研究活動情報

• Tubulointerstitial nephritis with IgM-positive plasma cells complicated by liver failure.
  Takashi Kudo; Daigo Nakazawa; Saori Nishio; Fumihiko Hattanda; Yusho Ueda; Junpei Yoshikawa; Satoka Shiratori-Aso; Sari Iwasaki; Takahiro Tsuji; Yasuni Nakanuma; Goki Suda; Koji Ogawa; Naoya Sakamoto; Tatsuya Atsumi
  CEN case reports, 14, 2, 253, 260, 2025年04月, ［国内誌］
  英語, 研究論文（学術雑誌）, Tubulointerstitial nephritis (TIN) is characterized by inflammation of the renal interstitium with the infiltration of immune cells, mainly consisting of T cells. Recently, patients with TIN with the predominant infiltration of immunoglobulin M (IgM)-positive plasma cells were reported, coined IgMPC-TIN. Here we report the case of a 70-year-old woman diagnosed with Fanconi syndrome and renal tubular acidosis. Renal biopsy revealed IgMPC-TIN. Her renal dysfunction and clinical findings improved after corticosteroid therapy. However, the patient died of progressive liver failure and spontaneous bacterial peritonitis. In laboratory tests, viral hepatitis was excluded, and autoantibodies associated with liver diseases were negative. Generally, IgMPC-TIN is often complicated by primary biliary cholangitis (PBC), whereas her autopsy revealed the local infiltration of IgM-positive plasma cells, obliterative portal venopathy, and nodular regenerative hyperplasia in liver. This case is the first demonstration that IgMPC-TIN is also seen in liver disease with nodular regenerative hyperplasia, although IgMPC-TIN is more common in anti-M2 antibody-positive disease.
• Transcription factor Nrf2 activation regulates NETosis, endothelial injury, and kidney disease in myeloperoxidase-positive antineutrophil cytoplasmic antibody-associated vasculitis.
  Yusho Ueda; Daigo Nakazawa; Saori Nishio; Satoka Shiratori-Aso; Takashi Kudo; Atsuko Miyoshi-Harashima; Kanako Watanabe-Kusunoki; Fumihiko Hattanda; Sari Iwasaki; Takahiro Tsuji; Utano Tomaru; Yasuaki Aratani; Mamiko Yamamoto; Akihiro Ishizu; Tatsuya Atsumi
  Kidney international, 105, 6, 1291, 1305, 2024年06月, ［国際誌］
  英語, 研究論文（学術雑誌）, Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis.
• Successful initiation of hemodialysis for a hemophilia A patient with factor VIII inhibitor: a case report and literature review.
  Maki Komatsumoto; Daigo Nakazawa; Tomoyuki Endo; Saori Nishio; Takuro Kawamura; Atsuko Miyoshi-Harashima; Shun Takenaka; Satoka Shiratori-Aso; Michiko Kurotori; Naoko Matsuoka; Tatsuya Atsumi
  CEN case reports, 13, 2, 117, 120, 2024年04月, ［国内誌］
  英語, 研究論文（学術雑誌）, We report the first case of hemophilia A with factor VIII (FVIII) inhibitor who received hemodialysis via an arteriovenous (AV) fistula. Hemophilia A is a congenital deficiency of blood coagulation FVIII that is characterized by prolonged bleeding. Approximately 30% of patients with hemophilia develop allogeneic antibodies of FVIII. The inhibitors decrease the hemostatic effect of replacement therapy; thus, the prophylaxis strategy should be well designed. Prophylactic treatment with invasive procedures is needed to prevent excessive bleeding in patients with hemophilia undergoing hemodialysis. On the contrary, hemodialysis requires attention to the development of intracircuit coagulation during dialysis. Peritoneal dialysis or hemodialysis with a long-term tunneled central venous catheter has mainly been selected as the dialysis modality for patients with hemophilia and end-stage renal disease requiring renal replacement therapy because hemodialysis with an arteriovenous fistula may result in bleeding from the puncture site after each hemodialysis session. In our patient, hemodialysis was safely performed without any anticoagulant agents, and replacement therapy with FVIII concentrates prevented bleeding after puncture of the AV fistula.
• The involvement of NETs in ANCA-associated vasculitis
  Satoka Shiratori-Aso; Daigo Nakazawa
  Frontiers in Immunology, 14, Frontiers Media SA, 2023年09月14日
  研究論文（学術雑誌）, Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a serious autoimmune disease that is characterized by vascular necrosis. The pathogenesis of AAV includes ANCA-mediated neutrophil activation, subsequent release of inflammatory cytokines and reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs). Excessive NETs could participate not only in ANCA-mediated vascular injury but also in the production of ANCAs per se as autoantigens. Thus, a vicious cycle of NET formation and ANCA production is critical for AAV pathogenesis. Elucidating the molecular signaling pathways in aberrant neutrophil activation and NETs clearance systems will allow specific therapeutics to regulate these pathways. Currently, standard therapy with high doses of glucocorticoids and immunosuppressants has improved outcomes in patients with AAV. However, AAV frequently develops in elderly people, and adverse effects such as severe infections in the standard regimens might contribute to the mortality. Mechanistically, cytokines or complement factors activate and prime neutrophils for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential replacement for glucocorticoids in clinical settings. Recent studies have demonstrated that receptor-interacting protein kinases (RIPK3) and cyclophilin D (CypD), which regulate cell necrosis, may be involved in ANCA-induced NETs formation. Meanwhile, targeting NETs clearance, including the addition of deoxyribonuclease I (DNase I) and macrophage engulfment, may improve vasculitis. In this review, we focus on the pathogenesis of NETs and discuss potential targeted therapies for AAV based on recent experimental evidence.
• Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury.
  Daigo Nakazawa; Yohei Takeda; Masatoshi Kanda; Utano Tomaru; Haruko Ogawa; Takashi Kudo; Satoka Shiratori-Aso; Kanako Watanabe-Kusunoki; Yusho Ueda; Atsuko Miyoshi; Fumihiko Hattanda; Saori Nishio; Ryo Uozumi; Akihiro Ishizu; Tatsuya Atsumi
  Cell death discovery, 9, 1, 293, 293, 2023年08月10日, ［国際誌］
  英語, 研究論文（学術雑誌）, Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.
• CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.
  Satoka Shiratori-Aso; Daigo Nakazawa; Takashi Kudo; Masatoshi Kanda; Yusho Ueda; Kanako Watanabe-Kusunoki; Saori Nishio; Sari Iwasaki; Takahiro Tsuji; Sakiko Masuda; Utano Tomaru; Akihiro Ishizu; Tatsuya Atsumi
  JCI insight, 8, 15, 2023年08月08日, ［国際誌］
  英語, 研究論文（学術雑誌）, Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed proinflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase-ANCA (MPO-ANCA) titers with a reduction in NET formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.
• Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase-Positive Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
  Takashi Kudo; Daigo Nakazawa; Kanako Watanabe-Kusunoki; Masatoshi Kanda; Satoka Shiratori-Aso; Nobuya Abe; Saori Nishio; Jun-Ichiro Koga; Sari Iwasaki; Takahiro Tsuji; Yuichiro Fukasawa; Miwako Yamasaki; Masahiko Watanabe; Sakiko Masuda; Utano Tomaru; Masaaki Murakami; Yasuaki Aratani; Akihiro Ishizu; Tatsuya Atsumi
  Arthritis & rheumatology (Hoboken, N.J.), 75, 1, 71, 83, 2023年01月, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. METHODS: We assessed the role and mechanism of CypD in ANCA-stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA-sequencing analysis on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD-knockout mice and wild-type mice using 2 different murine AAV models: anti-myeloperoxidase IgG transfer-induced AAV and spontaneous AAV. RESULTS: In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA-sequencing analyses in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA-induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD-dependent opening of mitochondrial permeability transition pores is associated with ANCA-induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSION: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.
• Transcriptional dynamics of granulocytes in direct response to incubation with SARS-CoV-2.
  Daigo Nakazawa; Yohei Takeda; Masatoshi Kanda; Utano Tomaru; Haruko Ogawa; Takashi Kudo; Satoka Shiratori-Aso; Kanako Watanabe-Kusunoki; Yusho Ueda; Atsuko Miyoshi; Fumihiko Hattanda; Saori Nishio; Ryo Uozumi; Akihiro Ishizu; Tatsuya Atsumi
  FEBS open bio, 13, 1, 60, 71, 2023年01月, ［国際誌］
  英語, 研究論文（学術雑誌）, Severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome and multiple organ dysfunction, in which the host immune response plays a pivotal role. Excessive neutrophil activation and subsequent superfluity of neutrophil extracellular traps (NETs) can lead to tissue damage, and several studies have shown the involvement of neutrophils in severe COVID-19. However, the detailed responses of each neutrophil subset to SARS-CoV-2 infection has not been fully described. To explore this issue, we incubated normal-density granulocytes (NDGs) and low-density granulocytes (LDGs) with different viral titers of SARS-CoV-2. NDGs form NETs with chromatin fibers in response to SARS-CoV-2, whereas LDGs incubated with SARS-CoV-2 display a distinct morphology with condensed nuclei and moderate transcriptional changes. Based on these transcriptional changes, we suggest that AGO2 possibly plays a role in LDG regulation in response to SARS-CoV-2.
• Soluble Interleukin-2 Receptor Predicts Treatment Outcome in Patients With Autoimmune Tubulointerstitial Nephritis. A Preliminary Study.
  Satoka Shiratori-Aso; Daigo Nakazawa; Saori Nishio; Yusho Ueda; Mina Eguchi; Ai Yokoyama; Junpei Yoshikawa; Takashi Kudo; Kanako Watanabe-Kusunoki; Sayo Takeda-Otera; Junya Yamamoto; Naoko Matsuoka; Nobuharu Kaneshima; Fumihiko Hattanda; Sari Iwasaki; Takahiro Tsuji; Yuichiro Fukasawa; Tatsuya Atsumi
  Frontiers in medicine, 9, 827388, 827388, 2022年, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Autoimmune tubulointerstitial nephritis (TIN) is characterized by immune-mediated tubular injury and requires immunosuppressive therapy. However, diagnosing TIN and assessing therapeutic response are challenging for clinicians due to the lack of useful biomarkers. Pathologically, CD4+ T cells infiltrate to renal tubulointerstitium, and soluble interleukin-2 receptor (sIL-2R) has been widely known as a serological marker of activated T cell. Here, we explored the usefulness of serum sIL-2R to predict the treatment outcome in patients with autoimmune TIN. METHODS: Study Design: Single-center retrospective observational study. PARTICIPANTS: 62 patients were diagnosed of TIN from 2005 to April 2018 at Hokkaido University Hospital. Among them, 30 patients were diagnosed with autoimmune TIN and treated with corticosteroids. We analyzed the association between baseline characteristics including sIL-2R and the change of estimated glomerular filtration rate (eGFR) after initiation of corticosteroids. RESULTS: The serum sIL-2R level in patients with autoimmune TIN was significantly higher than that in chronic kidney disease patients with other causes. Mean eGFR in autoimmune TIN patients treated with corticosteroids increased from 43.3 ± 20.4 mL/min/1.73 m2 (baseline) to 50.7 ± 19.9 mL/min/1.73 m2 (3 months) (ΔeGFR; 22.8 ± 26.0%). Multivariate analysis revealed that higher sIL-2R (per 100 U/mL, β = 1.102, P < 0.001) level was independently associated with the renal recovery. In ROC analysis, sIL-2R had the best area under the curve value (0.805) and the cutoff point was 1182 U/mL (sensitivity = 0.90, 1-specificity = 0.45). CONCLUSIONS: Our study showed that elevated serum sIL-2R levels might become a potential predictive marker for therapeutic response in autoimmune TIN.
• Two Cases of Chronic Gastritis with non-Helicobacter pylori Helicobacter Infection.
  Satoka Shiratori; Katsuhiro Mabe; Shinji Yoshii; Yasunari Takakuwa; Masaaki Sato; Masahiko Nakamura; Takahiko Kudo; Mototsugu Kato; Masahiro Asaka; Naoya Sakamoto
  Internal medicine (Tokyo, Japan), 55, 14, 1865, 9, 2016年, ［国内誌］
  英語, 研究論文（学術雑誌）, Two men, 48 and 54 years of age, were referred for medical checkups without any particular symptoms. Upper gastrointestinal endoscopy showed a normal gastric body, but white marbled appearance in the lesser curvature of the gastric angle and antrum. Biopsy specimens revealed relatively long and tightly coiled organisms. The two patients were diagnosed as having non-Helicobacter pylori helicobacter (NHPH) infection according to the findings of pathological and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. After triple therapy (amoxicillin, clarithromycin, and rabeprazole), endoscopy showed an improvement of the white marbled lesions and biopsy specimens showed no NHPH. The white marbled appearance limited to the gastric angle and antrum may be a potential characteristic finding of NHPH-infected gastritis.

• 腎生検での石灰沈着判明後に高Ca血症が顕在化し,非定型副甲状腺腫瘍の診断に至った1例
  立野 涼仁; 麻生 里佳; 大寺 紗夜; 牧田 実; 辻 隆裕; 島本 真実子, 日本腎臓学会誌, 67, 6-E, 825, 825, 2025年09月
  (一社)日本腎臓学会, 日本語
• ANCA関連血管炎におけるNrf2を介した炎症抑制機構
  上田 雄翔; 中沢 大悟; 三好 敦子; 麻生 里佳; 西尾 妙織; 外丸 詩野; 石津 明洋; 渥美 達也, 脈管学, 64, 1, 12, 13, 2024年02月
  (一社)日本脈管学会, 日本語
• 【SLEとAAVの新展開】NETosisとANCA関連血管炎
  麻生 里佳; 中沢 大悟; 石津 明洋, 腎と透析, 94, 6, 930, 933, 2023年06月
  (株)東京医学社, 日本語
• NCA関連血管炎におけるCD47・エフェロサイトーシスの役割
  麻生 里佳; 中沢 大悟; 三好 敦子; 上田 雄翔; 西尾 妙織; 外丸 詩野; 石津 明洋; 渥美 達也, 日本腎臓学会誌, 65, 3, 239, 239, 2023年05月
  (一社)日本腎臓学会, 日本語
• ANCA関連血管炎におけるNrf2を介した炎症抑制機構
  上田 雄翔; 中沢 大悟; 三好 敦子; 麻生 里佳; 西尾 妙織; 外丸 詩野; 石津 明洋; 渥美 達也, 日本腎臓学会誌, 65, 3, 281, 281, 2023年05月
  (一社)日本腎臓学会, 日本語
• HIF-PHD阻害薬が常染色体顕性多発性嚢胞腎の肝嚢胞形成に与える影響
  竹中 駿; 西尾 妙織; 川村 拓朗; 三好 敦子; 上田 雄翔; 麻生 里佳; 松岡 奈央子; 八反田 文彦; 中沢 大悟; 渥美 達也, 日本臨床分子医学会学術総会プログラム・抄録集, 58回, 54, 54, 2023年04月
  日本臨床分子医学会, 日本語
• ANCA関連血管炎におけるNrf2を介した炎症抑制機構
  上田 雄翔; 中沢 大悟; 三好 敦子; 麻生 里佳; 西尾 妙織; 外丸 詩野; 石津 明洋; 渥美 達也, 日本臨床分子医学会学術総会プログラム・抄録集, 58回, 62, 62, 2023年04月
  日本臨床分子医学会, 日本語
• IgG4異常高値を伴う著明なびまん性両腎腫大を呈した1例
  河田 喜大; 麻生 里佳; 中沢 大悟; 西尾 妙織; 渥美 達也, 日本リウマチ学会総会・学術集会プログラム・抄録集, 67回, 914, 914, 2023年03月
  (一社)日本リウマチ学会, 日本語
• Neutrophil extracellular traps(NETs)の測定方法と臨床的意義
  三好 敦子; 中沢 大悟; 上田 雄翔; 麻生 里佳, 日本血栓止血学会誌, 33, 5, 593, 597, 2022年10月
  (一社)日本血栓止血学会, 日本語
• ステロイドにミゾリビンを併用し寛解を達成したC1q腎症の一例
  清水 哲夫; 竹中 駿; 松岡 奈央子; 麻生 里佳; 八反田 文彦; 中沢 大悟; 西尾 妙織; 渥美 達也, 日本腎臓学会誌, 64, 6-E, 562, 562, 2022年10月
  (一社)日本腎臓学会, 日本語
• IgM陽性形質細胞を伴う尿細管間質性腎炎の一例
  今井 薫子; 西尾 妙織; 八反田 文彦; 辻 隆裕; 麻生 里佳; 松岡 奈央子; 中沢 大悟; 渥美 達也, 日本腎臓学会誌, 64, 6-E, 577, 577, 2022年10月
  (一社)日本腎臓学会, 日本語
• 【慢性腎臓病(CKD)一歩進んだ日常診療マネジメント】エビデンスとガイドラインに基づいた治療実践 免疫抑制療法 強皮症とSLEと血管炎
  麻生 里佳; 中沢 大悟, Medical Practice, 39, 6, 911, 914, 2022年06月
  (株)文光堂, 日本語
• HIF-PH阻害薬内服中の鉄欠乏による過凝固状態からシャント血栓性閉塞をきたしたと考えられた1例
  羽田 力; 上泉 洋; 辻 健志; 鈴木 麗美; 浜田 卓巳; 金沢 亮; 谷 安弘; 河合 朋昭; 稲垣 尚人; 伊藤 浩二; 麻生 里佳; 松岡 奈央子; 西尾 妙織, 日本透析医学会雑誌, 55, Suppl.1, 558, 558, 2022年05月
  (一社)日本透析医学会, 日本語
• 上腕動脈を自己血管・人工血管で置換し設置した上腕内シャントの2例
  辻 健志; 上泉 洋; 羽田 力; 河合 朋昭; 谷 安弘; 金沢 亮; 柏倉 さゆり; 浜田 卓巳; 鈴木 麗美; 稲垣 尚人; 伊藤 浩二; 麻生 里佳; 松岡 奈央子; 西尾 妙織, 日本透析医学会雑誌, 55, Suppl.1, 558, 558, 2022年05月
  (一社)日本透析医学会, 日本語
• 尿細管間質性腎炎の治療反応予測における可溶性IL-2受容体の有用性
  麻生 里佳; 中沢 大悟; 西尾 妙織; 渥美 達也, 日本内科学会雑誌, 111, 臨増, 176, 176, 2022年02月
  (一社)日本内科学会, 日本語
• ANCA関連血管炎におけるCD47・エフェロサイトーシスの役割
  麻生 里佳; 中沢 大悟; 三好 敦子; 上田 雄翔; 西尾 妙織; 外丸 詩野; 石津 明洋; 渥美 達也, 脈管学, 62, 2, 7, 8, 2022年02月
  (一社)日本脈管学会, 日本語
• 本邦における常染色体優性多発性嚢胞腎の予後因子の探索
  麻生 里佳; 西尾 妙織; 八反田 文彦; 島田 幸輝; 中川 直樹; 吉川 純平; 関 豊和; 中沢 大悟; 渥美 達也, 日本腎臓学会誌, 63, 4, 503, 503, 2021年06月
  (一社)日本腎臓学会, 日本語
• MO244CD47 BLOCKADE AMELIORATES AUTOIMMUNE VASCULITIS VIA THE EFFEROCYTOSIS OF NEUTROPHIL EXTRACELLULAR TRAPS*
  Satoka Shiratori-Aso; Daigo Nakazawa; Yusho Ueda; Takashi Kudo; Nishio Saori; Utano Tomaru; Akihiro Ishizu; Tatsuya Atsumi, Nephrology Dialysis Transplantation, 36, Supplement_1, 2021年05月01日
  Abstract
  
  Background and Aims
  
  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by systemic necrotizing vasculitis in small vessels. The necrotic lesions consist of ANCA-mediated neutrophil extracellular traps (NETs) which represent a form of lytic cell death. The persistent NETs serve as autoantigens against ANCAs and cause organ damage in a vicious cycle. Considering dead cells are essentially cleared by phagocytic cells as a process of efferocytosis, why the NETs persist in tissue remains unclear. During efferocytosis, macrophages engulf apoptotic cells to prevent the leakage of intracellular components including toxic enzyme into the surrounding cells and these processes are regulated by the expression of CD47 as a “don’t eat me” signal. In this study, we hypothesized that ANCA-mediated NETs in AAV escape from efferocytosis via the up-regulation of CD47 and the persistent NETs amplify the disease.
  
  Method
  
  Human data: Human kidney biopsy specimens from patients with AAV and minor glomerular abnormality (MGA, as a case control) were subjected to immunohistochemistry (IHC) staining for CD47. In vitro: The expression of CD47 on neutrophils was evaluated by flow cytometry (FCM). Human neutrophils from healthy donor were treated with ANCA-IgGs from MPO-AAV patients or control IgGs. For the efferocytosis assay, macrophages were co-incubated with unstimulated, apoptotic, and ANCA-IgGs treated neutrophils in the presence of anti-CD47 monoclonal antibody (mAb) or a control antibody. The neutrophils were labeled with CFMDA cell tracker (fluorescent probe) and the efferocytosis was evaluated as neutrophil engulfed (CFMDA positive) macrophages using fluorescent microscopy. In vivo: Spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice (8-week-old age) were treated with intraperitoneal injection of anti-CD47 mAb or a control antibody every 5 days for two weeks. The severity of glomerulonephritis was assessed by the levels of serum creatinine, haematuria, mRNA expression of pro-inflammatory genes, and histopathological findings. To address the immune response against the CD47 blockade, the titre of MPO-ANCA and the number of splenic cell subset was assessed by ELISA and FCM analysis, respectively.
  
  Results
  
  Human data: The IHC analysis of human renal specimens revealed that the positive area of CD47 of AAV was greater than that of MGA. In particular, the CD47-overexpressed cells were seen in glomeruli with necrotic crescent formation. In vitro: Mean fluorescence intensity (MFI) of CD47 in ANCA-IgGs treated neutrophils (NETs) was significantly higher than that in control IgGs treated neutrophils (ANCA-IgG; 442±21.4 a.u. vs control IgG; 402±10 a.u., p&lt;0.05). In efferocytosis assay, apoptotic neutrophils were engulfed by macrophages (efferocytosis rate/ apoptotic neutrophil; 20.5±3.8%, live neutrophils; 0.9±0.5%). The efferocytosis rate of ANCA-induced NETs significantly decreased compared to apoptotic neutrophil, but anti-CD47 mAb improved the efferocytosis of ANCA-NETs (efferocytosis rate/ anti-CD47 mAb; 19.1±4.2%, control antibody; 7.7±2.2%, p&lt;0.05). In vivo: the renal histopathological severity score, serum creatinine level of AAV mice treated with anti-CD47 mAb decreased compared to that of AAV mice treated with a control antibody (anti-CD47 mAb; 0.96±0.30 vs control antibody; 0.61±0.32 mg/dL). Although there was no significant difference in the number of splenic cells between anti-CD47 and control antibody treated mice, CD47 blockade therapy significantly reduced serum MPO-ANCA titre (28.5±10.4 vs 45.2±14.5 μg/mL) and renal mRNA expression (IFNα, IFNγ, MCP-1 and perforin) of AAV mice.
  
  Conclusion
  
  ANCA-mediated NETs might escape from efferocytosis through up-regulation of CD47 and provoke necrotizing vasculitis. CD47 blockade could be a potential novel therapeutic strategy for AAV., Oxford University Press (OUP)
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