Role of MRP8 in the progression of glomerulonephritis

• Project/Area Number: 19K08728
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kumamoto University
• Principal Investigator: Kuwabara Takashige 熊本大学, 大学院生命科学研究部(医), 准教授 (00393356)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 内因性リガンド / MRP8 / 抗GBM腎炎 / 透析患者 / 生命予後 / 糸球体腎炎 / 急性腎障害 / ペプチドワクチン / マクロファージ / GBM腎炎 / Mincle / 腎炎 / 自然炎症 / 接着因子

Outline of Research at the Start

非感染性の慢性炎症は生活習慣病やその合併症、自己免疫疾患、ガンなど現代病の病態に重要である。申請者らはこれまでの検討により、自然炎症の一端を担うTLR4、およびその内因性リガンドの一つであるMRP8（S100A8)が糖尿病性腎症の進展に重要であることを報告してきた。MRP8は炎症局所で発現が強力に誘導され、TLR4シグナルを増幅することで病態悪化に関与すると考えられる。本研究では内因性リガンドMRP8が慢性腎臓病(CKD)進展に果たす役割を明らかにすることで、創薬ターゲットあるいは病態反映マーカーとしての可能性を検討する。

Outline of Final Research Achievements

The present study revealed that myeloid-related protein 8 (MRP8), which is involved in chronic inflammation, plays an important role in the development of glomerulonephritis (more precisely, the anti-GBM nephritis model) by affecting the character of bone marrow-derived cells (Hata Y, Kuwabara T. Sci Rep 2020). Furthermore, in the patients undergoing maintenance hemodialysis with hyperphosphatemia, we found that blood MRP8 levels were significantly associated with life expectancy (Kanki T, Kuwabara T. BMC Nephrol 2020).

Academic Significance and Societal Importance of the Research Achievements

本研究により、腎臓病の中でも予後不良とされる抗糸球体基底膜抗体腎炎の病態の一端を明かにすることができた。その中で内因性リガンドの一つであるMRP8が重要な役割を果たすことが分かり、今後の新しい治療標的となりうることが期待される。
また、維持血液透析患者は非透析患者と比較して生命予後は悪く、予後不良と関連するMRP8の病態的意義を明らかにしていくことが今後の課題となる。とりわけ心血管疾患が死亡の大きな原因であり、MRP8が心血管イベントリスクとどのように関わるのか、その機序解明が必要である。

Research Products

• [Journal Article] Role of renin-angiotensin system blockade in advanced CKD: to use or not to use? (2022)
  • Author(s): Mukoyama Masashi、Kuwabara Takashige
  • Journal Title: Hypertension Research Volume: - Issue: 6 Pages: 1072-1075
  • DOI: 10.1038/s41440-022-00902-7
  • Peer Reviewed
• [Journal Article] A Novel VCP modulator KUS121 exerts renoprotective effects in ischemia-reperfusion injury with retaining ATP and restoring ERAD-processing capacity. (2022)
  • Author(s): Hata Yusuke、Date Ryosuke、Fujimoto Daisuke、Ikeda Hanako Ohashi、Umemoto Shuro、Kanki Tomoko、Nishiguchi Yoshihiko、Mizumoto Teruhiko、Hayata Manabu、Kakizoe Yutaka、Izumi Yuichiro、Kakizuka Akira、Mukoyama Masashi、Kuwabara Takashige
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: - Issue: 5 Pages: F577-F586
  • DOI: 10.1152/ajprenal.00392.2021
  • Peer Reviewed / Open Access
• [Journal Article] Hyperglycemia and Thrombocytopenia ― Combinatorially Increase the Risk of Mortality in Patients With Acute Myocardial Infarction Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation ― (2021)
  • Author(s): Okadome Yusuke、Morinaga Jun、Fukami Hirotaka、Hori Kota、Ito Teruhiko、Sato Michio、Miyata Keishi、Kuwabara Takashige、Mukoyama Masashi、Suzuki Ryusuke、Tsunoda Ryusuke、Oike Yuichi
  • Journal Title: Circulation Reports Volume: 3 Issue: 12 Pages: 707-715
  • DOI: 10.1253/circrep.CR-21-0043
  • NAID: 130008128243
  • ISSN: 2434-0790
  • Year and Date: 2021-12-10
  • Peer Reviewed / Open Access
• [Journal Article] Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia (2021)
  • Author(s): Fukami Hirotaka、Morinaga Jun、Nakagami Hironori、Hayashi Hiroki、Okadome Yusuke、Matsunaga Eiji、Kadomatsu Tsuyoshi、Horiguchi Haruki、Sato Michio、Sugizaki Taichi、Kuwabara Takashige、Miyata Keishi、Mukoyama Masashi、Morishita Ryuichi、Oike Yuichi
  • Journal Title: Cell Reports Medicine Volume: 2 Issue: 11 Pages: 100446-100446
  • DOI: 10.1016/j.xcrm.2021.100446
  • Peer Reviewed / Open Access
• [Journal Article] Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition (2021)
  • Author(s): Handa Takaya、Mori Keita P.、Ishii Akira、Ohno Shoko、Kanai Yugo、Watanabe-Takano Haruko、Yasoda Akihiro、Kuwabara Takashige、Takahashi Nobuyuki、Mochizuki Naoki、Mukoyama Masashi、Yanagita Motoko、Yokoi Hideki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 21835-21835
  • DOI: 10.1038/s41598-021-01095-8
  • Peer Reviewed / Open Access
• [Journal Article] Osteocrin, a bone-derived humoral factor, exerts a renoprotective role in ischemia-reperfusion injury in mice (2021)
  • Author(s): Nishiguchi Yoshihiko、Hata Yusuke、Date Ryosuke、Fujimoto Daisuke、Umemoto Shuro、Kanki Tomoko、Yokoi Hideki、Mori Keita P、Handa Takaya、Watanabe-Takano Haruko、Kanai Yugo、Yasoda Akihiro、Izumi Yuichiro、Kakizoe Yutaka、Mochizuki Naoki、Mukoyama Masashi、Kuwabara Takashige
  • Journal Title: Nephrology Dialysis Transplantation Volume: 37 Issue: 3 Pages: 444-453
  • DOI: 10.1093/ndt/gfab286
  • Peer Reviewed / Open Access
• [Journal Article] Salt-Sensitive Hypertension of the Renal Tubular Cell-Specific NFAT5 (Nuclear Factor of Activated T-Cells 5) Knockout Mice (2021)
  • Author(s): Hiramatsu Akiko、Izumi Yuichiro、Eguchi Koji、Matsuo Naomi、Deng Qinyuan、Inoue Hideki、Nakayama Yushi、Nonoguchi Hiroshi、Aramburu Jose、Lopez-Rodriguez Cristina、Kakizoe Yutaka、Adachi Masataka、Kuwabara Takashige、Kim-Mitsuyama Shokei、Mukoyama Masashi
  • Journal Title: Hypertension Volume: 78 Issue: 5 Pages: 1335-1346
  • DOI: 10.1161/hypertensionaha.121.17435
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mineralocorticoid receptor blockers for moderate kidney dysfunction: more merit than ever? (2021)
  • Author(s): Mukoyama Masashi、Kuwabara Takashige、Adachi Masataka
  • Journal Title: Hypertension Research Volume: 44 Issue: 10 Pages: 1352-1354
  • DOI: 10.1038/s41440-021-00690-6
  • Peer Reviewed
• [Journal Article] A serine protease inhibitor camostat mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats (2021)
  • Author(s): Mizumoto Teruhiko、Kakizoe Yutaka、Nakagawa Terumasa、Iwata Yasunobu、Miyasato Yoshikazu、Uchimura Kohei、Adachi Masataka、Deng Qinyuan、Hayata Manabu、Morinaga Jun、Miyoshi Taku、Izumi Yuichiro、Kuwabara Takashige、Sakai Yoshiki、Tomita Kimio、Kitamura Kenichiro、Mukoyama Masashi
  • Journal Title: Journal of Pharmacological Sciences Volume: 146 Issue: 4 Pages: 192-199
  • DOI: 10.1016/j.jphs.2021.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of Rhcg, an ammonia transporter, by aldosterone in the kidney. (2021)
  • Author(s): Eguchi K, Izumi Y, Yasuoka Y, Nakagawa T, Ono M, Maruyama K, Matsuo N, Hiramatsu A, Inoue H, Nakayama Y, Nonoguchi H, Lee HW, Weiner ID, Kakizoe Y, Kuwabara T, Mukoyama M.
  • Journal Title: J Endocrinol. Volume: in press Issue: 2 Pages: 95-112
  • DOI: 10.1530/joe-20-0267
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study. (2020)
  • Author(s): Fukami H, Morinaga J, Okadome Y, Nishiguchi Y, Iwata Y, Kanki T, Nakagawa T, Izumi Y, Kakizoe Y, Kuwabara T, Horiguchi H, Sato M, Kadomatsu T, Miyata K, Tajiri T, Oike Y, Mukoyama M.
  • Journal Title: Atherosclerosis. Volume: 315 Pages: 18-23
  • DOI: 10.1016/j.atherosclerosis.2020.10.890
  • Peer Reviewed / Open Access
• [Journal Article] Suppressed ER-associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease. (2020)
  • Author(s): Fujimoto D, Kuwabara T, Hata Y, Umemoto S, Kanki T, Nishiguchi Y, Mizumoto T, Hayata M, Kakizoe Y, Izumi Y, Takahashi S, Mukoyama M.
  • Journal Title: FASEB J Volume: 34 Issue: 11 Pages: 854-860
  • DOI: 10.1096/fj.202000078rr
  • Peer Reviewed / Open Access
• [Journal Article] The predictive role of serum calprotectin on mortality in hemodialysis patients with high phosphoremia (2020)
  • Author(s): Kanki Tomoko、Kuwabara Takashige、Morinaga Jun、Fukami Hirotaka、Umemoto Shuro、Fujimoto Daisuke、Mizumoto Teruhiko、Hayata Manabu、Kakizoe Yutaka、Izumi Yuichiro、Tajiri Saeko、Tajiri Tetsuya、Kitamura Kenichiro、Mukoyama Masashi
  • Journal Title: BMC Nephrology Volume: 21 Issue: 1 Pages: 158-158
  • DOI: 10.1186/s12882-020-01812-x
  • Peer Reviewed / Open Access
• [Journal Article] Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk (2020)
  • Author(s): Hata Yusuke、Kuwabara Takashige、Mori Kiyoshi、Kan Youngna、Sato Yuki、Umemoto Shuro、Fujimoto Daisuke、Kanki Tomoko、Nishiguchi Yoshihiko、Yokoi Hideki、Kakizoe Yutaka、Izumi Yuichiro、Yanagita Motoko、Mukoyama Masashi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 3056-3056
  • DOI: 10.1038/s41598-020-59970-9
  • NAID: 120006956435
  • Peer Reviewed / Open Access
• [Journal Article] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study (2019)
  • Author(s): Morinaga J, Kakuma T, Fukami H, Hayata M, Uchimura K, Mizumoto T, Kakizoe Y, Miyoshi T, Shiraishi N, Adachi M, Izumi Y, Kuwabara T, Okadome Y, Sato M, Horiguchi H, Sugizaki T, Kadomatsu T, Miyata K, Tajiri S, Tajiri T, Tomita K, Kitamura K, Oike Y, Mukoyama M.
  • Journal Title: Nephrology Dialysis Transplantation Volume: 印刷中 Issue: 5 Pages: 854-860
  • DOI: 10.1093/ndt/gfz236
  • Peer Reviewed / Open Access
• [Journal Article] Regression of hepatitis C virus‐associated membranoproliferative glomerulonephritis with direct‐acting antiviral therapy after liver transplantation (2019)
  • Author(s): Okamura Keiko、Kuwabara Takashige、Enoki Hiroko、Kohda Yukimasa、Adachi Masataka、Hayashida Shintaro、Inomata Yukihiro、Mukoyama Masashi
  • Journal Title: Nephrology Volume: 24 Issue: 11 Pages: 1198-1199
  • DOI: 10.1111/nep.13492
• [Journal Article] Insufficiency of urinary acid excretion of overweight or obese patients with chronic kidney disease and its involvement with renal tubular injury. (2019)
  • Author(s): Eguchi K, Izumi Y, Nakayama Y, Inoue H, Marume T, Matsuo N, Hiramatsu A, Ono M, Kakizoe Y, Kuwabara T, Nonoguchi H, Mukoyama M.
  • Journal Title: Nephrology Volume: 24 Issue: 11 Pages: 1131-1141
  • DOI: 10.1111/nep.13553
  • Peer Reviewed
• [Presentation] Renal complications of immune checkpoint inhibitors」 (2021)
  • Author(s): Takashige Kuwabara
  • Organizer: 10th CKD Frontier
  • Invited
• [Presentation] Suppressed ER-associated degradation by intraglomerular crosstalk between podocytes and mesangial cells causes podocyte injury in diabetic kidney disease (2020)
  • Author(s): 藤本大介、桒原孝成、秦雄介、西口佳彦、柿添豊、泉裕一郎、向山政志
  • Organizer: 第24回日本心血管内分泌代謝学会学術総会/24th CVEM
• [Presentation] 骨由来分泌因子Osteocrinが腎障害進展に果たす役割の検討 (2020)
  • Author(s): 西口佳彦、桒原孝成、藤本大介、神吉智子、秦雄介、森慶太、横井秀基、泉裕一郎、柿添豊、望月直樹、向山政志
  • Organizer: 第56回高血圧関連疾患モデル学会学術総会
• [Presentation] 糖尿病性腎臓病における自然炎症と細胞連関 (2020)
  • Author(s): 桒原孝成、向山政志
  • Organizer: 第93回日本内分泌学会学術総会
  • Invited
• [Presentation] 生物学的癌治療と腎障害：免疫チェックポイント阻害薬を中心に (2020)
  • Author(s): 桒原孝成、向山政志
  • Organizer: 第50回日本腎臓学会西部学術大会
  • Invited
• [Presentation] 地域におけるCKD対策への取組みと腎臓病療養指導士の役割「イントロダクション」 (2020)
  • Author(s): 桒原孝成、向山政志
  • Organizer: 第50回日本腎臓学会西部学術大会
  • Invited
• [Presentation] Intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ER-associated degradation processes and induces podocyte injury in diabetes. (2019)
  • Author(s): Daisuke Fujimoto, Takashige Kuwabara, Yusuke Hata, Shuro Umemoto, Tomoko Kanki, Yoshihiko Nishiguchi, Teruhiko Mizumoto, Manabu Hayata, Yuichiro Izumi, Yutaka Kakizoe, Masashi Mukoyama
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] ABLATION OF MRP8 IN MYELOID CELLS AMELIORATES GLOMERULONEPHRITIS BY AFFECTING MACROPHAGE CHARACTERIZATION (2019)
  • Author(s): Yusuke Hata1, Takashige Kuwabara1, Kiyoshi Mori2, Shuro Umemoto1, Tomoko Kanki1, Daisuke Fujimoto1, Yoshihiko Nishiguchi1, Yutaka kakizoe1, Yuichiro Izumi1, Hideki Yokoi2, Masashi Mukoyama1
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] The predictive role of serum MRP8/14 (S100A8/A9) on mortality in hemodialysis patients (2019)
  • Author(s): Tomoko Kanki, Takashige Kuwabara, Jun Morinaga, Hirotaka Fukami, Shuro Umemoto, Daisuke Fujimoto, Teruhiko Mizumoto, Manabu Hayata, Yutaka Kakizoe, Yuichiro Izumi, Masashi Mukoyama
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] A Case of Ischemic Enteritis Complicated with Chylous Ascites After the Administration of Azelnidipine in a Patient Undergoing Peritoneal Dialysis. (2019)
  • Author(s): Takashige Kuwabara, Makoto Ono, Yu Korogi, Akira Oda, Hideki Inoue, Masashi Mukoyama
  • Organizer: ISPD2019 in Nagoya
  • Int'l Joint Research
• [Presentation] Intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ER-associated degradation processes and induces podocyte injury in diabetic kidney disease. (2019)
  • Author(s): Daisuke Fujimoto, Takashige Kuwabara, Yusuke Hata, Shuro Umemoto, Tomoko Kanki, Yoshihiko Nishiguchi, Teruhiko Mizumoto, Manabu Hayata, Yuichiro Izumi, Yutaka Kakizoe, Masashi Mukoyama
  • Organizer: World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] POTENTIAL ROLE OF MRP8 IN GLOMERULAR INJURY THROUGH INTRAGLOMERULAR CROSSTALK AFFECTING MACROPHAGE CHARACTERIZATION (2019)
  • Author(s): Yusuke Hata1, Takashige Kuwabara1, Kiyoshi Mori2, Shuro Umemoto1, Tomoko Kanki1, Daisuke Fujimoto1, Yoshihiko Nishiguchi1, Hideki Yokoi3, Masashi Mukoyama1
  • Organizer: World Congress of Nephrology
  • Int'l Joint Research
• [Remarks] 熊本大学腎臓内科学
  • URL: http://www.kumadai-nephrology.com/
• [Remarks] 熊本大学腎臓内科
  • URL: http://www.kumadai-nephrology.com/
• [Patent(Industrial Property Rights)] 腎保護用の組成物 (2020)
  • Inventor(s): 桒原孝成、池田華子、垣塚彰
  • Industrial Property Rights Holder: 桒原孝成、池田華子、垣塚彰
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-194628
  • Filing Date: 2020