Non-renal and enzymatic regulation of neutrophils in inflammatory kidney diseases

• Project/Area Number: 18K08232
• 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: The University of Tokyo
• Principal Investigator: Nishi Hiroshi 東京大学, 医学部附属病院, 講師 (90784174)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 好中球 / 腎臓 / 炎症 / 神経 / 血管生物学 / 白血球 / 血栓 / 腎

Outline of Final Research Achievements

Neutrophils accumulate and promote tissue damage in the kidneys during the active and acute stages of various inflammatory renal diseases. Therefore, we sought methods to regulate neutrophil activation from outside the kidney and intracellular space.
As extra-renal stimuli, we spoted unknown function of neurotransmitter molecules. Our studies have shown that some of these neurotransmitters may act protectively against inflammation.
As intra-cellular signaling, we focus on the phosphorylation signal pathway stimulated by migratory factors. In particular, a number of kinases activated by DNA and RNA is required for reactive oxidative species production, adhesion to vascular endothelium, and vascular migration, which was shown to play a role to interact with cytoskeleton and mediated vascular inflammation.

Academic Significance and Societal Importance of the Research Achievements

好中球は種々の炎症性腎疾患の活動期及び急性期の腎に蓄積し，脱顆粒や活性酸素放出などのメカニズムを通じて，組織障害を助長すると考えられている．そこで，疾患活動期に注目して，特に炎症性腎疾患における腎外・細胞内からの好中球制御する手段を模索してきた．
今後，好中球内の分子を標的にするような低分子化合物や上流シグナル遮断が可能になれば，炎症性腎疾患の治療手段として大いに期待できる．

Research Products

• [Journal Article] β2-adrenergic receptor agonist counteracts skeletal muscle atrophy and oxidative stress in uremic mice (2021)
  • Author(s): Takaaki Higashihara、Hiroshi Nishi、Koji Takemura、Hiroshi Watanabe、Toru Maruyama、Reiko Inagi、Tetsuhiro Tanaka、Masaomi Nangaku
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 9130-9130
  • DOI: 10.1038/s41598-021-88438-7
  • Peer Reviewed / Open Access
• [Journal Article] Regional variance in the use of urine dipstick test for outpatients in Japan (2020)
  • Author(s): Hiroshi Nishi、Yui Yoshsida、Reiko Inoue、Koji Takemura、Masaomi Nangaku
  • Journal Title: Nephrology Volume: 25 Issue: 9 Pages: 676-682
  • DOI: 10.1111/nep.13715
  • Peer Reviewed
• [Journal Article] Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia (2020)
  • Author(s): Takemura Koji、Nishi Hiroshi、Inagi Reiko
  • Journal Title: Frontiers in Physiology Volume: 11 Pages: 565023-565023
  • DOI: 10.3389/fphys.2020.565023
  • Peer Reviewed / Open Access
• [Journal Article] Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach (2020)
  • Author(s): Nishi Hiroshi、Takemura Koji、Higashihara Takaaki、Inagi Reiko
  • Journal Title: Nutrients Volume: 12 Issue: 6 Pages: 1814-1814
  • DOI: 10.3390/nu12061814
  • Peer Reviewed / Open Access
• [Journal Article] Regional variance of the early use of tolvaptan for autosomal dominant polycystic kidney disease (2020)
  • Author(s): Reiko Inoue、Hiroshi Nishi、Daisuke Inoue、Kenjiro Honda、Masaomi Nangaku
  • Journal Title: Kidney360 Volume: 1 Issue: 8 Pages: 740-745
  • DOI: 10.34067/kid.0002262020
  • Peer Reviewed / Open Access
• [Journal Article] Kidney failure after lung transplantation in systemic scleroderma: a case report with literature review (2020)
  • Author(s): Takashi Ishide、Hiroshi Nishi、Hiroko Ambe、Kenjiro Honda、Motonobu Nakamura、Jiro Sato、Kota Yamamoto、Masaaki Sato、Masaomi Nangaku
  • Journal Title: Renal Replacement Therapy Volume: 6 Issue: 1 Pages: 0-0
  • DOI: 10.1186/s41100-020-00293-w
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic accuracy of urine dipstick for proteinuria category in Japanese workers (2020)
  • Author(s): Tomoko Usui, Yui Yoshida, Hiroshi Nishi, Shintaro Yanagimoto, Yutaka Matsuyama, Masaomi Nangaku
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Issue: 2 Pages: 151-156
  • DOI: 10.1007/s10157-019-01809-3
  • Peer Reviewed
• [Journal Article] Renal thrombotic microangiopathy during nintedanib treatment for idiopathic pulmonary fibrosis (2020)
  • Author(s): Daisuke Inoue, Hiroshi Nishi, Kenjiro Honda, Taisuke Ishii, Hiroyuki Abe, Masaaki Sato, Masaomi Nangaku
  • Journal Title: Clinical Nephrology Volume: 93 Issue: 1 Pages: 47-50
  • DOI: 10.5414/cn109900
  • Peer Reviewed
• [Journal Article] Lipotoxicity in kidney, heart, and skeletal muscle dysfunction (2019)
  • Author(s): Hiroshi Nishi, Takaaki Higashihara, Reiko Inagi
  • Journal Title: Nutrients Volume: 11 Issue: 7 Pages: 1664-1664
  • DOI: 10.3390/nu11071664
  • Peer Reviewed / Open Access
• [Journal Article] Gene-diet interactions associated with complex trait variation in an advanced intercross outbred mouse line (2019)
  • Author(s): Vorobyev, Gupta, Sezin, Koga, Bartsch, Belheouane, Kunzel, Sina, Schilf, Korber-Ahrens, Beltsiou, Lara Ernst, Khil'chenko, Al-Aasam, Manz, Diehl, Steinhaus, Jascholt, Kouki, Boehncke, Mayadas, Zillikens, Sadik, Nishi, Ehlers, Moller, Bieber, Baines, Ibrahim, Ludwig
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 4097-4097
  • DOI: 10.1038/s41467-019-11952-w
  • Peer Reviewed / Open Access
• [Journal Article] Podocyte lipotoxicity in diabetic kidney disease (2019)
  • Author(s): Hiroshi Nishi, Masaomi Nangaku
  • Journal Title: Kidney International Volume: 96 Issue: 4 Pages: 809-812
  • DOI: 10.1016/j.kint.2019.07.013
  • Peer Reviewed
• [Journal Article] Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury (2019)
  • Author(s): Hiroshi Maekawa, Tsuyoshi Inoue, haruki Ouchi, Tzu-Ming Jao, Reiko Inoue, Hiroshi Nishi, Rie Fujii, Fumiyoshi Ishidate, Tetsuhiro Tanaka, Yosuke Tanaka, Nobutaka Hirokawa, Masaomi Nangaku, Reiko Inagi
  • Journal Title: Cell Reports Volume: 29 Issue: 5 Pages: 1261-1273
  • DOI: 10.1016/j.celrep.2019.09.050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular Ehlers-Danlos syndrome diagnosed in a patient initiating hemodialysis (2019)
  • Author(s): Haruki Ouchi, Hiroshi Nishi, Motonobu Nakamura, Yosuke Hirakawa, Tetsuhiro Tanaka, Norifumi Takeda, Takafumi Akai, Yuichi Ohashi, Katsuyuki Hoshina, Toshio Takayama, Masaomi Nangaku
  • Journal Title: Kidney International Reports Volume: 4 Issue: 11 Pages: 1646-1648
  • DOI: 10.1016/j.ekir.2019.07.020
  • Peer Reviewed / Open Access
• [Journal Article] Porcupine’s dilemma in kidney fibrosis (2019)
  • Author(s): Hiroshi Nishi
  • Journal Title: Kidney International Volume: 96 Issue: 6 Pages: 1269-1271
  • DOI: 10.1016/j.kint.2019.07.020
  • Peer Reviewed
• [Journal Article] Neutrophils in lupus nephritis (2019)
  • Author(s): Nishi Hiroshi、Mayadas Tanya N.
  • Journal Title: Current Opinion in Rheumatology Volume: 31 Issue: 2 Pages: 193-200
  • DOI: 10.1097/bor.0000000000000577
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regional variance in patterns of prescriptions for chronic kidney disease in Japan (2019)
  • Author(s): Inoue Reiko、Nishi Hiroshi、Tanaka Tetsuhiro、Nangaku Masaomi
  • Journal Title: Clinical and Experimental Nephrology Volume: 印刷中 Issue: 6 Pages: 859-864
  • DOI: 10.1007/s10157-019-01720-x
  • Peer Reviewed
• [Journal Article] Tocilizumab for focal segmental glomerulosclerosis secondary to multicentric Castleman’s disease (2019)
  • Author(s): Ebisawa Kazutoshi、Masamoto Yosuke、Tokushige Junji、Nishi Hiroshi、Honda Kenjiro、Hinata Munetoshi、Toyama Kazuhiro、Nangaku Masaomi、Kurokawa Mineo
  • Journal Title: Annals of Hematology Volume: 印刷中 Issue: 8 Pages: 1995-1997
  • DOI: 10.1007/s00277-019-03616-y
  • Peer Reviewed
• [Presentation] β2-adrenergic receptor agonist averts indoxyl sulfate-induced skeletal muscle atrophy and oxidative stress in mice (2021)
  • Author(s): Takaaki Higashihara, Hiroshi Nishi, Koji Takemura, Masaomi Nangaku
  • Organizer: ISN World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] 尿毒素による骨格筋の萎縮に対するβ２受容体作動薬の効果 (2021)
  • Author(s): 東原崇明，西裕志，竹村浩至，南学正臣
  • Organizer: 日本腎臓リハビリテーション学会学術集会
• [Presentation] 尿毒素インドキシル硫酸は速筋線維優位に筋量・筋力を損ない，筋量低下にはβ2アドレナリン受容体刺激薬が有効である (2021)
  • Author(s): 東原崇明，西裕志，竹村浩至，南学正臣
  • Organizer: 日本Uremic Toxin研究会学術大会
• [Presentation] Regional variance in early adoption of tolvaptan for autosomal dominant polycystic kidney disease in Japan. (2020)
  • Author(s): Reiko Inoue, Hiroshi Nishi, Kenjiro Honda, Masaomi Nangaku
  • Organizer: Asian Pacific Society of Nephrology
  • Int'l Joint Research
• [Presentation] Neutrophil interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2) promotes adhesion in non-viral inflammatory kidney disease. (2020)
  • Author(s): Reiko Inoue, Hiroshi Nishi, Mizuko Osaka, Tsuyoshi Inoue, Masayui Yoshida, Masaomi Nangaku
  • Organizer: Asian Pacific Society of Nephrology
  • Int'l Joint Research
• [Presentation] Indoxyl sulfate decreases cell width of mouse skeletal C2C12 myotube that can be attenuated by β2-adrenergic receptor agonists. (2020)
  • Author(s): Takaaki Higashihara, Hiroshi Nishi, Koji Takemura, Masaomi Nangaku
  • Organizer: Asian Pacific Society of Nephrology
  • Int'l Joint Research
• [Presentation] HIF proryl hydroxylase inhibitor improves exercise endurance and hardly affects instantaneous force in mice (2020)
  • Author(s): Koji Takemura, Hiroshi Nishi, Takaaki Higashihara, Karina Kozaki, Koichi Nakazato, Naokata Ishii, Masaomi Nangaku
  • Organizer: Asian Pacific Society of Nephrology
  • Int'l Joint Research
• [Presentation] Indoxyl sulfate modulates expression of myosin heavy chain isoforms and induces sarcopenic phenotype in mouse (2020)
  • Author(s): Takaaki Higashihara, Hiroshi Nishi, Koji Takemura, Masaomi Nangaku
  • Organizer: American Society of Nephrology
  • Int'l Joint Research
• [Presentation] HIF prolyl hydroxylase inhibitor improves exercise endurance and hardly affects instantaneous force in mice (2020)
  • Author(s): Koji Takemura, Hiroshi Nishi, Takaaki Higashihara, Masaomi Nangaku
  • Organizer: American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Angiotensin converting enzyme-overexpressing neutrophils suppress glomerular injury in crescentic glomerulonephritis. (2020)
  • Author(s): Narihito Tatsumoto, Suguru Saito, Hiroshi Nishi, Kenneth E. Bernstein, Michifumi Yamashita
  • Organizer: American Society of Nephrology
  • Int'l Joint Research
• [Presentation] インドキシル硫酸がマウス骨格筋に与える影響解析と介入探索 (2020)
  • Author(s): 東原崇明，西裕志，竹村浩至，南学正臣
  • Organizer: 日本腎臓学会学術総会
• [Presentation] 好中球EIF2AK2阻害は血管内皮接着・血管外遊走を抑制し炎症性腎疾患急性期を制御する (2020)
  • Author(s): 井上玲子，西裕志，大坂瑞子，吉田雅幸，南学正臣
  • Organizer: 日本腎臓学会学術総会
• [Presentation] Neutrophil interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2) promotes neutrophil adhesion and transmigration in acute phase of glomerulonephritis (2020)
  • Author(s): Reiko Inoue, Hiroshi Nishi, Mizuko Osaka, Masayuki Yoshida, Masaomi Nangaku
  • Organizer: CKD Frontier Meeting
• [Presentation] PHD inhibitor and hypoxia influence on skeletal muscle glucose metabolism (2019)
  • Author(s): Koji Takemura, Hiroshi Nishi, Takaaki Higashihara, Masaomi Nangaku
  • Organizer: ISN World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] HIF stabilizer decreases mitochondrial oxygen consumption in skeletal C2C12 myotube (2019)
  • Author(s): Hiroshi Nishi, Koji Takemura, Takaaki Higashihara, Masaomi Nangaku
  • Organizer: European Renal Association - European Dialysis and Transplant Association Congress
  • Int'l Joint Research
• [Presentation] Neutrophil interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2) mediates vascular adhesion and transmigration in non-viral inflammatory disease (2019)
  • Author(s): Hiroshi Nishi, Reiko Inoue, Mizuko Osaka, Tsuyoshi Inoue, Masayuki Yoshida, Masaomi Nangaku
  • Organizer: International Congress of Immunology
  • Int'l Joint Research
• [Presentation] HIF stabilizer decreases mitochondrial oxygen consumption in skeletal C2C12 myotube (2019)
  • Author(s): Koji Takemura, Hiroshi Nishi, Takaaki Higashihara, Masaomi Nangaku
  • Organizer: American Society of Nephrology
  • Int'l Joint Research
• [Presentation] β2-receptor agonism averts indoxyl sulfate-induced sarcopenic phenotype of mouse skeletal C2C12 myotube (2019)
  • Author(s): Takaaki Higashihara, Hiroshi Nishi, Koji Takemura, Masaomi Nangaku
  • Organizer: American Society of Nephrology
  • Int'l Joint Research
• [Presentation] マウス骨格筋筋管細胞にインドキシル硫酸が与える変化とβ2刺激薬の薬理効果 (2019)
  • Author(s): 東原崇明，西裕志，竹村浩至，南学正臣
  • Organizer: 日本腎臓学会学術総会
• [Presentation] PHD阻害薬が骨格筋の形質や代謝に与える影響 (2019)
  • Author(s): 竹村浩至，西裕志，東原崇明，南学正臣
  • Organizer: 日本腎臓学会学術総会
• [Presentation] 尿毒素インドキシル硫酸がマウス骨格筋筋管細胞に与える形質変化とアドレナリンβ2受容体刺激薬の拮抗作用 (2019)
  • Author(s): 東原崇明，西裕志，竹村浩至，井上剛，南学正臣
  • Organizer: 日本心血管内分泌代謝学会学術総会
• [Presentation] Mitochondrial DNA leakage causes inflammation via the cGAS-STING axis in cisplatin-mediated tubular damage. (2019)
  • Author(s): Hiroshi Maekawa, Tzu-Ming jao, Reiko Inoue, Hiroshi Nishi, Tsuyoshi Inoue, Masaomi Nangaku, Reiko Inagi
  • Organizer: American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Neutrophil interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2) promotes vascular adhesion and transmigration in non-viral inflammatory disease. (2019)
  • Author(s): Hiroshi Nishi, Reiko Inoue, Mizuko Osaka, Tsuyoshi Inoue, Masayuki Yoshida, Masaomi Nangaku
  • Organizer: Keystone Symposia
  • Int'l Joint Research
• [Presentation] PHD inhibitor and hypoxia influence on skeletal muscle glucose metabolism. (2019)
  • Author(s): Koji Takemura, Hiroshi Nishi, Takaaki Higashihara, Masaomi Nangaku
  • Organizer: CKD Frontiers Meeting
• [Presentation] メルドニウム及びHIF刺激薬が骨格筋に与える代謝変化． (2019)
  • Author(s): 西裕志，東原崇明，竹村浩至，南学正臣
  • Organizer: 腎と脂質研究会
• [Presentation] FcγRIIA-driven glomerular neutrophil accumulation and proliferative glomerulonephritis are averted with inhibiton of neutrophil Bcr-Abl kinases. (2018)
  • Author(s): Hiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark Miller, Yunfeng Chen, Florencia Rosetti, Samantha Hamilton, Lihua Yang, Spencer Pittman, Jiexi Liao, Jan Herter, Jeffrey Berry, Cheng Zhu, George C. Tsokos, Tanya Mayadas
  • Organizer: 日本腎臓学会学術総会
• [Presentation] Neutrophil interferon-induced, double-stranded RNA-activated protein kinase regulates stimulation-induced migration and production of reactive oxygen species. (2018)
  • Author(s): Reiko Inoue, Hiroshi Nishi, Masaomi Nangaku
  • Organizer: 日本腎臓学会学術総会
• [Presentation] 白血球を介した腎の毛細血管における炎症制御． (2018)
  • Author(s): 西裕志
  • Organizer: Renal Pathology Seminar For Young Nephrologists
  • Invited
• [Presentation] Adverse health effect and repositioning of doping-agents (2018)
  • Author(s): 西裕志
  • Organizer: 一般社団法人日本アンチ・ドーピング研究コンソーシアム第2回シンポジウム
  • Invited
• [Presentation] PHD阻害薬が骨格筋の形質や代謝に与える影響の検討． (2018)
  • Author(s): 竹村浩至，東原崇明，西裕志，南学正臣
  • Organizer: 腎不全研究会
• [Book] 新薬と臨牀 (2020)
  • Author(s): 東原崇明，西裕志，南学正臣
  • Total Pages: 3
  • Publisher: 医薬情報研究所
• [Book] 腎と透析 (2020)
  • Author(s): 竹村浩至，西裕志，南学正臣
  • Total Pages: 3
  • Publisher: 東京医学社
• [Book] プロフェッショナル腎臓病学 (2020)
  • Author(s): 井上玲子，西裕志
  • Total Pages: 5
  • Publisher: 中外医学社
• [Book] Medical Practice (2019)
  • Author(s): 竹村浩至，西裕志
  • Total Pages: 5
  • Publisher: 文光堂
• [Book] 腎機能低下患者のための薬剤投与ポケットマニュアル・改訂第4版 (2019)
  • Author(s): 西裕志
  • Total Pages: 5
  • Publisher: 中外医学社
• [Book] 透析患者の検査値の読み方 改訂第4版 (2018)
  • Author(s): 西裕志，井上玲子
  • Total Pages: 3
  • Publisher: 日本メディカルセンター
• [Book] Medical Practice (2018)
  • Author(s): 坂下碧，西裕志
  • Total Pages: 6
  • Publisher: 文光堂