立大学, 大学院医学研究科, 講師 (30382154) ; 庄司 哲雄 大阪市立大学, 大学院医学研究科, 准教授 (40271192)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 動脈石灰化 / 慢性腎臓病 / 血管平滑筋細胞 / 骨芽細胞 / LPS / 血管石灰化 / アデニン負荷 / 高リン食 / エンドトキシン / 慢性腎不全 / 動脈硬化

Outline of Final Research Achievements

We investigated the roles of lipopolysaccharide (LPS) derived from intestinal bacteria in the development of vascular calcification in chronic kidney disease (CKD). Aortic medial calcified lesions were analyzed in LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ mice with adenine-induce CKD. Alizarin red-stained calcified lesions were more prevalent in C3H/HeJ than C3H/HeN mice. Biochemical data revealed that
renal impairment, hypocalcemia, and hyperphosphatemia are less severe in C3H/HeJ than C3H/HeN mice. On the other hand, we examined the effects of LPS on in vitro calcification of human aortic smooth muscle cells (HASMCs). In vitro calcification and alkaline phosphatase (ALP) activities in HASMC cultures were dose-dependently increased by LPS treatment. ALP mRNA levels were also up-regulated by LPS. Therefore, LPS may play an important role in the development of vascular calcification. However, its role in CKD-induced vascular calcification remains to be clarified.

Academic Significance and Societal Importance of the Research Achievements

本研究によりエンドトキシン(LPS)の血管石灰化における重要性が明らかにされた。エンドトキシンは慢性腎臓病だけでなく、様々な代謝性疾患(肥満、糖尿病、脂質代謝異常症など)における動脈硬化症の危険因子として注目されている。血管石灰化はこれらの動脈硬化性疾患の発症・進展にも深く関わっていることから、血管石灰化におけるLPSの臨床的意義を明らかにすることは今後の重要な課題である。

Research Products

• [Journal Article] The inhibitory roles of vitamin K in progression of vascular calcification. (2020)
  • Author(s): Shioi A, Morioka T, Shoji T, Emoto M
  • Journal Title: Nutrients Volume: 12 Issue: 2 Pages: 583-583
  • DOI: 10.3390/nu12020583
  • Peer Reviewed / Open Access
• [Journal Article] Adenosine Attenuates Aortic Smooth Muscle Cell Calcification through A₃ Adenosine Receptor (2019)
  • Author(s): Fujimoto K, Shioi A, Miki Y, Kakutani Y, Morioka T, Shoji T, Emoto M, Inaba M
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 249 Issue: 4 Pages: 275-283
  • DOI: 10.1620/tjem.249.275
  • NAID: 130007771873
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Plasma mention levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study. (2019)
  • Author(s): Nishimura M, Morioka T, Hayashi M, Kakutani Y, Yamazaki Y, Kurajoh M, Mori K, Fukumoto S, Shioi A, Shoji T, Inaba M, Emoto M
  • Journal Title: Cardiovascular Diabetes Volume: 167 Issue: 1 Pages: 167-167
  • DOI: 10.1186/s12933-019-0973-3
  • Peer Reviewed
• [Journal Article] Oncostatin M induces C2C12 myotube atrophy by modulating muscle differentiation and degradation. (2019)
  • Author(s): Miki Y, Morioka T, Shioi A, Fujimoto K, Sakura T, Uedono H, Kakutani Y, Ochi A, Mori K, Shoji T, Emoto M, Inaba M.
  • Journal Title: Biochem Biophys Res Commun Volume: 516 Issue: 3 Pages: 951-956
  • DOI: 10.1016/j.bbrc.2019.06.143
  • NAID: 120006882169
  • Peer Reviewed / Open Access
• [Journal Article] Plasma polyunsaturated fatty acid profile is associated with vascular endothelial function in patients with type 2 diabetes (2018)
  • Author(s): Morioka T, Emoto M, Imamura S, Kakitani Y, Yamazaki Y, Motoyama K, Mori K, Fukumoto S, Shioi A, Shoji T, Inaba M
  • Journal Title: Diabetes Vasc Dis Res Volume: 15 Issue: 4 Pages: 352-355
  • DOI: 10.1177/1479164118774314
  • NAID: 120006712087
  • Peer Reviewed
• [Journal Article] Plaque Calcification During Atherosclerosis Progression and Regression (2018)
  • Author(s): Shioi A, Ikari Y
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 25 Issue: 4 Pages: 294-303
  • DOI: 10.5551/jat.RV17020
  • NAID: 130006602383
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed
• [Journal Article] Altered Serum n-6 Polyunsaturated Fatty Acid Profile and Risks of Mortality and Cardiovascular Events in a Cohort of Hemodialysis Patients. (2018)
  • Author(s): Kuwamura Y, Shoji T, Okute Y, Yamazaki Y, Motoyama K, Morioka T, Mori K, Fukumoto S, Tsujimoto Y, Shioi A, Emoto M, Inaba M
  • Journal Title: J Ren Nutr Volume: 28 Issue: 1 Pages: 54-63
  • DOI: 10.1053/j.jrn.2017.07.001
  • Peer Reviewed
• [Journal Article] Plasma soluble leptin receptor levels are associated with pancreatic b-cell dysfunction in patients with type 2 diabetes. (2018)
  • Author(s): Morioka T, Emoto M, Yamazaki Y, Kurajoh M, Motoyama K, Mori K, Fukumoto S, Shioi A, Shoji T, Inaba M
  • Journal Title: J Diabetes Investig Volume: 9 Issue: 1 Pages: 55-62
  • DOI: 10.1111/jdi.12657
  • Peer Reviewed
• [Journal Article] Plasma homocysteine and cerebral small vessel disease as possible mediators between kidney and cognitive functions in patients with diabetes mellitus. (2017)
  • Author(s): Sonoda M, Shoji T, Kuwamura Y, Okute Y, Naganuma T, Shima H, Motoyama K, Morioka T, Mori K, Fukumoto S, Shioi A, Shimono T, Fujii H, Kabata D, Shintani A, Emoto M, Inaba M
  • Journal Title: Sci Rep Volume: 7 Issue: 1
  • DOI: 10.1038/s41598-017-04515-w
  • Peer Reviewed / Open Access
• [Journal Article] Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study. (2017)
  • Author(s): Sakura T, Morioka T, Shioi A, Kakitani Y, Miki Y, Yamazaki Y, Motoyama K, Mori K, Fukumoto S, Shoji T, Emoto M, Inaba M
  • Journal Title: Cardiovasc Diabetol Volume: 16 Issue: 1
  • DOI: 10.1186/s12933-017-0545-3
  • Peer Reviewed / Open Access
• [Journal Article] Cardiothoracic Ratio as a Predictor of Cardiovascular Events in a Cohort of Hemodialysis Patients (2017)
  • Author(s): Okute Y, Shoji T, Hayashi T, Kuwamura Y, Sonoda M, Mori K, Shioi A, Tsujimoto Y, Tabata T, Emoto M, Inaba M
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 4 Pages: 412-421
  • DOI: 10.5551/jat.36426
  • NAID: 130005529956
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed
• [Presentation] オンコスタチンMによるSTAT3経路を介した骨格筋萎縮への関与 (2019)
  • Author(s): 三木 祐哉, 森岡 与明, 塩井 淳, 佐倉 剛史, 角谷 佳則, 藤元 健太, 上殿 英記, 越智 章展, 森 克仁, 庄司 哲雄, 絵本 正憲, 稲葉 雅章
  • Organizer: 第40回日本肥満学会
• [Presentation] Δ5脂肪酸不飽和化酵素活性指標は2型糖尿病の動脈硬化合併症に関与する (2019)
  • Author(s): 森岡 与明, 絵本 正憲, 山崎 祐子, 角谷 佳則, 森 克仁, 福本 真也, 塩井 淳, 庄司 哲雄, 稲葉 雅章
  • Organizer: 第34回日本糖尿病合併症学会
• [Presentation] AdenosineはA3 receptorを介してERK1/2およびSTAT3のリン酸化を抑制することによりoncostatin Mによる血管平滑筋細胞の石灰化を抑制する (2019)
  • Author(s): 藤元 健太, 塩井 淳, 三木 祐哉, 角谷 佳則, 森岡 与明, 庄司 哲雄, 絵本 正憲, 稲葉 雅章
  • Organizer: 第51回日本動脈硬化学会
• [Presentation] Omentinは2型糖尿病のadiponectin高値群において動脈硬化に負に関連する (2019)
  • Author(s): 畑森 雅美, 森岡 与明, 林 麻里子, 角谷 佳則, 山崎 祐子, 森 克仁, 福本 真也, 塩井 淳, 庄司 哲雄, 絵本 正憲, 稲葉 雅章
  • Organizer: 第51回日本動脈硬化学会
• [Presentation] 2型糖尿病Diabetic Kidney Diseaseにおけるアルブミン尿を伴わない腎機能低下例頻度の年代間比較 (2019)
  • Author(s): 角谷 佳則, 絵本 正憲, 森 克仁, 越智 章展, 山崎 祐子, 森岡 与明, 福本 真也, 塩井 淳, 庄司 哲雄, 稲葉 雅章
  • Organizer: 第62回日本糖尿病学会
• [Presentation] Adenosineは」A3 receptorを介してヒト血管平滑筋細胞によるin Vitroでの石灰化を抑制する (2018)
  • Author(s): 藤元健太、塩井淳、三木祐哉、角谷佳則、森岡与明、庄司哲雄、絵本正憲、稲葉雅章
  • Organizer: 第50回日本動脈硬化学会総会・学術集会