Elucidation of clinical significance of fatty acid-binding protein 4 in the kidney

• Project/Area Number: 16K09621
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: Marenao Tanaka 札幌医科大学, 医学部, 研究員 (60533362)
• Co-Investigator(Kenkyū-buntansha): 古橋 眞人 札幌医科大学, 医学部, 講師 (20563852)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脂肪酸結合タンパク4 / 糸球体障害 / 糸球体内皮細胞 / マクロファージ / 尿バイオマーカー / 脂肪酸結合タンパク４ / 糸球体内皮細胞障害 / 脂肪酸結合タンパク / 腎病理

Outline of Final Research Achievements

We confirmed ectopic expression of fatty acid binding protein 4 (FABP4) in the impaired glomeruli by immunohistochemistry examination using renal biopsy specimen, and that its localization is in glomerular endothelial cells. In healthy subjects, urinary FABP4 excretion is related to urinary albumin and decline of renal function, and in renal biopsy cases, urinary FABP4 excretion is significantly negatively correlated with renal function and urinary protein. In addition, we confirmed the novel expression and secretion of FABP4 in injured arterial endothelial cells by in vivo studies using mice. In nephritis and diabetes model, we confirmed FABP4 is newly expressed in glomerular endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

本研究によって早期糸球体障害マーカーとしての尿中FABP4排泄量の有用性が明らかにされ、今後臨床応用されることにより慢性腎臓病の発症早期からの治療介入が可能となり得る。また腎疾患では腎生検組織をFABP4で免疫染色することにより、予後の推定や治療反応性の推測が可能になり得る。今後さらにFABP4が糸球体係蹄内細胞増殖や糸球体上皮細胞の形態保持などに与える影響を分子生物学的メカニズムまで掘り下げて検討することにより、腎機能増悪や尿タンパク出現の機序の一端を解明される可能性がある。

Research Products

• [Journal Article] Plasma Xanthine Oxidoreductase Activity as a Novel Biomarker of Metabolic Disorders in a General Population (2018)
  • Author(s): Furuhashi M, Matsumoto M, Tanaka M, Moniwa N, Murase T, Nakamura T, Ohnishi H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Circulation Journal Volume: 82 Issue: 7 Pages: 1892-1899
  • DOI: 10.1253/circj.CJ-18-0082
  • NAID: 130007410626
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-06-25
  • Peer Reviewed / Open Access
• [Journal Article] Circulating Fatty Acid-Binding Protein 4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication (2018)
  • Author(s): Masato Furuhashi, Satoshi Yuda, Atsuko Muranaka, Mina Kawamukai, Megumi Matsumoto, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura
  • Journal Title: Circulation Journal Volume: 82 Issue: 4 Pages: 1121-1129
  • DOI: 10.1253/circj.CJ-17-1295
  • NAID: 130006528585
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid (2018)
  • Author(s): Furuhashi M, Mori K, Tanaka M, Maeda T, Matsumoto M, Murase T, Nakamura T, Koyama M, Moniwa N, Ohnishi H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Endocrine Journal Volume: 65 Issue: 11 Pages: 1083-1092
  • DOI: 10.1507/endocrj.EJ18-0127
  • NAID: 130007537274
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Independent links between plasma xanthine oxidoreductase activity and levels of adipokines. (2018)
  • Author(s): Furuhashi M, Matsumoto M, Murase T, Nakamura T, Higashiura Y, Koyama M, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: J Diabetes Investig Volume: 印刷中 Issue: 4 Pages: 1059-1067
  • DOI: 10.1111/jdi.12982
  • Peer Reviewed / Open Access
• [Journal Article] Serum FABP5 concentration is a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages. (2017)
  • Author(s): Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Kawamukai M, Omori A, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Shimamoto K, Miura T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 217-217
  • DOI: 10.1038/s41598-017-00177-w
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ectopic Fatty Acid-Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury (2017)
  • Author(s): Fuseya Takahiro, Furuhashi Masato, Matsumoto Megumi, Watanabe Yuki, Hoshina Kyoko, Mita Tomohiro, Ishimura Shutaro, Tanaka Marenao, Miura Tetsuji
  • Journal Title: J Am Heart Assoc Volume: 6 Issue: 9
  • DOI: 10.1161/jaha.117.006377
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study (2017)
  • Author(s): Tanaka Marenao、Moniwa Norihito、Ohnishi Hirofumi、Yamashita Tomohisa、Koyama Masayuki、Gocho Yufu、Nishizawa Keitaro、Kimura Yukishige、Sugawara Hirohito、Murakami Sayaka、Okazaki Yusuke、Furuhashi Masato、Yoshida Hideaki、Miura Tetsuji
  • Journal Title: Kidney Blood Press Res Volume: 42 Issue: 3 Pages: 553-564
  • DOI: 10.1159/000480487
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Crescentic Glomerulonephritis Complicated with Hypocomplementemic Urticarial Vasculitis Syndrome and ANCA-Associated Vasculitis (2017)
  • Author(s): Tanaka Marenao、Moniwa Norihito、Mita Tomohiro、Tobisawa Toshiyuki、Matsumoto Tamaki、Mochizuki Atsushi、Yamashita Tomohisa、Yano Toshiyuki、Furuhashi Masato、Miura Tetsuji
  • Journal Title: Case Rep Nephrol Dial Volume: 7 Issue: 3 Pages: 144-153
  • DOI: 10.1159/000484476
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptome and metabolome analyses in exogenous FABP4- and FABP5-treated adipose-derived stem cells. (2016)
  • Author(s): Yamamoto T, Furuhashi M, Sugaya T, Oikawa T, Matsumoto M, Funahashi Y, Matsukawa N, Gotoh M, Miura T.
  • Journal Title: PLoS ONE Volume: 11 Issue: 12 Pages: 1-19
  • DOI: 10.1371/journal.pone.0167825
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Independent link between levels of proprotein convertase subtilisin/kexin type 9 and FABP4 in a general population without medication. (2016)
  • Author(s): Furuhashi M, Omori A, Matsumoto M, Kataoka Y, Tanaka M, Moniwa N, Ohnishi H, Yoshida H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Am J Cardiol Volume: 118 Issue: 2 Pages: 198-203
  • DOI: 10.1016/j.amjcard.2016.04.037
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Local production of fatty acid-binding protein 4 in epicardial/perivascular fat and macrophages is linked to coronary atherosclerosis. (2016)
  • Author(s): Furuhashi M, Fuseya T, Murata M, Hoshina K, Ishimura S, Mita T, Watanabe Y, Omori A, Matsumoto M, Sugaya T, Oikawa T, Nishida J, Kokubu N, Tanaka M, Moniwa N, Yoshida H, Sawada N, Shimamoto K, Miura T.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 36 Issue: 5 Pages: 825-834
  • DOI: 10.1161/atvbaha.116.307225
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters. (2016)
  • Author(s): Furuhashi M, Hiramitsu S, Mita T, Omori A, Fuseya T, Ishimura S, Watanabe Y, Hoshina K, Matsumoto M, Tanaka M, Moniwa N, Yoshida H, Ishii J, Miura T.
  • Journal Title: Lipids Health Dis Volume: 15 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s12944-016-0177-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of use of angiotensin II receptor blocker on all-cause mortality in hemodialysis patients: prospective cohort study using a propensity-score analysis. (2016)
  • Author(s): Tanaka M, Yamashita T, Koyama M, Moniwa N, Ohno K, Mitsumata K, Itoh T, Furuhashi M, Ohnishi H, Yoshida H, Tsuchihashi K, Miura T; BOREAS HD study Investigators.
  • Journal Title: Clin Exp Nephrol. Volume: 20 Issue: 3 Pages: 469-478
  • DOI: 10.1007/s10157-015-1182-3
  • Peer Reviewed
• [Presentation] Ectopic Expression of Fatty Acid-Binding Protein 4 in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury (2018)
  • Author(s): Furuhashi M, Fuseya T, Mita T, Ishimura S, Tanaka M, Miura T.
  • Organizer: 第82回 日本循環器学会学術集会
• [Presentation] 糖尿病や検尿異常のない場合もLDLコレステロール高値はCKDの危険因子となる (2018)
  • Author(s): 長南新太,山下智久,大西浩文,塙なぎさ,田中希尚,茂庭仁人,古橋眞人,三浦哲嗣
  • Organizer: 第115回 日本内科学会総会
• [Presentation] 脂肪酸結合タンパク4 (FABP4) 濃度は動脈硬化進展度の予測因子である (2018)
  • Author(s): 古橋眞人,湯田 聡,村中敦子,川向美奈,松本めぐみ,田中希尚,茂庭仁人,大西浩文,斎藤重幸,三浦哲嗣
  • Organizer: 第61回 日本糖尿病学会年次学術集会
• [Presentation] 一般住民における尿酸低値例での血漿キサンチン酸化還元酵素(XOR)活性の検討 (2018)
  • Author(s): 森 和真,古橋眞人,田中希尚,村瀬貴代,中村敬志,前田卓人,大西浩文,三浦哲嗣
  • Organizer: 第61回 日本腎臓学会学術総会
• [Presentation] 腎疾患症例における尿FABP4排泄量の臨床的意義：腎生検例を用いた検討 (2018)
  • Author(s): 田中希尚,古橋眞人,松本めぐみ,山下智久,茂庭仁人,後町結,前田卓人,滝沢英毅,三浦哲嗣
  • Organizer: 第61回 日本腎臓学会学術総会
• [Presentation] Ectopic Expression of FABP4 in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury (2018)
  • Author(s): Furuhashi M, Fuseya T, Mita T, Ishimura S, Tanaka M, Miura T
  • Organizer: 第66回 日本心臓病学会学術集会
• [Presentation] キサンチン酸化還元酵素 (XOR) 活性とアディポカインとの関連 (2018)
  • Author(s): 東浦幸村,古橋眞人,松本めぐみ,小山雅之,田中希尚,茂庭仁人,村瀬貴代,中村敬志,大西浩文,斎藤重幸,島本和明,三浦哲嗣.
  • Organizer: 第41回 日本高血圧学会総会
• [Presentation] 腎疾患症例における尿FABP4排泄量の臨床的意義:腎生検例を用いた検討 (2018)
  • Author(s): 田中希尚、古橋眞人、松本めぐみ、山下智久、茂庭仁人、三浦哲嗣、後町結、前田卓人、滝沢英毅
  • Organizer: 第61回日本腎臓学会学術総会
• [Presentation] Serum FABP5 is a Potential Biomarker for Residual Risk of Atherosclerosis in Relation to Cholesterol Efflux from Macrophages. (2018)
  • Author(s): Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Kawamukai M, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Shimamoto K, Miura T.
  • Organizer: 第81回日本循環器学会
• [Presentation] シンポジウム「慢性腎臓病研究の進歩から見えてきた高血圧成因」慢性腎臓病の新規治療ターゲットとしての異所性FABP4の発現の可能性 (2017)
  • Author(s): 古橋眞人、田中希尚、三浦哲嗣
  • Organizer: 第40回日本高血圧学会
• [Presentation] SGLT2阻害薬カナグリフロジン投与による脂肪酸結合タンパク4(FABP4)濃度の経時的変化とその因子の検討 (2017)
  • Author(s): 古橋眞人、松本めぐみ、平光伸也、田中希尚、茂庭仁人、石井潤一、三浦哲嗣
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] Serum FABP4 concentration is independently associated with atherosclerosis in a general population without medication. (2017)
  • Author(s): Furuhashi M, Yuda S, Muranaka A, Kawamukai M, Matsumoto M, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Shimamoto K, Miura T.
  • Organizer: 第49回日本動脈硬化学会
• [Presentation] 血液透析患者への抗血小板剤投与の影響 (2017)
  • Author(s): 田中希尚、茂庭仁人、山下智久、古橋眞人、三浦哲嗣、小山雅之
  • Organizer: 第62回日本透析医学会
• [Presentation] ベバシズマブにより糸球体内皮細胞障害と高度タンパク尿を呈し薬剤中止とARBにて軽快した一例 (2017)
  • Author(s): 木村幸滋、山下智久、田中希尚、茂庭仁人、古橋眞人、三浦哲嗣、小川弥生
  • Organizer: 第47回日本腎臓学会東部学術大会
• [Presentation] Ectopic FABP4 expression in the vascular endothelium is involved in neointima formation after vascular injury. (2017)
  • Author(s): Furuhashi M, Fuseya T, Matsumoto M, Mita T, Ishimura S, Tanaka M, Moniwa N, Miura T.
  • Organizer: European Society of Cardiology Congress
  • Int'l Joint Research
• [Presentation] Circulating FABP4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication. (2017)
  • Author(s): Furuhashi M, Yuda S, Muranaka A, Kawamukai M, Matsumoto M, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Shimamoto K, Miura T
  • Organizer: American Heart Association
  • Int'l Joint Research
• [Presentation] PTTMA (Posttransplantation thrombotic microangiopathy) の二例 (2016)
  • Author(s): 安部功記、山下智久、田中希尚、茂庭仁人、古橋眞人、三浦哲嗣
  • Organizer: 日本腎臓学会東部大会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-10-07
• [Presentation] 造影剤腎症、薬剤性急性間質性腎炎との鑑別に難渋したコレステロール塞栓症の一例 (2016)
  • Author(s): 西沢慶太郎、山下智久、田中希尚、茂庭仁人、古橋眞人、野口寛子、三浦哲嗣
  • Organizer: 日本腎臓学会東部大会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-10-07
• [Presentation] 心房細動合併血液透析患者への複数抗血小板剤投与は出血と死亡のリスクを増大する (2016)
  • Author(s): 安部功記、田中希尚、茂庭仁人、山下智久、小山雅之、瀬野 結、井垣勇祐、古橋眞人、吉田英昭、三浦哲嗣
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-06-17
• [Presentation] 血液透析患者への複数抗血栓剤投与の影響 (2016)
  • Author(s): 瀬野 結、田中希尚、茂庭仁人、山下智久、小山雅之、西沢慶太郎、水野雅司、古橋眞人、吉田英昭、三浦哲嗣
  • Organizer: 日本透析医学会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-06-10