Protein-bound uremic toxins-induced functional abnormalities of HDL cholesterol for prevention of atherosclerosis accelerated by chronic kidney disease

• Project/Area Number: 15K09249
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Niigata University
• Principal Investigator: Yamamoto Suguru 新潟大学, 医歯学総合病院, 准教授 (70444156)
• Co-Investigator(Renkei-kenkyūsha): KAZAMA Junichiro 福島県立医科大学, 医学部, 教授 (10345499) ; NARITA Ichiei 新潟大学, 医歯学系, 教授 (20272817) ; MARUYAMA Toru 熊本大学, 薬学部, 教授 (90423657) ; KOTANI Kazuhiko 自治医科大学, 医学部, 教授 (60335510)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: インドキシル硫酸 / マクロファージ / HDL / 吸着 / インフラマソーム / MAPK / NF-ｋB / 活性炭 / 尿毒症物質 / 慢性腎臓病 / 動脈硬化 / 直接血液灌流 / 血液透析 / HDLコレステロール / コレステロールイーフラックス

Outline of Final Research Achievements

Chronic　kidney　disease (CKD),　especially　those　undergoing　dialysis　treatment,　have　high　risk　of　cardiovascular disease.　We focused on function of high- density lipoprotein (HDL）and protein-bound　uremic　toxins　(PBUTs),　and　found　the　role　of　PBUTs　on　functional　abnormalities　of　HDL　to　macrophage. Further, we investigated the adsorption treatment for PBUTs with direct hemoperfusion. Thus, we have found the role of PBUTs for HDL and macrophage function and suggested a novel therapeutic strategies for removal of PBUTs for the prevention of cardiovascular disease in CKD patients.

Research Products

• [Journal Article] Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated (2018)
  • Author(s): Wakamatsu Takuya、Yamamoto Suguru、Ito Toru、Sato Yoko、Matsuo Koji、Takahashi Yoshimitsu、Kaneko Yoshikatsu、Goto Shin、Kazama Junichiro、Gejyo Fumitake、Narita Ichiei
  • Journal Title: Toxins Volume: 10 Issue: 3 Pages: 124-124
  • DOI: 10.3390/toxins10030124
  • Peer Reviewed / Open Access
• [Journal Article] Fatal visceral disseminated varicella zoster infection during initial remission induction therapy in a patient with lupus nephritis and rheumatoid arthritis?possible association with mycophenolate mofetil and high-dose glucocorticoid therapy: a case report (2018)
  • Author(s): Habuka Masato、Wada Yoko、Kurosawa Yoichi、Yamamoto Suguru、Tani Yusuke、Ohashi Riuko、Ajioka Yoichi、Nakano Masaaki、Narita Ichiei
  • Journal Title: BMC Research Notes Volume: 11 Issue: 1
  • DOI: 10.1186/s13104-018-3271-3
  • Peer Reviewed / Open Access
• [Journal Article] Attenuated Macrophage Infiltration in Glomeruli of Aged Mice Resulting in Ameliorated Kidney Injury in Nephrotoxic Serum Nephritis (2018)
  • Author(s): Kaneko Y, Cho T, Sato Y, Goto K, Yamamoto S, Goto S, Madaio MP, Narita I.
  • Journal Title: J Gerontol A Biol Sci Med Sci Volume: in press Issue: 9 Pages: 1178-1186
  • DOI: 10.1093/gerona/gly019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency (2017)
  • Author(s): Iguchi Akira、Yamamoto Suguru、Yamazaki Mihoko、Tasaki Kazuyuki、Suzuki Yasushi、Kazama Junichiro James、Narita Ichiei
  • Journal Title: Clinical and Experimental Nephrology Volume: 印刷中 Issue: 4 Pages: 789-796
  • DOI: 10.1007/s10157-017-1510-x
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of Earlobe Creases and Their Association With History of Cardiovascular Disease in Patients Undergoing Hemodialysis: A Cross-Sectional Study (2017)
  • Author(s): Wakasugi Minako、Kazama Junichiro James、Kawamura Kazuko、Yamamoto Suguru、Nagai Masaaki、Omori Kentaro、Yokota Saori、Fujikawa Hirokazu、Aoike Ikuo、Omori Tsukasa、Narita Ichiei
  • Journal Title: Therapeutic Apheresis and Dialysis Volume: 21 Issue: 5 Pages: 478-484
  • DOI: 10.1111/1744-9987.12567
  • NAID: 120006763625
  • Peer Reviewed / Open Access
• [Journal Article] Initiation of Sevelamer and Mortality among Hemodialysis Patients Treated with Calcium-Based Phosphate Binders (2017)
  • Author(s): Komaba Hirotaka、Wang Mia、Taniguchi Masatomo、Yamamoto Suguru、Nomura Takanobu、Schaubel Douglas E.、Smith Abigail R.、Zee Jarcy、Karaboyas Angelo、Bieber Brian、Fukagawa Masafumi、Tentori Francesca
  • Journal Title: Clinical Journal of the American Society of Nephrology Volume: 12 Issue: 9 Pages: 1489-1497
  • DOI: 10.2215/cjn.13091216
  • Peer Reviewed
• [Journal Article] Adsorption of Protein-Bound Uremic Toxins Through Direct Hemoperfusion With Hexadecyl-Immobilized Cellulose Beads in Patients Undergoing Hemodialysis (2017)
  • Author(s): Yamamoto Suguru、Sato Mami、Sato Yoko、Wakamatsu Takuya、Takahashi Yoshimitsu、Iguchi Akira、Omori Kentaro、Suzuki Yasushi、Ei Isei、Kaneko Yoshikatsu、Goto Shin、Kazama Junichiro J.、Gejyo Fumitake、Narita Ichiei
  • Journal Title: Artificial Organs Volume: 42 Issue: 1 Pages: 88-93
  • DOI: 10.1111/aor.12961
  • Peer Reviewed
• [Journal Article] Uremic Toxicity and Bone in CKD (2017)
  • Author(s): Yamamoto Suguru、Fukagawa Masafumi
  • Journal Title: Journal of Nephrology Volume: 30 Issue: 5 Pages: 623-627
  • DOI: 10.1007/s40620-017-0406-x
  • Peer Reviewed
• [Journal Article] A multicenter cross sectional study for bone-articular lesions associated with dialysis related amyloidosis in Japan. (2017)
  • Author(s): Nishi S, Hoshino J, Yamamoto S, Goto S, Fuji H, Ubara Y, Motomiya Y, Morita H, Takaichi K, Yamagata K, Shigematsu T, Ueda M, Ando Y
  • Journal Title: Nephrology Volume: 印刷中 Issue: 7 Pages: 640-645
  • DOI: 10.1111/nep.13077
  • Peer Reviewed / Open Access
• [Journal Article] The macrophage and its related cholesterol efflux as a HDL function index in atherosclerosis. (2016)
  • Author(s): Yamamoto S, Narita I, Kotani K.
  • Journal Title: Clin Chim Acta Volume: 457 Pages: 117-122
  • DOI: 10.1016/j.cca.2016.04.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Removal of uremic toxins by renal replacement therapies: A review of current progress and future perspectives (2016)
  • Author(s): Yamamoto, S, Kazama, J,J, Wakamatsu, T, Takahashi, Y, Kaneko, Y, Goto, S, Narita, I
  • Journal Title: Renal Replace Ther Volume: 2 Issue: 1 Pages: 43-43
  • DOI: 10.1186/s41100-016-0056-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Extracapillary proliferation and arteriolar hyalinosis are associated with long-term kidney survival in IgA nephropathy (2016)
  • Author(s): Kaneko Y, Yoshita K, Kono E, Ito Y, Imai N, Yamamoto S, Goto S, Narita I.
  • Journal Title: Clin Exp Nephrol Volume: in press Issue: 4 Pages: 569-577
  • DOI: 10.1007/s10157-015-1185-0
  • Peer Reviewed / Open Access
• [Journal Article] Leptin deficiency down-regulates IL-23 production in glomerular podocytes resulting in an attenuated immune response in nephrotoxic serum nephritis. (2015)
  • Author(s): Goto K, Kaneko Y, Sato Y, Otsuka T, Yamamoto S, Goto S, Yamamoto K, Yamamoto T, Kawachi H, Madaio MP, Narita I
  • Journal Title: Int Immunol Volume: 28 Issue: 4 Pages: 197-208
  • DOI: 10.1093/intimm/dxv067
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Administration of Ferric Citrate Hydrate Decreases Circulating FGF23 Levels Independently of Serum Phosphate Levels in Hemodialysis Patients with Iron Deficiency. (2015)
  • Author(s): Iguchi A, Kazama JJ, Yamamoto S, Yoshita K, Watanabe Y, Iino N, Narita I.
  • Journal Title: Nephron. Volume: 131 Issue: 3 Pages: 161-166
  • DOI: 10.1159/000440968
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Continuous Reduction of Protein-Bound Uraemic Toxins with Improved Oxidative Stress by Using the Oral Charcoal Adsorbent AST-120 in Haemodialysis Patients. (2015)
  • Author(s): Yamamoto S, Kazama JJ, Omori K, Matsuo K, Takahashi Y, Kawamura K, Matsuto T, Watanabe H, Maruyama T, Narita I.
  • Journal Title: Sci Rep. Volume: N/A Issue: 1 Pages: 14381-14381
  • DOI: 10.1038/srep14381
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Increased Proinflammatory Cytokine Production and Decreased Cholesterol Efflux Due to Downregulation of ABCG1 in Macrophages Exposed to Indoxyl Sulfate. (2015)
  • Author(s): Matsuo K, Yamamoto S, Wakamatsu T, Takahashi Y, Kawamura K, Kaneko Y, Goto S, Kazama JJ, Narita I.
  • Journal Title: Toxins Volume: 7 Issue: 8 Pages: 3155-3166
  • DOI: 10.3390/toxins7083155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. (2015)
  • Author(s): Yamamoto S, Zhong J, Yancey PG, Zuo Y, Linton MF, Fazio S, Yang H, Narita I, Kon V.
  • Journal Title: Atherosclerosis Volume: 242 Issue: 1 Pages: 56-64
  • DOI: 10.1016/j.atherosclerosis.2015.06.055
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Use of Renin-Angiotensin system inhibitors is associated with reduction of fracture risk in hemodialysis patients. (2015)
  • Author(s): Yamamoto S, Kido R, Onishi Y, Fukuma S, Akizawa T, Fukagawa M, Kazama JJ, Narita I, Fukuhara S.
  • Journal Title: PLoS One Volume: 10 Issue: 4 Pages: e0122691-e0122691
  • DOI: 10.1371/journal.pone.0122691
  • Peer Reviewed / Open Access
• [Presentation] Mineral bone disorder management in dialysis patients: Comparing PTH control practices in Japan with Europe and North America: the Dialysis Outcomes and Practice Patterns Study (DOPPS) (2017)
  • Author(s): Suguru Yamamoto, Angelo Karaboyas, Hirotaka Komaba, Masatomo Taniguchi, Takanobu Nomura, Brian A. Bieber, Ronald L. Pisoni, Bruce M. Robinson and Fukagawa M
  • Organizer: Kidney week 2017
  • Int'l Joint Research
• [Presentation] 慢性腎臓病に対する透析療法の進歩と課題 (2017)
  • Author(s): 山本卓
  • Organizer: 第726回新潟医学会
  • Invited
• [Presentation] Renin-angiotensin system inhibition ameliorates bone fragility due to altered material properties in uremic rats with secondary hyperparathyroidism (2017)
  • Author(s): Suguru Yamamoto, Takuya Wakamatsu, Yoshiko Iwasaki, Akemi Ito, Ichiei Narita, Masafumi Fukagawa, and Junichro James Kazama
  • Organizer: ASBMR 2017 Annual meeting
  • Int'l Joint Research
• [Presentation] Inhibition of the renin-angiotensin system ameliorates bone fragility through improved function and decreased apoptosis of osteocyte. (2017)
  • Author(s): Yoko Sato, Takuya Wakamatsu, Yoshiko Iwasakki, Suguru Yamamoto, Akemi Ito, Ichiei Narita, Masafumi Fukagawa, Junichiro J. Kazama
  • Organizer: ERA-EDTA 2017
  • Int'l Joint Research
• [Presentation] Protein-bound uremic toxin adsorption by hexadecyl-immobilized cellulose beads in hemodialysis (2016)
  • Author(s): Yamamoto, S, Sato M, Wakamatsu T, Takahashi Y, Iguchi A, Omori K, Suzuki Y, Ei I, Kazama JJ, Gejyo F, Narita I
  • Organizer: ASN Kidney Week 2016
  • Place of Presentation: イリノイ州（米国）
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] Molecular mechanisms and therapeutic interventions of uremic toxins-induced cardiovascular disease in CKD (2016)
  • Author(s): 山本卓
  • Organizer: 第59回日本腎臓学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-06-17
  • Invited
• [Presentation] ヘキサデシル基固定セルロースビーズは蛋白結合尿毒症物質を吸着する (2016)
  • Author(s): 山本卓、風間順一郎、佐藤茉美、若松拓也、高橋良光、惠以盛、大森健太郎、井口昭、鈴木靖、成田一衛
  • Organizer: 第61回日本透析医学会学術総会・集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-06-11
• [Presentation] Atherosclerosis Following Renal Injury is Ameliorated by Pioglitazone and Losartan via Macrophage Phenotype (2015)
  • Author(s): Suguru Yamamoto, Jianyong Zhong, Patricia G. Yancey, Yiqin Zuo, Macrae F. Linton, Sergio Fazio, Haichun Yang, Ichiei Narita and Valentina Kon
  • Organizer: Kidney week 2015
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] 血液透析導入時に1年予後を予測するスコアの開発と検証 (2015)
  • Author(s): 山本 卓 ,土井 俊樹 ,森永 貴理 ,佐田 憲映 ,栗田 宜明 ,大西 良浩
  • Organizer: 第60回日本透析医学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2015-06-26
• [Presentation] 尿毒素物質の除去と患者予後  (2015)
  • Author(s): 山本卓,風間順一郎,成田一衛
  • Organizer: 第60回日本透析医学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] 経口吸着炭薬は維持血液透析患者の蛋白結合尿毒素物質と酸化ストレスを減少させる (2015)
  • Author(s): 山本卓、大森健太郎、松尾浩司、 高橋良光 、川村和子、 丸山弘樹、渡邊博志、丸山徹、風間順一郎、成田一衛
  • Organizer: 第58回日本腎臓学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-06-08
• [Presentation] Indoxyl sulfate induces proinflammatory cytokine production and inhibits cholesterol efflux due to downregulation of ABCG1 in macrophages (2015)
  • Author(s): Koji Matsuo, Suguru Yamamoto, Yoshimitsu Takahashi, Kazuko Kawamura, Junichiro J. Kazama, Ichiei Narita
  • Organizer: ERA-EDTA 52nd congress
  • Place of Presentation: London (UK)
  • Year and Date: 2015-05-28
  • Int'l Joint Research
• [Book] 今日の治療指針2016年版 (2016)
  • Author(s): 山本卓
  • Total Pages: 2
  • Publisher: 医学書院
• [Book] 腎と骨ーCKD-MBDの概念から新たな展開へー (2015)
  • Author(s): 山本卓、成田一衛
  • Total Pages: 4
  • Publisher: 医学ジャーナル
• [Book] 腎と透析 (2015)
  • Author(s): 山本卓、風間順一郎、成田一衛
  • Total Pages: 4
  • Publisher: 東京医学社