SV2B is essential for the integrity of the glomerular filtration barrier

Fukusumi, Yoshiyasu; Wakamatsu, Ayako; Takashima, N; Hasegawa, Eietsu; Miyauchi, Naoko; Tomita, Masayuki; Kawachi, Hiroshi

doi:10.1038/labinvest.2015.39

Cited by 16 publications

(23 citation statements)

References 38 publications

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“…The immunofluorescence studies with CKO mice and rats were performed basically according to the method previously reported. [13][14][15][16] The antibodies used in this study are summarized in Supplemental Table 1. The stainings were evaluated in 30 glomeruli of each mouse, in a blinded manner.…”

Section: Rt-pcr Immunofluorescence Western Blot Analysis and Morphmentioning

confidence: 99%

Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway

Fukusumi

Zhang

Yamagishi

et al. 2018

JASN

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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. 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. Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, 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 a mutant 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. 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.

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Section: Rt-pcr Immunofluorescence Western Blot Analysis and Morphmentioning

confidence: 99%

Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway

Fukusumi

Zhang

Yamagishi

et al. 2018

JASN

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“…2). Duolink analysis (Soderberg et al 2006;Fukusumi et al 2015) showed the close localization of CN-A and nephrin within 40 nm (Fig. 3A).…”

Section: Discussionmentioning

confidence: 95%

“…The analysis was performed according to the method previously reported (Fukusumi et al. ). Briefly, rat kidney sections were incubated with rabbit anti‐CN‐A and mouse anti‐nephrin, and the interaction was analyzed with Duolink in situ PLA probe anti‐rabbit PLUS and Duolink in situ PLA probe anti‐mouse MINUS.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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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.

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“…The role of SV2B in regulating the activity of transporter and transmembrane transporter proteins, which then introduces glucose-induced particles into the plasma membrane, has been shown to be essential in providing nutrients for tumor cells [ 18–20 ]. Several other diseases, such as missense mutations in leukemia [ 21 ], Alzheimer's disease [ 22 ], retinal neuropathy [ 23 ] and kidney disease [ 24 ], have been known to be closely associated with SV2B, suggesting that the protein is involved in many aspects of human disease.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential core genes for glioblastoma

et al. 2020

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Background: Glioblastoma (GBM) has a high degree of malignancy, aggressiveness and recurrence rate. However, there are limited options available for the treatment of GBM, and they often result in poor prognosis and unsatisfactory outcomes. Materials and methods: In order to identify potential core genes in GBM that may provide new therapeutic insights, we analyzed three gene chips (GSE2223, GSE4290 and GSE50161) screened from the GEO database. Differentially expressed genes (DEG) from the tissues of GBM and normal brain were screened using GEO2R. To determine the functional annotation and pathway of DEG, Gene Ontology (GO) and KEGG pathway enrichment analysis were conducted using DAVID database. Protein interactions of DEG were visualized using PPI network on Cytoscape software. Next, 10 Hub nodes were screened from the differentially expressed network using MCC algorithm on CytoHubba software and subsequently identified as Hub genes. Finally, the relationship between Hub genes and the prognosis of GBM patients was described using GEPIA2 survival analysis web tool. Results: A total of 37 up-regulated and 187 down-regulated genes were identified through microarray analysis. Amongst the 10 Hub genes selected, SV2B appeared to be the only gene associated with poor prognosis in glioblastoma based on the survival analysis. Conclusion: Our study suggests that high expression of SV2B is associated with poor prognosis in GBM patients. Whether SV2B can be used as a new therapeutic target for GBM requires further validation.

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SV2B is essential for the integrity of the glomerular filtration barrier

Cited by 16 publications

References 38 publications

Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway

Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway

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

Bioinformatics analysis of potential core genes for glioblastoma

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