Updated on 2021/04/11

写真a

 
FUKUSUMI Yoshiyasu
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Associate Professor
Title
Associate Professor
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Degree

  • 博士(医学) ( 2008.3   金沢大学 )

Research Interests

  • 腎臓病態学

Research Areas

  • Life Science / Nephrology

Research History (researchmap)

  • Niigata University   Graduate School of Medical and Dental Sciences Center of Nephrology   Associate Professor

    2016.4

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  • Niigata University   Graduate School of Medical and Dental Sciences Institute of Nephrology   Associate Professor

    2015.3 - 2016.3

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  • Niigata University   Faculty of Medicine School of Medicine   Assistant Professor

    2011.5 - 2015.2

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  • Niigata University   Graduate School of Medical and Dental Sciences Institute of Nephrology   Assistant Professor

    2011.5 - 2015.2

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Research History

  • Niigata University   Faculty of Medicine Institute of Nephrology   Associate Professor

    2016.4

  • Niigata University   Faculty of Medicine Institute of Nephrology   Associate Professor

    2015.3 - 2016.3

  • Niigata University   Faculty of Medicine School of Medicine   Assistant Professor

    2011.5 - 2015.2

  • Niigata University   Faculty of Medicine Institute of Nephrology   Assistant Professor

    2011.5 - 2015.2

Education

  • Kanazawa University   医学系研究科  

    - 2008.3

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    Country: Japan

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Professional Memberships

 

Papers

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

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

    Journal of the American Society of Nephrology29 ( 5 ) 1462 - 1474   2018.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

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

    JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM17 ( 4 )   2016.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

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

    Physiological Reports4 ( 6 ) 1 - 13   2016.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

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

    CELL AND TISSUE RESEARCH362 ( 1 ) 201 - 213   2015.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

    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 NEUROSCIENCE35 ( 39 ) 13385 - 13401   2015.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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. Reviewed

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

    Laboratory Investigation   2015.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    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 Reviewed

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

    JOURNAL OF NEPHROLOGY27 ( 6 ) 627 - 634   2014.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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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  • Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules. Invited Reviewed

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

    World journal of nephrology   2014.8

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

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

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

    Glycobiology20 ( 10 ) 1311 - 1322   2010.10

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    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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  • マウス胚における内胚葉と中胚葉の分化にはWtapが必須である Reviewed

    Fukusumi Y, Naruse C, Asano M

    Developmental Dynamics237 ( 3 ) 618 - 629   2008.3

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    DOI: 10.1002/dvdy.21444

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  • Wtap is required for differentiation of endoderm and mesoderm in the mouse embryo Reviewed

    Yoshiyasu Fukusumi, Chie Naruse, Masahide Asano

    DEVELOPMENTAL DYNAMICS237 ( 3 ) 618 - 629   2008.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    Wilms' tumor 1-associating protein (WTAP) was previously identified as a protein associated with Wilms' tumor-1 (WT-1) protein that is essential for the development of the genitourinary system. Although WTAP has been suggested to function in alternative splicing, stabilization of mRNA, and cell growth, its in vivo function is still unclear. We generated Wtap mutant mice using a novel gene-trap approach and showed that Wtap mutant embryos exhibited defective egg-cylinder formation at the gastrulation stage and died by embryonic day 10.5. Although they could form extraembryonic tissues and anterior visceral endoderm, Wtap mutant embryos and embryonic stem cells failed to differentiate into endoderm. and mesoderm. The chimera analysis showed that Wtap in extraembryonic tissues was required for the formation of mesoderm and endoderm in embryonic tissues. Taken together, our findings indicate that Wtap is indispensable for differentiation of mesoderm and endoderm in the mouse embryo.

    DOI: 10.1002/dvdy.21444

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

    Chie Naruse, Yoshiyasu Fukusumi, Dai Kakiuchi, Masahide Asano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS361 ( 1 ) 109 - 115   2007.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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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Research Projects

  • 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

    2016.04 - 2020.03

    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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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3000000 ( Direct Cost: \2100000 、 Indirect Cost:\900000 )

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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

    2012.04 - 2016.03

    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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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3400000 ( Direct Cost: \2380000 、 Indirect Cost:\1020000 )

    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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