2022/12/01 更新

写真a

フクスミ ヨシヤス
福住 好恭
FUKUSUMI Yoshiyasu
所属
教育研究院 医歯学系 医学系列 准教授
医歯学総合研究科 腎研究センター 准教授
職名
准教授
外部リンク

学位

  • 博士(医学) ( 2008年3月   金沢大学 )

研究キーワード

  • 腎臓病態学

研究分野

  • ライフサイエンス / 腎臓内科学

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / 実験動物学

  • ライフサイエンス / 細胞生物学

経歴(researchmap)

  • 新潟大学   医歯学総合研究科 腎研究センター   准教授

    2016年4月 - 現在

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  • 新潟大学   医歯学総合研究科 腎研究施設   准教授

    2015年3月 - 2016年3月

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  • 新潟大学   医学部 医学科   助教

    2011年5月 - 2015年2月

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  • 新潟大学   医歯学総合研究科 腎研究施設   助教

    2011年5月 - 2015年2月

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  • ドイツヘルムホルツ研究所

    2008年5月 - 2011年4月

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経歴

  • 新潟大学   医歯学総合研究科 腎研究センター   准教授

    2016年4月 - 現在

  • 新潟大学   医歯学総合研究科 腎研究センター   准教授

    2015年3月 - 2016年3月

  • 新潟大学   医学部 医学科   助教

    2011年5月 - 2015年2月

  • 新潟大学   医歯学総合研究科 腎研究センター   助教

    2011年5月 - 2015年2月

学歴

  • 金沢大学   医学系研究科

    - 2008年3月

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    国名: 日本国

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所属学協会

 

論文

  • Th17 Cells Participate in Thy1.1 Glomerulonephritis Which Is Ameliorated by Tacrolimus. 査読 国際誌

    Syuhei Watanabe, Ying Zhang, Yoshiyasu Fukusumi, Hidenori Yasuda, Akira Takada, Junichiro J Kazama, Hiroshi Kawachi

    American journal of nephrology   53 ( 5 )   388 - 396   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Thy1.1 glomerulonephritis (Thy1.1 GN) in rats is widely used as an experimental model of mesangial proliferative glomerulonephritis (GN). We previously reported that T-helper (Th) cells were accumulated in glomeruli from the early phase of this model and that not Th2 cells but Th1 cells play an important role in the development of glomerular alterations. Although Th17 is reported to be involved in the pathogenesis of several autoimmune diseases, the role of Th17 cells in the pathogenesis of mesangial alterations in Thy1.1 GN remains unclear. METHODS: The kinetics of the infiltration of subsets of Th cells and the expression of IL-17 in Thy1.1 GN were analyzed. Next, the localization and the cell types of IL-17 receptor (IL-17R)-positive cells and IL-6-positive cells were analyzed. Then, the effect of tacrolimus on the expressions of Th17-related cytokines in Thy1.1 GN was analyzed. RESULTS: Not only Th1 cells but also Th17 cells were recruited into glomeruli from the early phase of the disease. mRNA expression of IL-17 in glomeruli was elevated. The increased positive expression of IL-17R was detected in the mesangial area, and some of IL-17R-positive cells were co-stained with IL-6. Tacrolimus treatment ameliorated mesangial alterations by suppressing the expressions of Th17-related cytokines such as IL-17 and IL-6. CONCLUSION: Th17 cells participate in the development of Thy1.1 GN, a mimic of mesangial proliferative GN, and Th17 cells and their related cytokines are pertinent therapeutic targets.

    DOI: 10.1159/000524111

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  • Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton. 査読 国際誌

    Hidenori Yasuda, Yoshiyasu Fukusumi, Veniamin Ivanov, Ying Zhang, Hiroshi Kawachi

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   35 ( 11 )   e21983   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F-actin). FKBP12 interacted with the actin-associated proteins 14-3-3 and synaptopodin. RNA silencing for FKBP12 reduced 14-3-3 expression, F-actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F-actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.

    DOI: 10.1096/fj.202101052R

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  • Synbindin Downregulation Participates in Slit Diaphragm Dysfunction. 査読 国際誌

    Veniamin Ivanov, Yoshiyasu Fukusumi, Ying Zhang, Hidenori Yasuda, Meiko Kitazawa, Hiroshi Kawachi

    American journal of nephrology   1 - 10   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Synbindin, originally identified as a neuronal cytoplasmic molecule, was found in glomeruli. The cDNA subtractive hybridization technique showed the mRNA expression of synbindin in glomeruli was downregulated in puromycin aminonucleoside (PAN) nephropathy, a mimic of minimal-change nephrotic syndrome. METHODS: The expression of synbindin in podocytes was analyzed in normal rats and 2 types of rat nephrotic models, anti-nephrin antibody-induced nephropathy, a pure slit diaphragm injury model, and PAN nephropathy, by immunohistochemical analysis and RT-PCR techniques. To elucidate the function of synbindin, a gene silencing study with human cultured podocytes was performed. RESULTS: Synbindin was mainly expressed at the slit diaphragm area of glomerular epithelial cells (podocytes). In both nephrotic models, decreased mRNA expression and the altered staining of synbindin were already detected at the early phase when proteinuria and the altered staining of nephrin, a key molecule of slit diaphragm, were not detected yet. Synbindin staining was clearly reduced when severe proteinuria was observed. When the cultured podocytes were treated with siRNA for synbindin, the cell changed to a round shape, and filamentous actin structure was clearly altered. The expression of ephrin-B1, a transmembrane protein at slit diaphragm, was clearly lowered, and synaptic vesicle-associated protein 2B (SV2B) was upregulated in the synbindin knockdown cells. CONCLUSION: Synbindin participates in maintaining foot processes and slit diaphragm as a downstream molecule of SV2B-mediated vesicle transport. Synbindin downregulation participates in slit diaphragm dysfunction. Synbindin can be an early marker to detect podocyte injury.

    DOI: 10.1159/000517975

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  • Nephrin-Ephrin-B1-Na+/H+ Exchanger Regulatory Factor 2-Ezrin-Actin Axis Is Critical in Podocyte Injury. 査読 国際誌

    Yoshiyasu Fukusumi, Hidenori Yasuda, Ying Zhang, Hiroshi Kawachi

    The American journal of pathology   191 ( 7 )   1209 - 1226   2021年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ephrin-B1 is one of the critical components of the slit diaphragm of kidney glomerular podocyte. However, the precise function of ephrin-B1 is unclear. To clarify the function of ephrin-B1, ephrin-B1-associated molecules were studied. RNA-sequencing analysis suggested that Na+/H+ exchanger regulatory factor 2 (NHERF2), a scaffolding protein, is associated with ephrin-B1. NHERF2 was expressed at the apical area and the slit diaphragm, and interacted with the nephrin-ephrin-B1 complex at the slit diaphragm. The nephrin-ephrin-B1-NHERF2 complex interacted with ezrin bound to F-actin. NHERF2 bound ephrin-B1 via its first postsynaptic density protein-95/disks large/zonula occludens-1 domain, and podocalyxin via its second postsynaptic density protein-95/disks large/zonula occludens-1 domain. Both in vitro analyses with human embryonic kidney 293 cells and in vivo study with rat nephrotic model showed that stimulaiton of the slit diaphragm, phosphorylation of nephrin and ephrin-B1, and dephosphorylation of NHERF2 and ezrin, disrupted the linkages of ephrin-B1-NHERF2 and NHERF2-ezrin. It is conceivable that the linkage of nephrin-ephrin-B1-NHERF2-ezrin-actin is a novel critical axis in the podocytes. Ephrin-B1 phosphorylation also disrupted the linkage of an apical transmembrane protein, podocalyxin, with NHERF2-ezrin-actin. The phosphorylation of ephrin-B1 and the consequent dephosphorylation of NHERF2 are critical initiation events leading to podocyte injury.

    DOI: 10.1016/j.ajpath.2021.04.004

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  • Xanthine oxidoreductase inhibitor topiroxostat ameliorates podocyte injury by inhibiting the reduction of nephrin and podoplanin. 査読 国際誌

    Ying Zhang, Yoshiyasu Fukusumi, Mutsumi Kayaba, Takashi Nakamura, Ryusuke Sakamoto, Naoki Ashizawa, Hiroshi Kawachi

    Nefrologia   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Topiroxostat, an inhibitor of xanthine oxidoreductase (XOR) was shown to reduce urinary albumin excretion of hyperuricemic patients with chronic kidney disease. However, its pharmacological mechanism is not well understood. In this study, we examined the effects of topiroxostat on glomerular podocytes. Podocyte is characterized by foot process and a unique cell-cell junction slit diaphragm functioning as a final barrier to prevent proteinuria. METHODS: The effects of topiroxostat on the expressions of podocyte functional molecules were analysed in db/db mice, a diabetic nephropathy model, anti-nephrin antibody-induced rat podocyte injury model and cultured podocytes treated with adriamycin. RESULTS: Topiroxostat treatment ameliorated albuminuria in db/db mice. The expression of desmin, a podocyte injury marker was increased, and nephrin and podocin, key molecules of slit diaphragm, and podoplanin, an essential molecule in maintaining foot process were downregulated in db/db mice. Topiroxostat treatment prevented the alterations in the expressions of these molecules in db/db mice. XOR activity in kidney was increased in rats with anti-nephrin antibody-induced podocyte injury. Topiroxostat treatment reduced XOR activity and restored the decreased expression of nephrin, podocin and podoplanin in the podocyte injury. Furthermore, topiroxostat enhanced the expression of podoplanin in injured human cultured podocytes. CONCLUSIONS: Podocyte injury was evident in db/db mice. Topiroxostat ameliorated albuminuria in diabetic nephropathy model by preventing podocyte injury. Increase of XOR activity in kidney contributes to development of podocyte injury caused by stimulation to slit diaphragm. Topiroxostat has an effect to stabilize slit diaphragm and foot processes by inhibiting the reduction of nephrin, podocin and podoplanin.

    DOI: 10.1016/j.nefro.2020.10.011

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  • New insight into podocyte slit diaphragm, a therapeutic target of proteinuria. 査読

    Hiroshi Kawachi, Yoshiyasu Fukusumi

    Clinical and experimental nephrology   24 ( 3 )   193 - 204   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dysfunction of slit diaphragm, a cell-cell junction of glomerular podocytes, is involved in the development of proteinuria in several glomerular diseases. Slit diaphragm should be a target of a novel therapy for proteinuria. Nephrin, NEPH1, P-cadherin, FAT, and ephrin-B1 were reported to be extracellular components forming a molecular sieve of the slit diaphragm. Several cytoplasmic proteins such as ZO-1, podocin, CD2AP, MAGI proteins and Par-complex molecules were identified as scaffold proteins linking the slit diaphragm to the cytoskeleton. In this article, new insights into these molecules and the pathogenic roles of the dysfunction of these molecules were introduced. The slit diaphragm functions not only as a barrier but also as a signaling platform transfer the signal to the inside of the cell. For maintaining the slit diaphragm function properly, the phosphorylation level of nephrin is strictly regulated. The recent studies on the signaling pathway from nephrin, NEPH1, and ephrin-B1 were reviewed. Although the mechanism regulating the function of the slit diaphragm had remained unclear, recent studies revealed TRPC6 and angiotensin II-regulating mechanisms play a critical role in regulating the barrier function of the slit diaphragm. In this review, recent investigations on the regulation of the slit diaphragm function were reviewed, and a strategy for the establishment of a novel therapy for proteinuria was proposed.

    DOI: 10.1007/s10157-020-01854-3

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  • Par-6-ephrin-B1 interaction is regulated by nephrin mediated signal and is crucial in maintaining slit diaphragm of podocyte 査読 国際誌

    Sayuri Takamura, Yoshiyasu Fukusumi, Ying Zhang, Ichiei Narita, Hiroshi Kawachi

    American Journal of Pathology   190 ( 2 )   333 - 346   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ajpath.2019.10.015

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  • Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AβPP as a Novel Interaction Partner of BACE1. 査読 国際誌

    Masakazu Miyamoto, Akira Kuzuya, Yasuha Noda, Sakiho Ueda, Megumi Asada-Utsugi, Shinji Ito, Yoshiyasu Fukusumi, Hiroshi Kawachi, Ryosuke Takahashi, Ayae Kinoshita

    Journal of Alzheimer's disease : JAD   75 ( 1 )   173 - 185   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer's disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear. OBJECTIVE: This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse. METHODS: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. RESULTS: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP. CONCLUSION: SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses.

    DOI: 10.3233/JAD-200071

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  • Nephrin-binding Ephrin-B1 at the slit diaphragm controls podocyte function through the JNK pathway 査読 国際誌

    Yoshiyasu Fukusumi, Ying Zhang, Ryohei Yamagishi, Kanako Oda, Toru Watanabe, Katsuyuki Matsui, Hiroshi Kawachi

    Journal of the American Society of Nephrology   29 ( 5 )   1462 - 1474   2018年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society of Nephrology  

    Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear. Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti-nephrin antibody-induced nephropathy. Results Compared with controls, ephrin-B1 conditional knockoutmice displayed altered podocytemorphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing amutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1- promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody-induced nephropathy. Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury.

    DOI: 10.1681/ASN.2017090993

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  • Possible role for glomerular-derived angiotensinogen in nephrotic syndrome 査読 国際誌

    Mihoko Yamazaki, Yoshiyasu Fukusumi, Mutsumi Kayaba, Yukina Kitazawa, Sayuri Takamura, Ichiei Narita, Hiroshi Kawachi

    JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM   17 ( 4 )   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE PUBLICATIONS LTD  

    Background and objective: Renin-angiotensin system (RAS) inhibitors reduce glomerular injury and proteinuria, indicating that angiotensin II (Ang II) is involved in glomerular diseases. Although the local RAS is reported to play an essential role in maintaining local tissue functions, the role of the local RAS in regulating glomerular function is not well evaluated. In this study, we analyzed the glomerular expression of RAS components in nephrotic models and the effect of Ang II receptor blockers (ARB) on the expression of angiotensinogen (AGT).
    Methods: The levels of glomerular expression of RAS components were analyzed in two nephrotic models: anti-nephrin antibody-induced nephropathy and PAN nephropathy, a mimic of human minimal change nephrotic syndrome. The effect of the ARB irbesartan on the expression of AGT in the nephrotic model was analyzed.
    Results: Glomerular expression of AGT and the receptors for Ang II was clearly increased in the nephrotic models, while the expression levels of renin, ACE and ACE2 were decreased. ARB treatment suppressed the increase of glomerular expression of AGT in the nephrotic model.
    Conclusion: It is conceivable that the promoted local RAS action participated in the glomerular dysfunction, and that ARB treatment ameliorated slit diaphragm injury by inhibiting the positive feedback loop of the activated local Ang II action.

    DOI: 10.1177/1470320316681223

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  • Role of calcineurin (CN) in kidney glomerular podocyte: CN inhibitor ameliorated proteinuria by inhibiting the redistribution of CN at the slit diaphragm 査読 国際誌

    Ayako Wakamatsu, Yoshiyasu Fukusumi, Eriko Hasegawa, Masayuki Tomita, Toru Watanabe, Ichiei Narita, Hiroshi Kawachi

    Physiological Reports   4 ( 6 )   1 - 13   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley-Blackwell Publishing Ltd  

    Although calcineurin (CN) is distributed in many cell types and functions in regulating cell functions, the precise roles of CN remained in each type of the cells are not well understood yet. A CN inhibitor (CNI) has been used for steroid-resistant nephrotic syndrome. A CNI is assumed to ameliorate proteinuria by preventing the overproduction of T-cell cytokines. However, recent reports suggest that CNI has a direct effect on podocyte. It is accepted that a slit diaphragm (SD), a unique cell-cell junction of podocytes, is a critical barrier preventing a leak of plasma protein into urine. Therefore, we hypothesized that CNI has an effect on the SD. In this study, we analyzed the expression of CN in physiological and in the nephrotic model caused by the antibody against nephrin, a critical component of the SD. We observed that CN is expressed at the SD in normal rat and human kidney sections and has an interaction with nephrin. The staining of CN at the SD was reduced in the nephrotic model, while CN activity in glomeruli was increased. We also observed that the treatment with tacrolimus, a CNI, in this nephrotic model suppressed the redistribution of CN, nephrin, and other SD components and ameliorated proteinuria. These observations suggested that the redistribution and the activation of CN may participate in the development of the SD injury.

    DOI: 10.14814/phy2.12679

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  • Alteration in the podoplanin-ezrin-cytoskeleton linkage is an important initiation event of the podocyte injury in puromycin aminonucleoside nephropathy, a mimic of minimal change nephrotic syndrome 査読 国際誌

    Koichi Suzuki, Yoshiyasu Fukusumi, Mihoko Yamazaki, Hiroshi Kaneko, Kazushi Tsuruga, Hiroshi Tanaka, Etsuro Ito, Katsuyuki Matsui, Hiroshi Kawachi

    CELL AND TISSUE RESEARCH   362 ( 1 )   201 - 213   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Podoplanin was identified as a protein associated with the transformation of arborized foot processes of glomerular epithelial cells (podocytes) to flat feet. However, the function of podoplanin in the podocyte is not yet fully clarified. In this study, we analyzed the molecular nature of podoplanin, and its expression in rat nephrotic models and patients with minimal change nephrotic syndrome (MCNS). We demonstrated here that podoplanin has two forms: one contains abundant sialic acid and the other a lesser amount of sialic acid. Podoplanin bound ezrin to interact with the cytoskeleton. The silencing of podoplanin in cultured podocytes caused a change in the cell shape and the distribution of ezrin and actin. The expression of podoplanin was clearly reduced before the onset of proteinuria in puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, and the decrease in the expression of podoplanin became more evident at the proteinuric stage. Podoplanin was detected in normal urine samples, and the amount of urinary podoplanin markedly increased on day 1 of PAN nephropathy. Urinary ezrin was also detected. The amount of the phosphorylated ezrin was reduced, while the amount of the podoplanin-interacting ezrin increased. The podoplanin expression was reduced in a patient with active-phase MCNS. It is conceivable that the alteration of the podoplanin-ezrin-cytoskeleton linkage is an important event of the podocyte injury in MCNS.

    DOI: 10.1007/s00441-015-2178-8

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  • Dickkopf 3 Promotes the Differentiation of a Rostrolateral Midbrain Dopaminergic Neuronal Subset In Vivo and from Pluripotent Stem Cells In Vitro in the Mouse 査読 国際誌

    Yoshiyasu Fukusumi, Florian Meier, Sebastian Goetz, Friederike Matheus, Martin Irmler, Ruth Beckervordersandforth, Theresa Faus-Kessler, Eleonora Minina, Benedict Rauser, Jingzhong Zhang, Ernest Arenas, Elisabet Andersson, Christof Niehrs, Johannes Beckers, Antonio Simeone, Wolfgang Wurst, Nilima Prakash

    JOURNAL OF NEUROSCIENCE   35 ( 39 )   13385 - 13401   2015年9月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Wingless-related MMTV integration site 1 (WNT1)/beta-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson's disease (PD). However, the precise functions of WNT1/beta-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/beta-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1 alpha) and PITX3 (paired-like homeodomain transcription factor 3) expression in the wcorresponding mdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD.

    DOI: 10.1523/JNEUROSCI.1722-15.2015

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  • SV2B is essential for the integrity of the glomerular filtration barrier. 査読 国際誌

    Fukusumi Y, Wakamatsu A, Takashima N, Hasegawa E, Miyauchi N, Tomita M, Kawachi H

    Laboratory Investigation   95 ( 5 )   534 - 45   2015年3月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/labinvest.2015.39.

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  • Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin 査読

    Aya Takahashi, Yoshiyasu Fukusumi, Mihoko Yamazaki, Mutsumi Kayaba, Yukina Kitazawa, Masayuki Tomita, Hiroshi Kawachi

    JOURNAL OF NEPHROLOGY   27 ( 6 )   627 - 634   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WICHTIG EDITORE  

    The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain.
    The glomerular expressions of the slit diaphragm (SD) molecules nephrin, podocin and NEPH1 in rat puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, were analyzed. The effects of Ang II receptor blockade (ARB) (irbesartan 15 mg/kg body weight/day) on proteinuria and on the expression of the SD molecules were analyzed.
    mRNA expressions of nephrin, podocin and NEPH1 were decreased to an undetectable level at 1 h. The staining of these SD molecules shifted to a discontinuous pattern, and their intensity was reduced. NEPH1 staining was reduced to an undetectable level on day 10. ARB treatment ameliorated the peak value of proteinuria (237.6 +/- A 97.0 vs. 359.0 +/- A 63.3 mg/day, p < 0.05), and prevented the decrease in the mRNA expression of the SD molecules (nephrin 66.96 %, podocin 60.40 %, NEPH1 77.87 % of normal level). The immunofluorescence staining of NEPH1 was restored by ARB. ARB treatment enhanced the expression of NEPH1 of normal rats.
    Dysfunction of the SD molecules including NEPH1 is a crucial initiation event of PAN nephropathy. ARB treatment ameliorates proteinuria in PAN nephropathy by inhibiting the reduction of NEPH1 and nephrin. Ang II action regulates the expression of NEPH1 and nephrin in not only the pathological but also physiological state.

    DOI: 10.1007/s40620-014-0147-z

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  • Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin. 国際誌

    Takahashi Aya, Fukusumi Yoshiyasu, Yamazaki Mihoko, Kayaba Mutsumi, Kitazawa Yukina, Tomita Masayuki, Kawachi Hiroshi

    J Nephrol   27 ( 6 )   627 - 34   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s40620-014-0147-z

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  • Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules. 招待 査読 国際誌

    Fukusumi Y, Miyauchi N, Hashimoto T, Saito A, Kawachi H

    World journal of nephrology   3 ( 3 )   77 - 84   2014年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.5527/wjn.v3.i3.77.

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  • Beta4-galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development. 査読 国際誌

    Nishie T, Hikimochi Y, Zama K, Fukusumi Y, Ito M, Yokoyama H, Naruse C, Ito M, Asano M

    Glycobiology   20 ( 10 )   1311 - 1322   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/glycob/cwq098

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  • β4-Galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development 査読

    Toshikazu Nishie, Yoko Hikimochi, Kota Zama, Yoshiyasu Fukusumi, Mitutoshi Ito, Haruka Yokoyama, Chie Naruse, Makoto Ito, Masahide Asano

    Glycobiology   20 ( 10 )   1311 - 1322   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Glycosphingolipids (GSLs) are important for various biological functions in the nervous system, the immune system, embryogenesis and in other tissues and processes. Lactosylceramide (LacCer), which is synthesized from glucosylceramide (GlcCer) by LacCer synthase, is a core structure of GSLs, including gangliosides. LacCer synthase was reported to be synthesized by the β4-galactosyltransferase-6 (β4GalT-6) gene in the rat brain. However, the existence of another LacCer synthase gene was shown in cultured cells lacking β4GalT-6. Here, we report that LacCer synthase is mainly synthesized by the β4GalT-5 gene during early mouse embryogenesis, and its disruption is embryonic lethal. β4GalT-5-deficient embryos showed developmental retardation from E7.5 and died by E10.5 as reported previously. LacCer synthase activity was significantly reduced in β4GalT-5-deficient embryos and extra-embryonic endoderm (XEN) cells derived from blastocysts, and it was recovered when β4GalT-5 cDNA was introduced into β4GalT-5-deficient XEN cells. The amounts of LacCer and GM3 ganglioside were drastically reduced, while GlcCer accumulated in the β4GalT-5- deficient XEN cells. Hematoma and ectopically accumulated trophoblast giant cells were observed in the anti-mesometrial pole of the extra-embryonic tissues, although all three embryonic layers formed. β4GalT-5-deficient embryos developed until E12.5 as chimeras with wild-type tetraploid cells, which formed the extra-embryonic membranes, indicating that extra-embryonic defects caused the early embryonic lethality. Our results suggest that β4GalT-5 is essential for extra-embryonic development during early mouse embryogenesis. © 2010 The Author.

    DOI: 10.1093/glycob/cwq098

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  • Wtap is required for differentiation of endoderm and mesoderm in the mouse embryo 査読 国際誌

    Fukusumi Y, Naruse C, Asano M

    Developmental Dynamics   237 ( 3 )   618 - 629   2008年3月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:学位論文(その他)  

    DOI: 10.1002/dvdy.21444

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  • A novel gene trapping for identifying genes expressed under the control of specific transcription factors 査読 国際誌

    Chie Naruse, Yoshiyasu Fukusumi, Dai Kakiuchi, Masahide Asano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   361 ( 1 )   109 - 115   2007年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Gene trapping is a powerful method for identifying novel genes and for analyzing their functions. It is, however, difficult to select trapped genes on the basis of their function. To identify genes regulated by transcription factors that are important in the mesodermal formation, we selected trapped ES clones by infection of adenoviral vectors expressing Pax1, Brachyury, and Foxa2. Among 366 trapped genes, seven seemed to be controlled by these transcription factors in the first screening. The trapped genes were identified by 5' RACE, and a Northern blotting revealed that expressions of three trapped genes were regulated by these transcription factors. Expression patterns of Cx43 and HPI gamma implicated their functional relationships to Foxa2 in the formation of the notochord and the neural tube. Furthermore, Wtap mutant mice derived from the trapped clone showed defects in the mesendoderm formation. Our results indicate that trapped ES clones could be selected effectively using transcription factors. (c) 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2007.06.161

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MISC

  • 各種ポドサイト機能分子の病勢診断マーカーとしての有用性の検討:ラットPAN腎症モデルを用いた解析

    金子博司, 若松彩子, 広瀬絵理子, 高島奈津美, 山崎美穂子, 福住好恭, 河内裕

    日本腎臓学会誌   56 ( 3 )   2014年

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受賞

  • 学長賞(若手教員研究奨励)

    2018年11月   新潟大学  

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  • 第4回分子腎臓フォーラム優秀賞

    2013年9月   分子腎臓フォーラム  

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共同研究・競争的資金等の研究

  • 腎糸球体上皮細胞スリット膜におけるNeurexinの役割の解明

    研究課題/領域番号:20K08587  2020年4月 - 2024年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    福住 好恭, 張 エイ, 安田 英紀, 河内 裕

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • ポドサイト機能維持におけるCa2+活性化型陽イオンチャネルTRPM4の役割

    研究課題/領域番号:19K08720  2019年4月 - 2023年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    張 エイ, 河内 裕, 福住 好恭

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    TRPM4は、チャネル機能を持つTRPM4b 、チャネル機能を持たないTRPM4aなど各種分子型の発現があることが報告されているが、各臓器、組織における各分子型の発現は十分に検討されていない。ポドサイト特異的KOマウスの確立に先立ち、初年度はポドサイトにおけるTRPM4の発現分子型の検討を行った。糸球体材料を用いた検討で、exon 4単独欠損の新しいvariantが存在し、ポドサイトでは他組織に比べ、同variant並びにTRPM4aの発現が多いことを明らかにした。また、TRPM4チャネル阻害剤である9-Phenanthnol処理によりexon 4単独欠損variantの発現が低下することを観察した。ネフローゼ症候群モデルでは、TRPM4b 、TRPM4aの発現の低下を観察したが、exon 4単独欠損variantの発現に変化はなかった。一方ですべてのvariantsに共通する部分を認識するprimer pairでの検討では、発現の低下が見られた。これらの観察結果は、ポドサイトには別の新たなvariantが存在することを示唆していると考えられた。
    ポドサイトにおけるTRPM4の局在、発生期、病態における発現動態の検討を行なった。二重免疫蛍光法、Duolink in situ assay法での検討で、TRPM4は主にnephrin近傍のスリット膜並びにそのやや頂部に主に発現していることを明らかにした。発生期糸球体ではTRPM4はS字管期初期に既に発現しており、S字管期後期nephrin発現と同時にその近傍に発現することを観察した。ネフローゼ症候群モデルでの検討で、蛋白尿発症時スリット膜部TRPM4の発現が変化し、頂部にシフトすることを観察した。

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  • 脳腎連関:シナプス関連分子を標的とした新規蛋白尿抑制治療薬の開発

    研究課題/領域番号:19H03673  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    河内 裕, 葛谷 聡, 福住 好恭, 松井 克之, 内許 玉楓, 安田 英紀

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    各種シナプス関連分子(synaptic vesicle protein 2B (SV2B)、Neurexin、Ephrin-B1)が腎糸球体上皮細胞(ポドサイト)に発現していること、その分子機能の低下が蛋白尿発症に関与していることを明らかにしてきた。今年度は、Neurexin についての検討を中心に行った。Neurexinは各種分子型が存在するが、Neurexin1αがポドサイト障害発症時に発現が低下し、局在変化が著明であることを確認したためNeurexin1αKOマウスを確立した。Neurexin1α KOマウスは全身のKOマウスにおいても致死とならないとの報告があるため、Neurexin1α KOマウスを作製し、腎、その他臓器における表現型の解析を進めた。ヘテロマウス同士の交配で得られたNeurexin1α KOマウスの出生率は約10%で有意に低かった。得られたKOマウスは野生型マウスと比較して有意に小さく体重が軽かった。 KOマウス腎糸球体では、スリット膜機能分子であるNephrin、CD2AP、ZO-1、Ephrin-B1の染色強度が低下していた。一方で、Podocin、NEPH1、Synaptopodin、Podocalyxin染色の明確な変化は観察されなかった。またNeurexin1αとスリット膜機能分子との相互作用の検討を行い、Neurexin1αはCD2APだけでなくNephrinとも親和性を持つことをHEK293細胞強制発現系での検討で明らかにした。
    SV2Bは研究代表者らが蛋白尿発症に重要な役割を果たしていることを示した分子で、SV2Aなど他のシナプス小胞関連分子に比べ神経領域での検討は進んでいなかった。分担者はSV2Bがアルツハイマー病の発症に関与していることを報告した。

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  • 蛋白尿発症機序におけるEphrin-B1の役割の解明

    2017年11月 - 2018年10月

    金原一郎記念医学医療振興財団  第32回基礎医学医療研究助成金 

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  • 腎糸球体上皮細胞スリット膜の 形成、維持機構の解明

    2016年11月 - 2017年10月

    武田科学振興財団  医学系研究奨励賞 

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  • 腎糸球体上皮細胞スリット膜の形成、維持におけるEphrin-B1の役割の解明

    2016年4月 - 2020年3月

    日本学術振興会  科学研究費助成事業  若手研究(B)

    福住 好恭

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3000000円 ( 直接経費:2100000円 、 間接経費:900000円 )

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  • 次世代シーケンサー解析によるネフローゼ症候群の新規治療標的分子の探索

    研究課題/領域番号:16K19483  2016年4月 - 2019年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    張 エイ, 河内 裕, 福住 好恭

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    ネフローゼ症候群に対する新規治療の標的候補分子を探索するため、次世代シーケンサーRNA-Seq法を用いて、ネフローゼ症候群モデルラット糸球体で発現が変化している分子の網羅的解析を行った。発現変化した分子群を用いたGene Ontology (GO)、KEGG pathway生物学的統計法での解析、並びに病態モデルでの発現動態解析により、Rap1 signaling pathway関連分子、Hmgcs2、Lnpep、Ptar1、カルシウムイオン活性化型陽イオンチャネルTRPM4、がネフローゼ症候群に対する新規治療標的候補分子として有望であることを示した。

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  • 腎糸球体上皮細胞スリット膜の形成・維持におけるシナプス小胞輸送機構の解明

    2012年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業  若手研究(B)

    福住好恭

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3400000円 ( 直接経費:2380000円 、 間接経費:1020000円 )

    本研究課題は、ポドサイトの濾過障壁形成・維持機構におけるシナプス小胞輸送機構の機能を解析する。具体的には、Synaptic Vesicle2A/B 遺伝子破壊(SV2A/B 遺伝子KO)マウスを用いて、シナプス小胞輸送関連分子のポドサイトの濾過障壁形成・維持機構における役割を明らかにする。

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  • 遺伝子変異マウスを用いたWtapの選択的スプライシング制御機構の解析

    研究課題/領域番号:06J54132  2006年 - 2008年

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    福住 好恭

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    配分額:1900000円 ( 直接経費:1900000円 )

    Wilms' tumor-1 associating protein(以下Wtap)遺伝子は、選択的スプライシング機能やcyclinA2 mRNAの安定性、細胞増殖などに関与することが報告されている。私はWtapの生体内での機能を明らかにするためにWtap遺伝子変異マウスを作成し、Wtapはマウス胚とES細胞において内胚葉と中胚葉の分化に必要であることを明らかにした。しかし、マウス胚における内胚葉と中胚葉の分化は胚体外組織からのシグナルを受けて開始されることが知られており、Wtapが胚体外あるいは胚体組織のどちらで機能するかは不明であった。この疑問を解明するために本年度はキメラ解析を行った。
    『Wtap変異ES細包と野生型胚』、『Wtap変異胚と野生型ES細胞』の2つの組み合わせでキメラ胚を作成した。その結果、正常な胚体外組織はWtapホモ変異ES細胞の生体内での三胚葉への分化を誘導できた。しかし、ホモ変異胚由来の胚体外組織は野生型ES細胞の内胚葉と中胚葉への分化を誘導することができず、このキメラ胚は円筒胚が形成できないWtapホモ変異胚の形態と酷似していた。
    また、マウス胚におけるcycIin A2のタンパク質発現を免疫染色法により解析を行ったが、Wtap変異胚においてcyclin A2タンパク質発現はコントロール胚と変わらないことが分かった。さらに、細胞増殖マーカーであるリン酸化ピストンH3抗体を用いて解析したが、コントロール胚と明らかな差は見られなかった。
    以上の結果から、少なくともマウス初期胚におけるWtapは、これまで言われていたcyclin A2のmRNAの安定化や細胞増殖の制御よりも、内胚葉と中胚葉の分化に必要であることを明らかにした。

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