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• Author Correction: Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its internalization.

  Abe E, Yamashita A, Hirota K, Yamaji T, Azushima K, Urate S, Suzuki T, Tanaka S, Taguchi S, Tsukamoto S, Uehara T, Wakui H, Tamura K, Takahashi H

  Scientific reports ( Scientific Reports )  12 ( 1 ) 21322   2022.12 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its internalization.

  Abe E, Yamashita A, Hirota K, Yamaji T, Azushima K, Urate S, Suzuki T, Tanaka S, Taguchi S, Tsukamoto S, Uehara T, Wakui H, Tamura K, Takahashi H

  Scientific reports ( Scientific Reports )  12 ( 1 ) 17376 - 17376   2022.10 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Kidney fibrosis is a common pathway that leads to chronic kidney disease. Angiotensin II type-1 receptor (AT1R)-associated protein (ATRAP) was originally identified as an AT1R-binding protein. Previously, we reported that systemic knockout of ATRAP exacerbates kidney fibrosis in aged mice. Although these effects of ATRAP appeared to be AT1R-independent actions, the molecular mechanism remains poorly understood. To elucidate the molecular mechanism of ATRAP independent of AT1R, we explored novel ATRAP-interacting proteins. Mass spectrometric analysis of the immunoprecipitants of a Flag-tagged ATRAP complex revealed 376 candidate proteins that potentially interact with ATRAP. Gene ontology analysis revealed that proteins related to vesicle trafficking, membrane transport, and many membrane proteins, including transferrin receptor 1 (TfR1), were enriched. Because TfR1 promotes cellular iron uptake and iron is a key factor involved in kidney fibrosis, we focused on TfR1 and confirmed that it interacts with ATRAP. In addition, our findings revealed that enhanced ATRAP expression decreased cell-surface TfR1 expression without altering the overall cellular TfR1 expression levels. Furthermore, enhanced ATRAP expression attenuated cellular iron levels. Together, our results highlight the role of ATRAP as a suppressor of TfR1 that functions by facilitating TfR1 internalization, which affects iron metabolism and oxidative stress signaling.

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• Deficiency of the kidney tubular angiotensin II type1 receptor-associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization

  Haruhara Kotaro, Suzuki Toru, Wakui Hiromichi, Azushima Kengo, Kurotaki Daisuke, Kawase Wataru, Uneda Kazushi, Kobayashi Ryu, Ohki Kohji, Kinguchi Sho, Yamaji Takahiro, Kato Ikuma, Ohashi Kenichi, Yamashita Akio, Tamura Tomohiko, Tsuboi Nobuo, Yokoo Takashi, Tamura Kouichi

  KIDNEY INTERNATIONAL ( Kidney International )  101 ( 5 ) 912 - 928   2022.05 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.

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• Effects of tumor necrosis factor-alpha inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy

  Taguchi Shinya, Azushima Kengo, Yamaji Takahiro, Urate Shingo, Suzuki Toru, Abe Eriko, Tanaka Shohei, Tsukamoto Shunichiro, Kamimura Daisuke, Kinguchi Sho, Yamashita Akio, Wakui Hiromichi, Tamura Kouichi

  SCIENTIFIC REPORTS ( Scientific Reports )  11 ( 1 ) 23587 - 23587   2021.12 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

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• Distinct RNA polymerase transcripts direct the assembly of phase-separated DBC1 nuclear bodies in different cell lines.

  Mannen T, Goto M, Yoshizawa T, Yamashita A, Hirose T, Hayano T

  Molecular biology of the cell   32 ( 21 ) ar33   2021.11 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  The mammalian cell nucleus is a highly organized organelle that contains membrane-less structures referred to as nuclear bodies (NBs). Some NBs carry specific RNA types that play architectural roles in their formation. Here, we show two types of RNase-sensitive DBC1-containing NBs, DBC1 nuclear body (DNB) in HCT116 cells and Sam68 nuclear body (SNB) in HeLa cells, that exhibit phase-separated features and are constructed using RNA polymerase I or II transcripts in a cell type-specific manner. We identified additional protein components present in DNB by immunoprecipitation-mass spectrometry, some of which (DBC1 and heterogeneous nuclear ribonucleoprotein L [HNRNPL]) are required for DNB formation. The rescue experiment using the truncated HNRNPL mutants revealed that two RNA-binding domains and intrinsically disordered regions of HNRNPL play significant roles in DNB formation. All these domains of HNRNPL promote in vitro droplet formation, suggesting the need for multivalent interactions between HNRNPL and RNA as well as proteins in DNB formation.

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• 腎近位尿細管AT1受容体結合因子がアンジオテンシン依存性高血圧に及ぼす影響(Effects of AT1 Receptor-Associated Protein in Renal Proximal Tubules on Angiotensin II-Mediated Hypertension)

  金口 翔, 涌井 広道, 小豆島 健護, 春原 浩太郎, 高口 知之, 大城 光二, 畝田 一司, 白 善雅, 山地 孝拡, 山田 貴之, 小林 竜, 石上 友章, 山下 暁朗, 藤川 哲也, 田村 功一

  日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  42回   200 - 200   2019.10

   

• 慢性腎臓病CKDと抗加齢医学 受容体結合性機能制御蛋白と腎性老化

  田村 功一, 涌井 広道, 山地 孝拡, 畝田 一司, 小林 竜, 大城 光二, 金口 翔, 山田 貴之, 浦手 進吾, 山下 暁朗

  Anti-aging Science ( (株)メディカルレビュー社 )  10 ( 1 ) 45 - 45   2018.12

   

• 不死化RPTEC(Renal Proximal Tubule Epithelial Cells)のクローン化による近位尿細管細胞株の樹立及びクローン化細胞におけるATRAPの発現調節の検討

  山地 孝拡, 山下 暁朗, 涌井 広道, 春原 浩太郎, 金口 翔, 山田 貴之, 浦手 進吾, 鈴木 徹, 川井 有紀, 田村 功一

  日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  41回   PB05 - 04   2018.09

   

• 糖脂質代謝障害における1型アンジオテンシンII受容体結合蛋白ATRAPの機能的意義

  大城 光二, 涌井 広道, 小豆島 健護, 畝田 一司, 小林 竜, 春原 浩太郎, 岸尾 望, 中島 淳, 山下 暁朗, 田村 功一

  日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  93 ( 4 ) 1383 - 1383   2017.12

   

• 糖脂質代謝障害における1型アンジオテンシンII受容体結合蛋白ATRAPの機能的意義

  大城 光二, 涌井 広道, 小豆島 健護, 畝田 一司, 小林 竜, 春原 浩太郎, 岸尾 望, 中島 淳, 山下 暁朗, 田村 功一

  日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  93 ( 4 ) 1383 - 1383   2017.12

   

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Grant-in-Aid for Scientific Research 【 display / non-display 】

Grant-in-Aid for Scientific Research 【 display / non-display 】

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

• A pathophysiological significance of receptor-binding factor in aging-associated cerebral cardiovascular disease

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

• Grant-in-Aid for Scientific Research(B)

  Project Year: 2020.04  -  2023.03 

  Direct: 13,600,000 (YEN)  Overheads: 17,680,000 (YEN)  Total: 4,080,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

• A pathophysiological significance of receptor-binding factor in aging-associated cerebral cardiovascular disease

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,300,000 (YEN)  Overheads: 4,290,000 (YEN)  Total: 990,000 (YEN)

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