The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5
Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the...
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| Veröffentlicht in: | Journal of the American Society of Nephrology 2011, Vol.22 (1), p.137-145 |
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| creator | GOICOECHEA DE JORGE, Elena MACOR, Paolo PAIXAO-CAVALCANTE, Danielle ROSE, Kirsten L TEDESCO, Franco TERENCE COOK, H BOTTO, Marina PICKERING, Matthew C |
| description | Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS. |
| doi_str_mv | 10.1681/asn.2010050451 |
| format | Article |
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Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS.</description><identifier>ISSN: 1046-6673</identifier><identifier>EISSN: 1533-3450</identifier><identifier>DOI: 10.1681/asn.2010050451</identifier><identifier>PMID: 21148255</identifier><identifier>CODEN: JASNEU</identifier><language>eng</language><publisher>Washington, DC: American Society of Nephrology</publisher><subject>Animals ; Atypical Hemolytic Uremic Syndrome ; Basic Research ; Biological and medical sciences ; Complement C3 - metabolism ; Complement C5 - deficiency ; Complement C5 - genetics ; Complement C5 - physiology ; Complement C9 - metabolism ; Complement Factor H - deficiency ; Complement Factor H - genetics ; Complement Factor H - physiology ; Disease Models, Animal ; Glomerular Mesangium - metabolism ; Hematologic and hematopoietic diseases ; Hemolytic-Uremic Syndrome - physiopathology ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Knockout ; Nephrology. Urinary tract diseases ; Nephropathies. Renovascular diseases. Renal failure ; Platelet diseases and coagulopathies ; Renal failure</subject><ispartof>Journal of the American Society of Nephrology, 2011, Vol.22 (1), p.137-145</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 by the American Society of Nephrology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c485t-9f2cdda0173a80fda128abcac0da9cf12744ea572ddb89da4acb22eeaf82630f3</citedby><cites>FETCH-LOGICAL-c485t-9f2cdda0173a80fda128abcac0da9cf12744ea572ddb89da4acb22eeaf82630f3</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/PMC3014042/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014042/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,4010,27900,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23740486$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21148255$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GOICOECHEA DE JORGE, Elena</creatorcontrib><creatorcontrib>MACOR, Paolo</creatorcontrib><creatorcontrib>PAIXAO-CAVALCANTE, Danielle</creatorcontrib><creatorcontrib>ROSE, Kirsten L</creatorcontrib><creatorcontrib>TEDESCO, Franco</creatorcontrib><creatorcontrib>TERENCE COOK, H</creatorcontrib><creatorcontrib>BOTTO, Marina</creatorcontrib><creatorcontrib>PICKERING, Matthew C</creatorcontrib><title>The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS.</description><subject>Animals</subject><subject>Atypical Hemolytic Uremic Syndrome</subject><subject>Basic Research</subject><subject>Biological and medical sciences</subject><subject>Complement C3 - metabolism</subject><subject>Complement C5 - deficiency</subject><subject>Complement C5 - genetics</subject><subject>Complement C5 - physiology</subject><subject>Complement C9 - metabolism</subject><subject>Complement Factor H - deficiency</subject><subject>Complement Factor H - genetics</subject><subject>Complement Factor H - physiology</subject><subject>Disease Models, Animal</subject><subject>Glomerular Mesangium - metabolism</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hemolytic-Uremic Syndrome - physiopathology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred CBA</subject><subject>Mice, Knockout</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Nephropathies. Renovascular diseases. Renal failure</subject><subject>Platelet diseases and coagulopathies</subject><subject>Renal failure</subject><issn>1046-6673</issn><issn>1533-3450</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1v1DAQxS0Eoh9w5YhyQZyyjL8S54K02lKKVJVD27M1a49pUBIHO1tp_3tcurRwmpHm9948zTD2jsOKN4Z_wjytBHAADUrzF-yYaylrqTS8LD2opm6aVh6xk5x_AnAt2vY1OxKcKyO0PmZXN3dUndE9DXEeaVqqGKr1sp97h0N1QWMc9kvvqttEYynX-8mnOD4oZpp8ruJUbeI4D_RHu9Fv2KuAQ6a3h3rKbs-_3Gwu6svvX79t1pe1U0YvdReE8x6BtxINBI9cGNw6dOCxc4GLVilC3Qrvt6bzqNBthSDCYEQjIchT9vnRd95tR_KubE842Dn1I6a9jdjb_ydTf2d_xHsrgStQohh8PBik-GtHebFjnx0NA04Ud9kaITrgBrpCrh5Jl2LOicLTFg724Qd2fX1ln39QBO__zfaE_z16AT4cAMzlzCHh5Pr8zMm2RDSN_A1sBJDd</recordid><startdate>2011</startdate><enddate>2011</enddate><creator>GOICOECHEA DE JORGE, Elena</creator><creator>MACOR, Paolo</creator><creator>PAIXAO-CAVALCANTE, Danielle</creator><creator>ROSE, Kirsten L</creator><creator>TEDESCO, Franco</creator><creator>TERENCE COOK, H</creator><creator>BOTTO, Marina</creator><creator>PICKERING, Matthew C</creator><general>American Society of Nephrology</general><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>2011</creationdate><title>The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5</title><author>GOICOECHEA DE JORGE, Elena ; MACOR, Paolo ; PAIXAO-CAVALCANTE, Danielle ; ROSE, Kirsten L ; TEDESCO, Franco ; TERENCE COOK, H ; BOTTO, Marina ; PICKERING, Matthew C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c485t-9f2cdda0173a80fda128abcac0da9cf12744ea572ddb89da4acb22eeaf82630f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Atypical Hemolytic Uremic Syndrome</topic><topic>Basic Research</topic><topic>Biological and medical sciences</topic><topic>Complement C3 - metabolism</topic><topic>Complement C5 - deficiency</topic><topic>Complement C5 - genetics</topic><topic>Complement C5 - physiology</topic><topic>Complement C9 - metabolism</topic><topic>Complement Factor H - deficiency</topic><topic>Complement Factor H - genetics</topic><topic>Complement Factor H - physiology</topic><topic>Disease Models, Animal</topic><topic>Glomerular Mesangium - metabolism</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hemolytic-Uremic Syndrome - physiopathology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred CBA</topic><topic>Mice, Knockout</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Nephropathies. Renovascular diseases. Renal failure</topic><topic>Platelet diseases and coagulopathies</topic><topic>Renal failure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GOICOECHEA DE JORGE, Elena</creatorcontrib><creatorcontrib>MACOR, Paolo</creatorcontrib><creatorcontrib>PAIXAO-CAVALCANTE, Danielle</creatorcontrib><creatorcontrib>ROSE, Kirsten L</creatorcontrib><creatorcontrib>TEDESCO, Franco</creatorcontrib><creatorcontrib>TERENCE COOK, H</creatorcontrib><creatorcontrib>BOTTO, Marina</creatorcontrib><creatorcontrib>PICKERING, Matthew C</creatorcontrib><collection>Pascal-Francis</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Society of Nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GOICOECHEA DE JORGE, Elena</au><au>MACOR, Paolo</au><au>PAIXAO-CAVALCANTE, Danielle</au><au>ROSE, Kirsten L</au><au>TEDESCO, Franco</au><au>TERENCE COOK, H</au><au>BOTTO, Marina</au><au>PICKERING, Matthew C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5</atitle><jtitle>Journal of the American Society of Nephrology</jtitle><addtitle>J Am Soc Nephrol</addtitle><date>2011</date><risdate>2011</risdate><volume>22</volume><issue>1</issue><spage>137</spage><epage>145</epage><pages>137-145</pages><issn>1046-6673</issn><eissn>1533-3450</eissn><coden>JASNEU</coden><abstract>Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS.</abstract><cop>Washington, DC</cop><pub>American Society of Nephrology</pub><pmid>21148255</pmid><doi>10.1681/asn.2010050451</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Atypical Hemolytic Uremic Syndrome Basic Research Biological and medical sciences Complement C3 - metabolism Complement C5 - deficiency Complement C5 - genetics Complement C5 - physiology Complement C9 - metabolism Complement Factor H - deficiency Complement Factor H - genetics Complement Factor H - physiology Disease Models, Animal Glomerular Mesangium - metabolism Hematologic and hematopoietic diseases Hemolytic-Uremic Syndrome - physiopathology Medical sciences Mice Mice, Inbred C57BL Mice, Inbred CBA Mice, Knockout Nephrology. Urinary tract diseases Nephropathies. Renovascular diseases. Renal failure Platelet diseases and coagulopathies Renal failure |
| title | The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5 |
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