Proteomic analysis of IgA immune complxes in IgA nephropathy

• Project/Area Number: 16K09632
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Fujita Health University
• Principal Investigator: Takahashi Kazuo 藤田医科大学, 医学部, 講師 (90631391)
• Co-Investigator(Kenkyū-buntansha): 湯澤 由紀夫 藤田医科大学, 医学部, 教授 (00191479) ; 水野 智博 名城大学, 薬学部, 助教 (40711669)
• Research Collaborator: Novak Jan University of Alabama at Birmingham
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: IgA腎症 / プロテオミクス / 質量分析計 / 免疫複合体 / 糖鎖 / 質量分析 / バイオマーカー開発

Outline of Final Research Achievements

Serum level of abnormally glycosylated IgA1 is elevated in patients with IgA nephropathy (IgAN) and formation of circulating IgA-immune complexes (IgA-IC) leads glomerular deposition. To address molecular characterization of IgA-IC, we quantitatively identified proteins in IgA-IC as well as in glomeruli derived from IgAN patients. Quantitative assessment of IgA-protein complex identified 38 proteins increasing more in IgAN than healthy control. Within these 38 proteins, 10 proteins were decreasing after treatment. Regarding glomerular proteome, we detected 290 proteins increasing in IgAN. Proteins increasing both in blood and glomerulus seems to be proteins related with glomerular deposition and/ or pathogenic pathway. Analysis of both IgA-IC from serum and tissue by proteomic technique is a promising powerful method to identify specific proteins related with the pathogenesis of IgAN.

Academic Significance and Societal Importance of the Research Achievements

IgA腎症ではIgA免疫複合体が沈着し腎炎を発症すると考えられるため，糸球体沈着性IgA免疫複合体の構造を明らかとすることより，IgA免疫複合体沈着機序の解明，IgA免疫複合体の新規バイオマーカーとしての応用，さらにはIgA免疫複合体をターゲットとした新規創薬に繋がることが期待される。

Research Products

• [Journal Article] Detection and identification of potential transglutaminase 2 substrates in the mouse renal glomeruli. (2018)
  • Author(s): Ｉｔｏ Ｙ．， Ｔａｔｓｕｋａｗａ Ｈ．， Ｙａｍａｇｕｃｈｉ Ｈ．， Ｔａｋａｈａｓｈｉ Ｋ．， Ｈｉｔｏｍｉ Ｋ．， ａｎｄ Ｙｕｓｚａｗａ Ｙ．
  • Journal Title: Arch. Biochem. Biophys. Volume: 660 Pages: 11-19
  • DOI: 10.1016/j.abb.2018.10.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mass spectrometry-based approach for development of biomarkers in IgA nephropathy: a pilot trial (2018)
  • Author(s): Kondo A, Takahashi K, Yamaguchi H, Yoshida Y, Mizuno T, Nakajima K, Hayashi H, Koide S, Inaguma D, Hasegawa M, Hiki Y, Yuzawa Y.
  • Journal Title: Fujita Medical Journal Volume: 4 Issue: 2 Pages: 36-41
  • DOI: 10.20407/fmj.4.2_36
  • NAID: 130007381892
  • ISSN: 2189-7247, 2189-7255
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification and characterization of UDP-mannose in human cell lines and mouse organs: Differential distribution across brain regions and organs (2018)
  • Author(s): Nakajima Kazuki、Kizuka Yasuhiko、Yamaguchi Yoshiki、Hirabayashi Yoshio、Takahashi Kazuo、Yuzawa Yukio、Taniguchi Naoyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 1 Pages: 401-407
  • DOI: 10.1016/j.bbrc.2017.10.173
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chondroitin sulfate protects vascular endothelial cells from toxicities of extracellular histones (2018)
  • Author(s): Nagano Fumihiko、Mizuno Tomohiro、Mizumoto Shuji、Yoshioka Kengo、Takahashi Kazuo、Tsuboi Naotake、Maruyama Shoichi、Yamada Shuhei、Nagamatsu Tadashi
  • Journal Title: European Journal of Pharmacology Volume: 826 Pages: 48-55
  • DOI: 10.1016/j.ejphar.2018.02.043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mass spectrometry-based approach for development of biomarkers in IgA nephropathy: a pilot trial (2018)
  • Author(s): Ayako Kondo, Kazuo Takahashi, Hisateru Yamaguchi, Yuri Yoshida, Tomohiro Mizuno, Kazuki Nakajima, Hiroki Hayashi, Shigehisa Koide, Daijo Inaguma, Midori Hasegawa, Yoshiyuki Hiki, Yukio Yuzawa
  • Journal Title: Fujita Medical Journal Volume: 4
  • NAID: 130007381892
  • Peer Reviewed / Open Access
• [Journal Article] The Level of IgA Antibodies to Endothelial Cells Correlates with Histological Evidence of Disease Activity in Patients with Lupus Nephritis. (2016)
  • Author(s): Kondo A, Takahashi K, Mizuno T, Kato A, Hirano D, Yamamoto N, Hayashi H, Koide S, Takahashi H, Hasegawa M, Hiki Y, Yoshida S, Miura K, Yuzawa Y.
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0163085-e0163085
  • DOI: 10.1371/journal.pone.0163085
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] omparison of IgA1 hinge-region O-glycoforms between patients with IgA nephropathy and healthy subjects. (2018)
  • Author(s): Ohyama Y, Takahashi K, Yamaguchi H, Matsushita S, Nakajima K, Hayashi H, Koide S, Inaguma D, Hasegawa M, Renfrow MB, Novak J, Hiki Y, Yuzawa Y.
  • Organizer: Kidney Week 2018
  • Int'l Joint Research
• [Presentation] Comparison of IgA1 hinge-region O-glycoforms and Gd-IgA level between patients with IgA nephropathy and healthy subjects. (2018)
  • Author(s): Ohyama Y, Takahashi K, Yamaguchi H, Matsushita S, Nakajima K, Hayashi H, Koide S, Inaguma D, Hasegawa M, Renfrow MB, Novak J, Hiki Y, Yuzawa Y.
  • Organizer: International IgA Nephropathy Symposium 2018
  • Int'l Joint Research
• [Presentation] Detection and Identification of Potential Transglutaminase Substrates in Mouse Renal Glomeruli. (2018)
  • Author(s): Ito Y, Tatsukawa H, Yamaguchi H, Takahashi K, Yuzawa Y, Hitomi K.
  • Organizer: Gordon Research Conference on Transglutaminases in Human Disease Processes. 2018
  • Int'l Joint Research
• [Presentation] Analysis of IgA1 hinge-region O-glycoforms of multiracial healthy subjects by mass spectrometry. (2018)
  • Author(s): Ohyama Y, Takahashi K, Matsushita S, Yamaguchi H, Nakajima K, Mizuno T, Hayashi H, Koide S, Inaguma D, Hasegawa M, Renfrow MB, Novak J, Hiki Y, Yuzawa Y.
  • Organizer: ISN Frontiers Meeting 2018
  • Int'l Joint Research
• [Presentation] 腎疾患におけるプロテオーム解析を用いたバイオマーカー開発とその展望 (2018)
  • Author(s): 高橋 和男，湯澤 由紀夫
  • Organizer: 第61回日本腎臓学会学術総会 2018
• [Presentation] DKDの新規バイオマーカー開発 (2018)
  • Author(s): 中嶋 和紀，高橋 和男，湯澤 由紀夫
  • Organizer: 第48回日本腎臓学会西部学術大会 2018
• [Presentation] 糖尿病モデルマウスにおけるキヌレニン経路代謝物の腎組織イメージング質量分析． (2018)
  • Author(s): 松下 祥子，高橋 和男，伊藤 辰将，山本 康子，藤垣 英嗣，毛利 彰宏，中嶋 和紀，尾之内 高慶，辰川 英樹，釘田 雅則，長尾 静子，人見 清隆，齋藤 邦明，瀬藤 光利，湯澤 由紀夫．
  • Organizer: 第61回日本腎臓学会学術総会 2018
• [Presentation] 糖脂質合成酵素阻害剤はグルコース代謝を介してADPKDの病態を抑制する． (2018)
  • Author(s): 中嶋 和紀，石橋 洋平，釘田 雅則，中尾 静羽，高橋 和男，永松 正，長尾 静子，湯澤 由紀夫．
  • Organizer: 第61回日本腎臓学会学術総会 2018
• [Presentation] 健常人ＩｇＡ１糖鎖構造人種間比較． (2018)
  • Author(s): 大山 友香子，高橋 和男，山口 央輝，松下 祥子，中嶋 和紀，林 宏樹，小出 滋久，稲熊 大城，長谷川 みどり，比企 能之，湯澤 由紀夫．
  • Organizer: 第61回日本腎臓学会学術総会 2018
• [Presentation] 腎糸球体におけるタンパク質架橋接着酵素 (Transglutaminase 2) の基質候補探索と同定． (2018)
  • Author(s): 伊藤 辰将, 辰川 英樹, 山口 央輝, 高橋 和男, 人見 清隆, 湯澤 由紀夫．
  • Organizer: 第9回分子腎臓フォーラム 2018
• [Presentation] マウス腎糸球体内で架橋される組織型トランスグルタミナーゼ基質候補タンパク質の網羅的解析． (2018)
  • Author(s): 伊藤 辰将，辰川 英樹，山口 央輝，高橋 和男，人見 清隆，湯澤 由紀夫．
  • Organizer: 第43回日本医用マススペクトル学会年会 2018
• [Presentation] 腎糸球体病変特異的なタンパク質の解析． (2018)
  • Author(s): 松下 祥子，高橋 和男，大山 友香子，山口 央輝，中嶋 和紀，湯澤 由紀夫．
  • Organizer: 第45回BMSコンファレンス 2018
• [Presentation] 段階的脱グリコシル化法を用いた正常人IgA1 O結合型糖鎖構造の人種間比較． (2018)
  • Author(s): 大山 友香子，高橋 和男，山口 央輝，加藤 彰浩，松下 祥子，吉田 祐理，水野 智博，深町 幸宏，横井 靖人，比企 能之，湯澤 由紀夫．
  • Organizer: 日本質量分析学会・日本プロテオーム学会2018年合同大会 2018
• [Presentation] IgA1 O結合型糖鎖構造の人種間比較． (2018)
  • Author(s): 大山 友香子，高橋 和男，松下 祥子，山口 央輝，Matthew B. Renfrow，Jan Novak，比企 能之，湯澤 由紀夫．
  • Organizer: 第4１回ＩｇＡ腎症研究会学術集会 2018
• [Presentation] Analysis of IgA1 hinge-region O-glycoforms of multiracial healthy subjects by mass spectrometry. (2018)
  • Author(s): Yukako Ohyama, Kazuo Takahashi, Shoko Matsushita, Hisateru Yamaguchi, Kazuki Nakajima, Tomohiro Mizuno, Hiroki Hayashi, Shigehisa Koide, Daijo Inaguma, Midori Hasegawa, Matthew B. Renfrow, Jan Novak, Yoshiyuki Hiki, Yukio Yuzawa
  • Organizer: ISN Frontiers Meeting 2018
• [Presentation] Racial Comparison of IgA1 Hinge-Region O-Glycoforms by High-Resolution Mass Spectrometry. (2017)
  • Author(s): ukako Ohyama, Kazuo Takahashi, Shoko Matsushita, Hisateru Yamaguchi, Kazuki Nakajima, Tomohiro Mizuno, Hiroki Hayashi, Shigehisa Koide, Daijo Inaguma, Midori Hasegawa, Jan Novak, Yoshiyuki Hiki, Yukio Yuzawa.
  • Organizer: Kidney Week 2017
• [Presentation] Comprehensive high-throughput analysis of IgA1 O-glycoforms by a sequential deglycosylation protocol. (2017)
  • Author(s): Kazuo Takahashi, Hisateru Yamaguchi, Yukako Ohyama, Akihiro Kato, Shoko Matsushita, Yuri Yoshida, Tomohiro Mizuno, Yukihiro Fukamachi, Yasuto Yokoi, Yoshiyuki Hiki, Matthew B. Renfrow, Jan Novak, Yukio Yuzawa.
  • Organizer: 16th Human Proteome Organisation World Congress.
• [Presentation] 1.Comprehensive Analysis of IgA1 Hinge-region O-glycoforms in Patients with IgA Nephropathy. (2016)
  • Author(s): Takahashi K, Yamaguchi H, Ohyama Y, Kato A, Mizuno T, Hiki Y, Renfrow MB, Novak J, Yuzawa Y.
  • Organizer: Annual Meeting of American Society of Nephrology
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] 2.Elucidation of the Roles of Tissue Transglutaminase in Mesangial Proliferative Glomerulonephritis. (2016)
  • Author(s): Kato A, Mizuno T, Takahashi K, Yoshida Y, Tatsukawa H, Mizuno M, Hitomi K, Yuzawa Y.
  • Organizer: Annual Meeting of American Society of Nephrology
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of IgA1 hinge-region O-glycoforms by a sequential deglycosylation protoco (2016)
  • Author(s): Takahashi K, Yamaguchi H, Ohyama Y, Kato A, Yoshida Y, Mizuno T, Hiki Y, Renfrow MB, Novak J, Yuzawa Y.
  • Organizer: International IgA Nephropathy Symposium
  • Place of Presentation: Tour, France
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Presentation] Mesangial Tissue Transglutaminase Activity in Patients with IgA Nephropathy: Implications for the Pathogenesis (2016)
  • Author(s): Takahashi K, Mizuno T, Onouchi T, Yoshida Y, Ohyama Y, Akiyama S, Tatsukawa H, Hiki Y, Kusaka M, Nagamatsu T, Tsutsumi Y, Maruyama S, Kitamura H, Novak J, Hitomi K, Yuzawa Y
  • Organizer: International IgA Nephropathy Symposium
  • Place of Presentation: Tour, France
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Remarks] 藤田医科大学医学部腎臓内科学IgA腎症研究グループ
  • URL: http://fujita-jin.blogat.jp/blog/2013/02/iga-f52d.html
• [Remarks] 藤田保健衛生大学医学部腎内科学IgA腎症研究グループ
  • URL: http://fujita-jin.blogat.jp/blog/2013/02/iga-f52d.html