Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway
Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly su...
Gespeichert in:
| Veröffentlicht in: | FEBS letters 2007-02, Vol.581 (3), p.421-426 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 426 |
|---|---|
| container_issue | 3 |
| container_start_page | 421 |
| container_title | FEBS letters |
| container_volume | 581 |
| creator | Takano, Yosuke Yamauchi, Kozue Hayakawa, Kunihiro Hiramatsu, Nobuhiko Kasai, Ayumi Okamura, Maro Yokouchi, Makiko Shitamura, Akihiro Yao, Jian Kitamura, Masanori |
| description | Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms’ tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases. |
| doi_str_mv | 10.1016/j.febslet.2006.12.051 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_68963769</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0014579307000208</els_id><sourcerecordid>68963769</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5728-5bc9ff530cd1d7b438c9d130782bfb71e686aeca6f1df2c2eb33b9631850c4f63</originalsourceid><addsrcrecordid>eNqNkctu1DAUhi0EokPhEUBZsUvqS2I7bFCpehOVQFDWluMcM54mcbA9U-UZeGk8mpG6LJIlyz7f-W2dD6H3BFcEE362qSx0cYBUUYx5RWiFG_ICrYgUrGQ1ly_RCmNSl41o2Ql6E-MG57Mk7Wt0QgRlreRkhf7eBz1FE9ycnJ_0UMTtPAeIMZ8Kb4sJ5nVwU5HX7HtvlgSx6JZi1Cb4ea1_Q_xU_PBDvs20m-ygx1EnH5Yis_7BTbmipz6Xdn7YwQhT2pNpDcX3W_b17PwhFbNO60e9vEWvrB4ivDvup-jX1eX9xU159-369uL8rjSNoLJsOtNa2zBsetKLrmbStD1hWEja2U4Q4JJrMJpb0ltqKHSMdS1nRDbY1JazU_TxkDsH_2cLManRRQPDoCfw26i4zLTg7bMgxTUWNccZbA5gHkqMAayagxt1WBTBaq9LbdRRl9rrUoSqrCv3fTg-sO1G6J-6jn4ycHMAHt0Ay_-lqqvLL_Tn3v1ePRZZO8UyR30-REEe7c5BUNE4mAz0LoBJqvfumd_-A6c1wbo</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20407460</pqid></control><display><type>article</type><title>Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway</title><source>Wiley-Blackwell Journals</source><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><source>Free E-Journal (出版社公開部分のみ）</source><source>Wiley Open Access</source><source>Alma/SFX Local Collection</source><creator>Takano, Yosuke ; Yamauchi, Kozue ; Hayakawa, Kunihiro ; Hiramatsu, Nobuhiko ; Kasai, Ayumi ; Okamura, Maro ; Yokouchi, Makiko ; Shitamura, Akihiro ; Yao, Jian ; Kitamura, Masanori</creator><creatorcontrib>Takano, Yosuke ; Yamauchi, Kozue ; Hayakawa, Kunihiro ; Hiramatsu, Nobuhiko ; Kasai, Ayumi ; Okamura, Maro ; Yokouchi, Makiko ; Shitamura, Akihiro ; Yao, Jian ; Kitamura, Masanori</creatorcontrib><description>Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms’ tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases.</description><identifier>ISSN: 0014-5793</identifier><identifier>EISSN: 1873-3468</identifier><identifier>DOI: 10.1016/j.febslet.2006.12.051</identifier><identifier>PMID: 17239861</identifier><language>eng</language><publisher>England: Elsevier B.V</publisher><subject>12-o-tetradecanoylphorbol-13-acetate ; all-trans retinoic acid ; Animals ; ATRA ; Cell Communication ; Cells, Cultured ; Cytokines - metabolism ; Cytokines - pharmacology ; Down-Regulation - drug effects ; FBS ; fetal bovine serum ; GAPDH ; glyceraldehydes-3-phosphate dehydrogenase ; hepatocyte growth factor ; HGF ; Humans ; IL-1β ; Inflammation Mediators - metabolism ; Inflammation Mediators - pharmacology ; Interleukin-1beta - metabolism ; Interleukin-1beta - pharmacology ; lipopolysaccharide ; LPS ; Macrophage ; macrophage-conditioned medium ; Macrophages - immunology ; Macrophages - metabolism ; Membrane Proteins - genetics ; Mice ; MϕCM ; Nephrin ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphatidylinositol-3-kinase ; phosphophatidylinositol-3-kinase ; PI3K ; PKC ; Podocyte ; Podocytes - drug effects ; Podocytes - metabolism ; Promoter Regions, Genetic ; protein kinase C ; Proto-Oncogene Proteins c-akt - metabolism ; RAR ; RARE ; REPON ; reporter podocytes for nephrin ; retinoic acid receptor ; retinoic acid response element ; reverse transcriptase-polymerase chain reaction ; RT-PCR ; SEAP ; secreted alkaline phosphatase ; TNF-α ; TPA ; Tumor Necrosis Factor-alpha - metabolism ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>FEBS letters, 2007-02, Vol.581 (3), p.421-426</ispartof><rights>2007 Federation of European Biochemical Societies</rights><rights>FEBS Letters 581 (2007) 1873-3468 © 2015 Federation of European Biochemical Societies</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5728-5bc9ff530cd1d7b438c9d130782bfb71e686aeca6f1df2c2eb33b9631850c4f63</citedby><cites>FETCH-LOGICAL-c5728-5bc9ff530cd1d7b438c9d130782bfb71e686aeca6f1df2c2eb33b9631850c4f63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2Fj.febslet.2006.12.051$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.febslet.2006.12.051$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>315,781,785,1418,1434,3551,27928,27929,45578,45579,45999,46413,46837</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17239861$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takano, Yosuke</creatorcontrib><creatorcontrib>Yamauchi, Kozue</creatorcontrib><creatorcontrib>Hayakawa, Kunihiro</creatorcontrib><creatorcontrib>Hiramatsu, Nobuhiko</creatorcontrib><creatorcontrib>Kasai, Ayumi</creatorcontrib><creatorcontrib>Okamura, Maro</creatorcontrib><creatorcontrib>Yokouchi, Makiko</creatorcontrib><creatorcontrib>Shitamura, Akihiro</creatorcontrib><creatorcontrib>Yao, Jian</creatorcontrib><creatorcontrib>Kitamura, Masanori</creatorcontrib><title>Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway</title><title>FEBS letters</title><addtitle>FEBS Lett</addtitle><description>Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms’ tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases.</description><subject>12-o-tetradecanoylphorbol-13-acetate</subject><subject>all-trans retinoic acid</subject><subject>Animals</subject><subject>ATRA</subject><subject>Cell Communication</subject><subject>Cells, Cultured</subject><subject>Cytokines - metabolism</subject><subject>Cytokines - pharmacology</subject><subject>Down-Regulation - drug effects</subject><subject>FBS</subject><subject>fetal bovine serum</subject><subject>GAPDH</subject><subject>glyceraldehydes-3-phosphate dehydrogenase</subject><subject>hepatocyte growth factor</subject><subject>HGF</subject><subject>Humans</subject><subject>IL-1β</subject><subject>Inflammation Mediators - metabolism</subject><subject>Inflammation Mediators - pharmacology</subject><subject>Interleukin-1beta - metabolism</subject><subject>Interleukin-1beta - pharmacology</subject><subject>lipopolysaccharide</subject><subject>LPS</subject><subject>Macrophage</subject><subject>macrophage-conditioned medium</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Membrane Proteins - genetics</subject><subject>Mice</subject><subject>MϕCM</subject><subject>Nephrin</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphatidylinositol-3-kinase</subject><subject>phosphophatidylinositol-3-kinase</subject><subject>PI3K</subject><subject>PKC</subject><subject>Podocyte</subject><subject>Podocytes - drug effects</subject><subject>Podocytes - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>protein kinase C</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>RAR</subject><subject>RARE</subject><subject>REPON</subject><subject>reporter podocytes for nephrin</subject><subject>retinoic acid receptor</subject><subject>retinoic acid response element</subject><subject>reverse transcriptase-polymerase chain reaction</subject><subject>RT-PCR</subject><subject>SEAP</subject><subject>secreted alkaline phosphatase</subject><subject>TNF-α</subject><subject>TPA</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>0014-5793</issn><issn>1873-3468</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctu1DAUhi0EokPhEUBZsUvqS2I7bFCpehOVQFDWluMcM54mcbA9U-UZeGk8mpG6LJIlyz7f-W2dD6H3BFcEE362qSx0cYBUUYx5RWiFG_ICrYgUrGQ1ly_RCmNSl41o2Ql6E-MG57Mk7Wt0QgRlreRkhf7eBz1FE9ycnJ_0UMTtPAeIMZ8Kb4sJ5nVwU5HX7HtvlgSx6JZi1Cb4ea1_Q_xU_PBDvs20m-ygx1EnH5Yis_7BTbmipz6Xdn7YwQhT2pNpDcX3W_b17PwhFbNO60e9vEWvrB4ivDvup-jX1eX9xU159-369uL8rjSNoLJsOtNa2zBsetKLrmbStD1hWEja2U4Q4JJrMJpb0ltqKHSMdS1nRDbY1JazU_TxkDsH_2cLManRRQPDoCfw26i4zLTg7bMgxTUWNccZbA5gHkqMAayagxt1WBTBaq9LbdRRl9rrUoSqrCv3fTg-sO1G6J-6jn4ycHMAHt0Ay_-lqqvLL_Tn3v1ePRZZO8UyR30-REEe7c5BUNE4mAz0LoBJqvfumd_-A6c1wbo</recordid><startdate>20070206</startdate><enddate>20070206</enddate><creator>Takano, Yosuke</creator><creator>Yamauchi, Kozue</creator><creator>Hayakawa, Kunihiro</creator><creator>Hiramatsu, Nobuhiko</creator><creator>Kasai, Ayumi</creator><creator>Okamura, Maro</creator><creator>Yokouchi, Makiko</creator><creator>Shitamura, Akihiro</creator><creator>Yao, Jian</creator><creator>Kitamura, Masanori</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20070206</creationdate><title>Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway</title><author>Takano, Yosuke ; Yamauchi, Kozue ; Hayakawa, Kunihiro ; Hiramatsu, Nobuhiko ; Kasai, Ayumi ; Okamura, Maro ; Yokouchi, Makiko ; Shitamura, Akihiro ; Yao, Jian ; Kitamura, Masanori</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5728-5bc9ff530cd1d7b438c9d130782bfb71e686aeca6f1df2c2eb33b9631850c4f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>12-o-tetradecanoylphorbol-13-acetate</topic><topic>all-trans retinoic acid</topic><topic>Animals</topic><topic>ATRA</topic><topic>Cell Communication</topic><topic>Cells, Cultured</topic><topic>Cytokines - metabolism</topic><topic>Cytokines - pharmacology</topic><topic>Down-Regulation - drug effects</topic><topic>FBS</topic><topic>fetal bovine serum</topic><topic>GAPDH</topic><topic>glyceraldehydes-3-phosphate dehydrogenase</topic><topic>hepatocyte growth factor</topic><topic>HGF</topic><topic>Humans</topic><topic>IL-1β</topic><topic>Inflammation Mediators - metabolism</topic><topic>Inflammation Mediators - pharmacology</topic><topic>Interleukin-1beta - metabolism</topic><topic>Interleukin-1beta - pharmacology</topic><topic>lipopolysaccharide</topic><topic>LPS</topic><topic>Macrophage</topic><topic>macrophage-conditioned medium</topic><topic>Macrophages - immunology</topic><topic>Macrophages - metabolism</topic><topic>Membrane Proteins - genetics</topic><topic>Mice</topic><topic>MϕCM</topic><topic>Nephrin</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphatidylinositol-3-kinase</topic><topic>phosphophatidylinositol-3-kinase</topic><topic>PI3K</topic><topic>PKC</topic><topic>Podocyte</topic><topic>Podocytes - drug effects</topic><topic>Podocytes - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>protein kinase C</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>RAR</topic><topic>RARE</topic><topic>REPON</topic><topic>reporter podocytes for nephrin</topic><topic>retinoic acid receptor</topic><topic>retinoic acid response element</topic><topic>reverse transcriptase-polymerase chain reaction</topic><topic>RT-PCR</topic><topic>SEAP</topic><topic>secreted alkaline phosphatase</topic><topic>TNF-α</topic><topic>TPA</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takano, Yosuke</creatorcontrib><creatorcontrib>Yamauchi, Kozue</creatorcontrib><creatorcontrib>Hayakawa, Kunihiro</creatorcontrib><creatorcontrib>Hiramatsu, Nobuhiko</creatorcontrib><creatorcontrib>Kasai, Ayumi</creatorcontrib><creatorcontrib>Okamura, Maro</creatorcontrib><creatorcontrib>Yokouchi, Makiko</creatorcontrib><creatorcontrib>Shitamura, Akihiro</creatorcontrib><creatorcontrib>Yao, Jian</creatorcontrib><creatorcontrib>Kitamura, Masanori</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>FEBS letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takano, Yosuke</au><au>Yamauchi, Kozue</au><au>Hayakawa, Kunihiro</au><au>Hiramatsu, Nobuhiko</au><au>Kasai, Ayumi</au><au>Okamura, Maro</au><au>Yokouchi, Makiko</au><au>Shitamura, Akihiro</au><au>Yao, Jian</au><au>Kitamura, Masanori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway</atitle><jtitle>FEBS letters</jtitle><addtitle>FEBS Lett</addtitle><date>2007-02-06</date><risdate>2007</risdate><volume>581</volume><issue>3</issue><spage>421</spage><epage>426</epage><pages>421-426</pages><issn>0014-5793</issn><eissn>1873-3468</eissn><abstract>Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms’ tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases.</abstract><cop>England</cop><pub>Elsevier B.V</pub><pmid>17239861</pmid><doi>10.1016/j.febslet.2006.12.051</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0014-5793 |
| ispartof | FEBS letters, 2007-02, Vol.581 (3), p.421-426 |
| issn | 0014-5793 1873-3468 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_68963769 |
| source | Wiley-Blackwell Journals; MEDLINE; Elsevier ScienceDirect Journals Complete; Free E-Journal (出版社公開部分のみ）; Wiley Open Access; Alma/SFX Local Collection |
| subjects | 12-o-tetradecanoylphorbol-13-acetate all-trans retinoic acid Animals ATRA Cell Communication Cells, Cultured Cytokines - metabolism Cytokines - pharmacology Down-Regulation - drug effects FBS fetal bovine serum GAPDH glyceraldehydes-3-phosphate dehydrogenase hepatocyte growth factor HGF Humans IL-1β Inflammation Mediators - metabolism Inflammation Mediators - pharmacology Interleukin-1beta - metabolism Interleukin-1beta - pharmacology lipopolysaccharide LPS Macrophage macrophage-conditioned medium Macrophages - immunology Macrophages - metabolism Membrane Proteins - genetics Mice MϕCM Nephrin Phosphatidylinositol 3-Kinases - metabolism Phosphatidylinositol-3-kinase phosphophatidylinositol-3-kinase PI3K PKC Podocyte Podocytes - drug effects Podocytes - metabolism Promoter Regions, Genetic protein kinase C Proto-Oncogene Proteins c-akt - metabolism RAR RARE REPON reporter podocytes for nephrin retinoic acid receptor retinoic acid response element reverse transcriptase-polymerase chain reaction RT-PCR SEAP secreted alkaline phosphatase TNF-α TPA Tumor Necrosis Factor-alpha - metabolism Tumor Necrosis Factor-alpha - pharmacology |
| title | Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T13%3A51%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Transcriptional%20suppression%20of%20nephrin%20in%20podocytes%20by%20macrophages:%20Roles%20of%20inflammatory%20cytokines%20and%20involvement%20of%20the%20PI3K/Akt%20pathway&rft.jtitle=FEBS%20letters&rft.au=Takano,%20Yosuke&rft.date=2007-02-06&rft.volume=581&rft.issue=3&rft.spage=421&rft.epage=426&rft.pages=421-426&rft.issn=0014-5793&rft.eissn=1873-3468&rft_id=info:doi/10.1016/j.febslet.2006.12.051&rft_dat=%3Cproquest_cross%3E68963769%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=20407460&rft_id=info:pmid/17239861&rft_els_id=S0014579307000208&rfr_iscdi=true |