Role of local inflammation in the kidney for the development and progression of chronic kidney disease and its regulation toward novel therapeutic strategy

• Project/Area Number: 17K09706
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kumamoto University
• Principal Investigator: MUKOYAMA Masashi 熊本大学, 大学院生命科学研究部(医), 教授 (40270558)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 慢性腎臓病 / 糖尿病性腎症 / 腎炎 / 自然炎症 / マクロファージ / ERストレス / ANGPTL2 / MRP8 / 糖尿病性腎臓病 / 慢性炎症 / 細胞連関 / メサンギウム / ポドサイト / バイオマーカー

Outline of Final Research Achievements

Diabetes and glomerulonephritis are the leading cause of chronic kidney disease (CKD), an important disease category with high prevalence in Japan. The mechanisms for CKD development and progression are still poorly understood, and therefore we investigated the role of chronic homeostatic inflammation in the kidney in this pathophysiology.
We found that a macrophage-derived proinflammatory factor MRP8 (myeloid-related protein 8, or S100A8) is critical in the progression of nephrotoxic serum-induced glomerulonephritis in mice, by affecting macrophage characterization toward an M1 phenotype. In human studies, the serum MRP8/MRP14 heterodimer level was increased in chronic hemodialysis patients, which was significantly associated with high risk of all-cause mortality among the high phosphate group. Also, a high serum level of ANGPTL2 was an independent risk factor for all-cause mortality in hemodialysis patients. These findings may provide potential therapeutic targets for CKD.

Academic Significance and Societal Importance of the Research Achievements

生活習慣病や腎炎における局所因子の意義、特にマクロファージ由来MRP8の増悪因子としての役割を明らかにすることで、これをターゲットとした新たな創薬への基盤となる。さらに、急性腎障害の慢性化に及ぼす因子を明らかにすることにより、それらへの介入によって腎症進展抑止のための治療戦略となる。MRP8やANGPTL2はその候補分子であり、これらを標的とした治療法はなく、病態での意義の解析から新たな治療戦略の提案へとつながる可能性がある。一方で、これらの血中濃度高値は透析患者の予後と相関することから、バイオマーカーとしての意義が示唆され、今後の腎疾患診療に対して多大な波及効果をもたらすと考えられる。

Research Products

• [Int'l Joint Research] Max Planck Institute(ドイツ)
• [Int'l Joint Research] University of Bristol(United Kingdom)
• [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] Pivotal role of podocyte autophagy against glomerular endothelial dysfunction in diabetes. (2020)
  • Author(s): Yoshibayashi M, Kume S, Yasuda-Yamahara M, Yamahara K, Takeda N, Osawa N, Chin-Kanasaki M, Nakae Y, Yokoi H, Mukoyama M, Asanuma K, Maegawa H, Araki SI.
  • Journal Title: Biochem Biophys Res Commun. Volume: 525 Issue: 2 Pages: 319-325
  • DOI: 10.1016/j.bbrc.2020.02.088
  • 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] Usefulness of the quantitative measurement of urine protein at a community-based health checkup: A cross-sectional study. (2020)
  • Author(s): M. Naruse、M. Mukoyama、J. Morinaga、M. Miyazaki、K. Iseki、K. Yamagata
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Issue: 1 Pages: 45-52
  • DOI: 10.1007/s10157-019-01789-4
  • Peer Reviewed
• [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] Autosomal dominant Alport syndrome due to a COL4A4 mutation with an additional ESPN variant detected by whole-exome analysis (2019)
  • Author(s): Izumi Yuichiro, Hamaguchi Ami, Miura Rei, Nakagawa Terumasa, Nakagawa Miyuki, Saida Ken, Miyake Noriko, Nagayoshi Yu, Kakizoe Yutaka, Miyoshi Taku, Kohda Yukimasa, Misumi Yohei, Matsumoto Naomichi, Ando Yukio, Mukoyama Masashi.
  • Journal Title: CEN Case Reports Volume: 9 Issue: 1 Pages: 59-64
  • DOI: 10.1007/s13730-019-00429-w
  • Peer Reviewed / Open Access
• [Journal Article] Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity (2019)
  • Author(s): Narita Yuki、Hamamura Kana、Kashiyama Mami、Utsumi Sara、Kakizoe Yutaka、Kondo Yuki、Ishitsuka Yoichi、Jono Hirofumi、Irie Tetsumi、Mukoyama Masashi、Saito Hideyuki、Kadowaki Daisuke、Hirata Sumio、Kitamura Kenichiro
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 17 Pages: 4140-4140
  • DOI: 10.3390/ijms20174140
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Roles of matricellular CCN2 deposited by osteocytes in osteoclastogenesis and osteoblast differentiation (2019)
  • Author(s): Nishida T, Kubota S, Yokoi H, Mukoyama M, Takigawa M
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10913-10913
  • DOI: 10.1038/s41598-019-47285-3
  • Peer Reviewed / Open Access
• [Journal Article] Manipulation of nephron-patterning signals enables selective induction of podocytes from human pluripotent stem cells. (2019)
  • Author(s): Yoshimura Y, Taguchi A, Tanigawa S, Yatsuda J, Kamba T, Takahashi S, Kurihara H, Mukoyama M, Nishinakamura R.
  • Journal Title: Journal of the American Society of Nephrology Volume: 30 Issue: 2 Pages: 304-321
  • DOI: 10.1681/asn.2018070747
  • Peer Reviewed
• [Journal Article] Sirtuin 7 Deficiency Ameliorates Cisplatin-induced Acute Kidney Injury Through Regulation of the Inflammatory Response (2018)
  • Author(s): Miyasato Yoshikazu、Yoshizawa Tatsuya、Sato Yoshifumi、Nakagawa Terumasa、Miyasato Yuko、Kakizoe Yutaka、Kuwabara Takashige、Adachi Masataka、Ianni Alessandro、Braun Thomas、Komohara Yoshihiro、Mukoyama Masashi、Yamagata Kazuya
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5927-5927
  • DOI: 10.1038/s41598-018-24257-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guanylyl cyclase A in both renal proximal tubular and vascular endothelial cells protects the kidney against acute injury in rodent experimental endotoxemia models. (2018)
  • Author(s): Kidney against Acute Injury in Rodent Experimental Endotoxemia Models. Kitamura H, Nakano D, Sawanobori Y, Asaga T, Yokoi H, Yanagita M, Mukoyama M, Tokudome T, Kangawa K, Shirakami G, Nishiyama A.
  • Journal Title: Anesthesiology Volume: 印刷中 Issue: 2 Pages: 296-310
  • DOI: 10.1097/aln.0000000000002214
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Doxycycline attenuates cisplatin-induced acute kidney injury through pleiotropic effects (2018)
  • Author(s): Nakagawa T, Kakizoe Y, Iwata Y, Miyasato Y, Mizumoto T, Adachi M, Izumi Y, Kuwabara T, Suenaga N, Narita Y, Jono H, Saito H, Kitamura K, Mukoyama M
  • Journal Title: Am J Physiol Renal Physiol Volume: 315 Issue: 5 Pages: 1347-1357
  • DOI: 10.1152/ajprenal.00648.2017
  • Peer Reviewed
• [Journal Article] Association of circulating ANGPTL 3, 4, and 8 levels with medical status in a population undergoing routine medical checkups: A cross-sectional study. (2018)
  • Author(s): Morinaga J, Zhao J, Endo M, Kadomatsu T, Miyata K, Sugizaki T, Okadome Y, Tian Z, Horiguchi H, Miyashita K, Maruyama N, Mukoyama M, Oike Y.
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0193731-e0193731
  • DOI: 10.1371/journal.pone.0193731
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation (2017)
  • Author(s): Toda Naohiro、Mori Kiyoshi、Kasahara Masato、Koga Kenichi、Ishii Akira、Mori Keita P、Osaki Keisuke、Mukoyama Masashi、Yanagita Motoko、Yokoi Hideki
  • Journal Title: Nephrology Dialysis Transplantation Volume: - Issue: 6 Pages: 943-953
  • DOI: 10.1093/ndt/gfx317
  • Peer Reviewed / Open Access
• [Journal Article] Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition. (2017)
  • Author(s): Y. Kato, K. Mori, M. Kasahara, K. Osaki, A. Ishii, K.P. Mori, N. Toda, S. Ohno, T. Kuwabara, T. Tokudome, I. Kishimoto, M.A. Saleem, T. Matsusaka, K. Nakao, M. Mukoyama, M. Yanagita, H. Yokoi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 46624-46624
  • DOI: 10.1038/srep46624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TSS-Seq analysis of low pH-induced gene expression in intercalated cells of the renal collecting duct (2017)
  • Author(s): Izumi Y
  • Journal Title: PLos One Volume: 12 Issue: 8 Pages: e0184185-e0184185
  • DOI: 10.1371/journal.pone.0184185
  • Peer Reviewed / Open Access
• [Journal Article] O-linked β-N-acetylglucosamine modification of proteins is essential for foot process maturation and survival in podocytes. (2017)
  • Author(s): Ono S, Kume S, Yasuda-Yamahara M, Yamahara K, Takeda N, Chin-Kanasaki M, Araki H, Sekine O, Yokoi H, Mukoyama M, Uzu T, Araki SI, Maegawa H.
  • Journal Title: Nephrol Dial Transplant. Volume: 未定 Issue: 9 Pages: 000-000
  • DOI: 10.1093/ndt/gfw463
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A protease-activated receptor-1 antagonist protects against podocyte injury in a mouse model of nephropathy (2017)
  • Author(s): Guan Yu、Nakano Daisuke、Zhang Yifan、Li Lei、Liu Wenhua、Nishida Motohiro、Kuwabara Takashige、Morishita Asahiro、Hitomi Hirofumi、Mori Kiyoshi、Mukoyama Masashi、Masaki Tsutomu、Hirano Katsuya、Nishiyama Akira
  • Journal Title: J Pharmacol Sci Volume: 135 Issue: 2 Pages: 81-88
  • DOI: 10.1016/j.jphs.2017.09.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance. (2017)
  • Author(s): Kanai Y, Yasoda A, Mori KP, Watanabe-Takano H, Nagai-Okatani C, Yamashita Y, Hirota K, Ueda Y, Yamauchi I, Kondo E, Yamanaka S, Sakane Y, Nakao K, Fujii T, Yokoi H, Minamino N, Mukoyama M, Mochizuki N, Inagaki N.
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 11 Pages: 4136-4147
  • DOI: 10.1172/jci94912
  • Peer Reviewed / Open Access
• [Journal Article] Obesity-promoting and anti-thermogenic effects of neutrophil gelatinase-associated lipocalin in mice (2017)
  • Author(s): Ishii Akira、Katsuura Goro、Imamaki Hirotaka、Kimura Hiroyuki、Mori Keita P.、Kuwabara Takashige、Kasahara Masato、Yokoi Hideki、Ohinata Kousaku、Kawanishi Tomoko、Tsuchida Junichi、Nakamoto Yuji、Nakao Kazuwa、Yanagita Motoko、Mukoyama Masashi、Mori Kiyoshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 15501-15501
  • DOI: 10.1038/s41598-017-15825-4
  • Peer Reviewed / Open Access
• [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
  • Organizer: ISN 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 Hata
  • Organizer: ISN World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] Investigation of the role of renal tubular NFAT5 in renal fibrogenesis caused by unilateral ureteral obstruction. (2019)
  • Author(s): Makoto Ono
  • 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 Hata
  • Organizer: Annual Meeting of the American society of Nephrology
  • Int'l Joint Research
• [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
  • 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
  • Organizer: Annual Meeting of the American society of Nephrology
  • Int'l Joint Research
• [Presentation] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study. (2019)
  • Author(s): Jun Morinaga
  • Organizer: Annual Meeting of the American society of Nephrology
  • Int'l Joint Research
• [Presentation] Urinary plasmin plays pathogenic roles for the development of hypertension in Dahl salt-sensitive rats. (2019)
  • Author(s): Yasunobu Iwata
  • Organizer: Annual Meeting of the American society of Nephrology
  • Int'l Joint Research
• [Presentation] Regulation of Rhcg protein in the intercalated cells of the outer medullary collecting ducts by aldosterone. (2019)
  • Author(s): Yuichiro Izumi
  • Organizer: Annual Meeting of the American society of Nephrology
  • Int'l Joint Research
• [Presentation] 高血圧・腎臓病の病態と臓器連関：Na利尿ペプチド系および炎症・プロテアーゼの意義 (2019)
  • Author(s): 向山政志
  • Organizer: 第62回日本腎臓学会学術総会
  • Invited
• [Presentation] メタボリック症候群や慢性腎臓病におけるホルモン異常と高血圧 (2019)
  • Author(s): 柿添 豊、向山政志
  • Organizer: 第42回日本高血圧学会総会
  • Invited
• [Presentation] 高血圧、CKDの病態と臓器連関：内分泌因子と炎症の意義 (2019)
  • Author(s): 向山政志
  • Organizer: 第13回日本腎臓病薬物療法学会学術集会・総会
  • Invited
• [Presentation] Post-translational modification of MRP8 (S100A8) and its role in chronic kidney disease. (2018)
  • Author(s): Tomoko Kanki
  • Organizer: The 55th ERA-EDTA Congress
  • Int'l Joint Research
• [Presentation] The effects of serine protease inhibition on salt-sensitive hypertension and podocyte injury in metabolic syndrome model rats. (2018)
  • Author(s): Yutaka Kakizoe
  • Organizer: The 55th ERA-EDTA Congress
  • Int'l Joint Research
• [Presentation] Serine protease inhibition attenuates glomerular injuries in salt-sensitive hypertension. (2018)
  • Author(s): Yasunobu Iwata
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension
  • Int'l Joint Research
• [Presentation] Effects of obesity on urinary acid excretion and kidney injury in chronic kidney disease. (2018)
  • Author(s): Yuichiro Izumi
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension
  • Int'l Joint Research
• [Presentation] Intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ER-associated degradation processes and induces podocyte injury in diabetic nephropathy. (2018)
  • Author(s): Daisuke Fujimoto
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Effects of TGF-beta1 on the activity of NFAT5, an osmoprotective transcriptional factor. (2018)
  • Author(s): Yuichiro Izumi
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Expression of vascular endothelial growth factor-C in the kidney of aldosterone- and salt-induced hypertension in mice. (2018)
  • Author(s): Akiko Hara
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Osteocrin, a bone-derived humoral factor, exerts a renoprotective role in ischemia-reperfusion injury in mice. (2018)
  • Author(s): Yoshihiko Nishiguchi
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] 内分泌からみた心腎連関. (2018)
  • Author(s): 向山政志
  • Organizer: 第22回日本心血管内分泌代謝学会学術総会
  • Invited
• [Presentation] 糖尿病性腎臓病における腎局所炎症と小胞体ストレス応答障害. (2018)
  • Author(s): 桑原孝成, 藤本大介, 向山政志
  • Organizer: 第91回日本内分泌学会学術総会
  • Invited
• [Presentation] CKDにおけるMR拮抗薬の位置づけ. (2018)
  • Author(s): 向山政志
  • Organizer: 第41回日本高血圧学会総会
  • Invited
• [Presentation] 内分泌からみた心腎連関 (2018)
  • Author(s): 向山政志
  • Organizer: 第22回日本心血管内分泌代謝学会学術総会
  • Invited
• [Presentation] Local inflammatory mechanism aggravated by intraglomerular crosstalk in diabetic kidney. (2017)
  • Author(s): Shuro Umemoto
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] The effect of serine protease inhibition on glomerular injuries in salt-sensitive hypertension. (2017)
  • Author(s): Yasunobu Iwata
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Urinary acid excretion in overweight patients with chronic kidney disease. (2017)
  • Author(s): Yuichiro Izumi
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Upregulation of matrix metalloproteinase-10 in glomerular cells and macrophages by inflammation. (2017)
  • Author(s): Keisuke Osaki
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] 高血圧の成因・病態における慢性炎症と免疫 (2017)
  • Author(s): 向山政志
  • Organizer: 第40回日本高血圧学会総会
  • Invited
• [Presentation] 新規降圧薬の開発に向けて：ARNiの可能性 (2017)
  • Author(s): 向山政志
  • Organizer: 第53回高血圧関連疾患モデル学会学術総会
  • Invited