IRF‐1 promotes renal fibrosis by downregulation of Klotho
Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD pati...
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| Veröffentlicht in: | The FASEB journal 2020-03, Vol.34 (3), p.4415-4429 |
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| creator | Li, Yan Liu, Yong Huang, Yinghui Yang, Ke Xiao, Tangli Xiong, Jiachuan Wang, Kailong Liu, Chi He, Ting Yu, Yanlin Han, Wenhao Wang, Yue Bi, Xianjin Zhang, Jingbo Huang, Yunjian Zhang, Bo Zhao, Jinghong |
| description | Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD. |
| doi_str_mv | 10.1096/fj.201902446R |
| format | Article |
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In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.201902446R</identifier><identifier>PMID: 31965641</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Blotting, Western ; Cell Line ; Chromatin Immunoprecipitation ; chronic kidney disease ; Glucuronidase - genetics ; Glucuronidase - metabolism ; HEK293 Cells ; Humans ; Immunoprecipitation ; Interferon Regulatory Factor-1 - genetics ; Interferon Regulatory Factor-1 - metabolism ; IRF ; Kidney - drug effects ; Kidney - metabolism ; Kidney - pathology ; Klotho ; Male ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Rats ; Real-Time Polymerase Chain Reaction ; renal fibrosis ; Renal Insufficiency, Chronic - metabolism ; Renal Insufficiency, Chronic - pathology ; TNF‐α ; Tumor Necrosis Factor-alpha - pharmacology ; Ureteral Obstruction - metabolism ; Ureteral Obstruction - pathology</subject><ispartof>The FASEB journal, 2020-03, Vol.34 (3), p.4415-4429</ispartof><rights>2020 Federation of American Societies for Experimental Biology</rights><rights>2020 Federation of American Societies for Experimental Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3779-649a7ad6d9a9b8abe78f197084518779a050fd067d13e58c6853102a8339e6943</citedby><cites>FETCH-LOGICAL-c3779-649a7ad6d9a9b8abe78f197084518779a050fd067d13e58c6853102a8339e6943</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.201902446R$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.201902446R$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31965641$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Liu, Yong</creatorcontrib><creatorcontrib>Huang, Yinghui</creatorcontrib><creatorcontrib>Yang, Ke</creatorcontrib><creatorcontrib>Xiao, Tangli</creatorcontrib><creatorcontrib>Xiong, Jiachuan</creatorcontrib><creatorcontrib>Wang, Kailong</creatorcontrib><creatorcontrib>Liu, Chi</creatorcontrib><creatorcontrib>He, Ting</creatorcontrib><creatorcontrib>Yu, Yanlin</creatorcontrib><creatorcontrib>Han, Wenhao</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Bi, Xianjin</creatorcontrib><creatorcontrib>Zhang, Jingbo</creatorcontrib><creatorcontrib>Huang, Yunjian</creatorcontrib><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Zhao, Jinghong</creatorcontrib><title>IRF‐1 promotes renal fibrosis by downregulation of Klotho</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Chromatin Immunoprecipitation</subject><subject>chronic kidney disease</subject><subject>Glucuronidase - genetics</subject><subject>Glucuronidase - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Interferon Regulatory Factor-1 - genetics</subject><subject>Interferon Regulatory Factor-1 - metabolism</subject><subject>IRF</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Klotho</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Biological</subject><subject>Rats</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>renal fibrosis</subject><subject>Renal Insufficiency, Chronic - metabolism</subject><subject>Renal Insufficiency, Chronic - pathology</subject><subject>TNF‐α</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><subject>Ureteral Obstruction - metabolism</subject><subject>Ureteral Obstruction - pathology</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90LtOwzAYBWALgWgpjKwoI0vK70t8ERNUFCoqIRWYLSexIVUSlzhR1Y1H4Bl5EoJaYGM6y6ejo4PQKYYxBsUv3HJMACsgjPHFHhrihELMJYd9NASpSMw5lQN0FMISADBgfogGFCuecIaH6HK2mH6-f-Bo1fjKtzZEja1NGbkibXwoQpRuotyv68a-dKVpC19H3kX3pW9f_TE6cKYM9mSXI_Q8vXma3MXzh9vZ5GoeZ1QIFXOmjDA5z5VRqTSpFdJhJUCyBMseGEjA5cBFjqlNZMZlQjEQIylVlitGR-h829tvfOtsaHVVhMyWpamt74ImlFGmhJDQ03hLs359aKzTq6aoTLPRGPT3X9ot9d9fvT_bVXdpZfNf_XNQD9gWrIvSbv5v09PHa0KASEW_AAHldCk</recordid><startdate>202003</startdate><enddate>202003</enddate><creator>Li, Yan</creator><creator>Liu, Yong</creator><creator>Huang, Yinghui</creator><creator>Yang, Ke</creator><creator>Xiao, Tangli</creator><creator>Xiong, Jiachuan</creator><creator>Wang, Kailong</creator><creator>Liu, Chi</creator><creator>He, Ting</creator><creator>Yu, Yanlin</creator><creator>Han, Wenhao</creator><creator>Wang, Yue</creator><creator>Bi, Xianjin</creator><creator>Zhang, Jingbo</creator><creator>Huang, Yunjian</creator><creator>Zhang, Bo</creator><creator>Zhao, Jinghong</creator><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>7X8</scope></search><sort><creationdate>202003</creationdate><title>IRF‐1 promotes renal fibrosis by downregulation of Klotho</title><author>Li, Yan ; Liu, Yong ; Huang, Yinghui ; Yang, Ke ; Xiao, Tangli ; Xiong, Jiachuan ; Wang, Kailong ; Liu, Chi ; He, Ting ; Yu, Yanlin ; Han, Wenhao ; Wang, Yue ; Bi, Xianjin ; Zhang, Jingbo ; Huang, Yunjian ; Zhang, Bo ; Zhao, Jinghong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3779-649a7ad6d9a9b8abe78f197084518779a050fd067d13e58c6853102a8339e6943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Chromatin Immunoprecipitation</topic><topic>chronic kidney disease</topic><topic>Glucuronidase - genetics</topic><topic>Glucuronidase - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Interferon Regulatory Factor-1 - genetics</topic><topic>Interferon Regulatory Factor-1 - metabolism</topic><topic>IRF</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Klotho</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Biological</topic><topic>Rats</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>renal fibrosis</topic><topic>Renal Insufficiency, Chronic - metabolism</topic><topic>Renal Insufficiency, Chronic - pathology</topic><topic>TNF‐α</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><topic>Ureteral Obstruction - metabolism</topic><topic>Ureteral Obstruction - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Liu, Yong</creatorcontrib><creatorcontrib>Huang, Yinghui</creatorcontrib><creatorcontrib>Yang, Ke</creatorcontrib><creatorcontrib>Xiao, Tangli</creatorcontrib><creatorcontrib>Xiong, Jiachuan</creatorcontrib><creatorcontrib>Wang, Kailong</creatorcontrib><creatorcontrib>Liu, Chi</creatorcontrib><creatorcontrib>He, Ting</creatorcontrib><creatorcontrib>Yu, Yanlin</creatorcontrib><creatorcontrib>Han, Wenhao</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Bi, Xianjin</creatorcontrib><creatorcontrib>Zhang, Jingbo</creatorcontrib><creatorcontrib>Huang, Yunjian</creatorcontrib><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Zhao, Jinghong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yan</au><au>Liu, Yong</au><au>Huang, Yinghui</au><au>Yang, Ke</au><au>Xiao, Tangli</au><au>Xiong, Jiachuan</au><au>Wang, Kailong</au><au>Liu, Chi</au><au>He, Ting</au><au>Yu, Yanlin</au><au>Han, Wenhao</au><au>Wang, Yue</au><au>Bi, Xianjin</au><au>Zhang, Jingbo</au><au>Huang, Yunjian</au><au>Zhang, Bo</au><au>Zhao, Jinghong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IRF‐1 promotes renal fibrosis by downregulation of Klotho</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2020-03</date><risdate>2020</risdate><volume>34</volume><issue>3</issue><spage>4415</spage><epage>4429</epage><pages>4415-4429</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD.</abstract><cop>United States</cop><pmid>31965641</pmid><doi>10.1096/fj.201902446R</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Blotting, Western Cell Line Chromatin Immunoprecipitation chronic kidney disease Glucuronidase - genetics Glucuronidase - metabolism HEK293 Cells Humans Immunoprecipitation Interferon Regulatory Factor-1 - genetics Interferon Regulatory Factor-1 - metabolism IRF Kidney - drug effects Kidney - metabolism Kidney - pathology Klotho Male Mice Mice, Inbred C57BL Models, Biological Rats Real-Time Polymerase Chain Reaction renal fibrosis Renal Insufficiency, Chronic - metabolism Renal Insufficiency, Chronic - pathology TNF‐α Tumor Necrosis Factor-alpha - pharmacology Ureteral Obstruction - metabolism Ureteral Obstruction - pathology |
| title | IRF‐1 promotes renal fibrosis by downregulation of Klotho |
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