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Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis
Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis dev...
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Published in: | Arthritis research & therapy 2022-12, Vol.24 (1), p.284-12, Article 284 |
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description | Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice.
In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated.
Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity.
Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN. |
doi_str_mv | 10.1186/s13075-022-02965-w |
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In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated.
Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity.
Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.</description><identifier>ISSN: 1478-6362</identifier><identifier>ISSN: 1478-6354</identifier><identifier>EISSN: 1478-6362</identifier><identifier>DOI: 10.1186/s13075-022-02965-w</identifier><identifier>PMID: 36578056</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Animals ; Anti-GBM nephritis ; Axl receptor tyrosine kinase ; BUN ; Cell Proliferation ; Cellular signal transduction ; Complications and side effects ; Development and progression ; Glomerulonephritis ; Glomerulonephritis - complications ; Glomerulonephritis - drug therapy ; Glomerulonephritis - metabolism ; Health aspects ; Immunological research ; Kidney - pathology ; Lupus Erythematosus, Systemic - metabolism ; Lupus nephritis ; Lupus Nephritis - pathology ; Mice ; Mice, Inbred MRL lpr ; Protein tyrosine kinase ; R428 ; Systemic lupus erythematosus ; T cell infiltration</subject><ispartof>Arthritis research & therapy, 2022-12, Vol.24 (1), p.284-12, Article 284</ispartof><rights>2022. The Author(s).</rights><rights>COPYRIGHT 2022 BioMed Central Ltd.</rights><rights>The Author(s) 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-81bb70b3c03e59a27f24ab14e01216c0b8c1ae20c465f906da5fda5b9a08ddd73</citedby><cites>FETCH-LOGICAL-c535t-81bb70b3c03e59a27f24ab14e01216c0b8c1ae20c465f906da5fda5b9a08ddd73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9795606/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9795606/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36578056$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhen, Yuxuan</creatorcontrib><creatorcontrib>Ren, Yan</creatorcontrib><creatorcontrib>Medvedovic, Mario</creatorcontrib><creatorcontrib>Adams, David E</creatorcontrib><creatorcontrib>Wang, Diping</creatorcontrib><creatorcontrib>Shao, Wen-Hai</creatorcontrib><title>Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis</title><title>Arthritis research & therapy</title><addtitle>Arthritis Res Ther</addtitle><description>Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice.
In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated.
Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity.
Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.</description><subject>Animals</subject><subject>Anti-GBM nephritis</subject><subject>Axl receptor tyrosine kinase</subject><subject>BUN</subject><subject>Cell Proliferation</subject><subject>Cellular signal transduction</subject><subject>Complications and side effects</subject><subject>Development and progression</subject><subject>Glomerulonephritis</subject><subject>Glomerulonephritis - complications</subject><subject>Glomerulonephritis - drug therapy</subject><subject>Glomerulonephritis - metabolism</subject><subject>Health aspects</subject><subject>Immunological research</subject><subject>Kidney - pathology</subject><subject>Lupus Erythematosus, Systemic - metabolism</subject><subject>Lupus nephritis</subject><subject>Lupus Nephritis - pathology</subject><subject>Mice</subject><subject>Mice, Inbred MRL lpr</subject><subject>Protein tyrosine kinase</subject><subject>R428</subject><subject>Systemic lupus erythematosus</subject><subject>T cell infiltration</subject><issn>1478-6362</issn><issn>1478-6354</issn><issn>1478-6362</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNptUttu1DAQjRCIlsIP8IAs8ZzWl9iJX5BWFZdKlXiBZ2viS9bFiSM72YW_x2yg6krIGl9mzhx7xqeq3hJ8TUgnbjJhuOU1prSYFLw-PqsuSdN2tWCCPn-yv6he5fyAC1LS5mV1wQRvO8zFZZV3PwNKdlgDLNagvKaDP0C4mVMM3tkEi48TmuxyjOkHgskgv2S07EtktuviNfLTYtPBTiegn9AY12zLbGzIKDo0hDjatIY42Xmf_OLz6-qFg5Dtm7_rVfX908dvt1_q-6-f725397XmjC91R_q-xT3TmFkugbaONtCTxmJCidC47zQBS7FuBHcSCwPcFesl4M4Y07Kr6m7jNREe1Jz8COmXiuDVyRHToCCVEoJV1EDPCW96kLo0jQED6bAB66QuB1a4Pmxc89qP1uhSb4JwRnoemfxeDfGgZCu5wKIQvN8IBij3-cnFAtOjz1rtWkY47wQhBXX9H1QZxo5elxY6X_xnCXRL0CnmnKx7fBLB6o9K1KYSVf5enVSijiXp3dNiHlP-yYL9BgqbvNM</recordid><startdate>20221228</startdate><enddate>20221228</enddate><creator>Zhen, Yuxuan</creator><creator>Ren, Yan</creator><creator>Medvedovic, Mario</creator><creator>Adams, David E</creator><creator>Wang, Diping</creator><creator>Shao, Wen-Hai</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</general><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>5PM</scope><scope>DOA</scope></search><sort><creationdate>20221228</creationdate><title>Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis</title><author>Zhen, Yuxuan ; Ren, Yan ; Medvedovic, Mario ; Adams, David E ; Wang, Diping ; Shao, Wen-Hai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-81bb70b3c03e59a27f24ab14e01216c0b8c1ae20c465f906da5fda5b9a08ddd73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Anti-GBM nephritis</topic><topic>Axl receptor tyrosine kinase</topic><topic>BUN</topic><topic>Cell Proliferation</topic><topic>Cellular signal transduction</topic><topic>Complications and side effects</topic><topic>Development and progression</topic><topic>Glomerulonephritis</topic><topic>Glomerulonephritis - complications</topic><topic>Glomerulonephritis - drug therapy</topic><topic>Glomerulonephritis - metabolism</topic><topic>Health aspects</topic><topic>Immunological research</topic><topic>Kidney - pathology</topic><topic>Lupus Erythematosus, Systemic - metabolism</topic><topic>Lupus nephritis</topic><topic>Lupus Nephritis - pathology</topic><topic>Mice</topic><topic>Mice, Inbred MRL lpr</topic><topic>Protein tyrosine kinase</topic><topic>R428</topic><topic>Systemic lupus erythematosus</topic><topic>T cell infiltration</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhen, Yuxuan</creatorcontrib><creatorcontrib>Ren, Yan</creatorcontrib><creatorcontrib>Medvedovic, Mario</creatorcontrib><creatorcontrib>Adams, David E</creatorcontrib><creatorcontrib>Wang, Diping</creatorcontrib><creatorcontrib>Shao, Wen-Hai</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Arthritis research & therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhen, Yuxuan</au><au>Ren, Yan</au><au>Medvedovic, Mario</au><au>Adams, David E</au><au>Wang, Diping</au><au>Shao, Wen-Hai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis</atitle><jtitle>Arthritis research & therapy</jtitle><addtitle>Arthritis Res Ther</addtitle><date>2022-12-28</date><risdate>2022</risdate><volume>24</volume><issue>1</issue><spage>284</spage><epage>12</epage><pages>284-12</pages><artnum>284</artnum><issn>1478-6362</issn><issn>1478-6354</issn><eissn>1478-6362</eissn><abstract>Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice.
In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated.
Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity.
Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>36578056</pmid><doi>10.1186/s13075-022-02965-w</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Anti-GBM nephritis Axl receptor tyrosine kinase BUN Cell Proliferation Cellular signal transduction Complications and side effects Development and progression Glomerulonephritis Glomerulonephritis - complications Glomerulonephritis - drug therapy Glomerulonephritis - metabolism Health aspects Immunological research Kidney - pathology Lupus Erythematosus, Systemic - metabolism Lupus nephritis Lupus Nephritis - pathology Mice Mice, Inbred MRL lpr Protein tyrosine kinase R428 Systemic lupus erythematosus T cell infiltration |
title | Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis |
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