Activated protein C protects against renal ischaemia/reperfusion injury, independent of its anticoagulant properties
Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated protein...
Saved in:
| Published in: | Thrombosis and haemostasis Vol. 116; no. 1; p. 124 |
|---|---|
| Main Authors: | , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Germany
04.07.2016
|
| Subjects: | |
| ISSN: | 2567-689X, 2567-689X |
| Online Access: | Get more information |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated protein C (APC) might be of importance in the pathogenesis of renal I/R. APC is a serine protease which has anticoagulant but also several anti-inflammatory and cytoprotective effects such as protection of endothelial barrier function. It was our objective to study the role of cytoprotective and anticoagulant functions of APC during renal I/R. C57BL/6j mice subjected to renal I/R were treated with intraperitoneally injected exogenous human APC, or two mutant forms of APC (200 µg/kg) which specifically lack anticoagulant or signalling properties. In a different experiment mice received specific monoclonal antibodies (20 mg/kg) that block the cytoprotective and/or anticoagulant properties of endogenous APC. Treatment with APC reduced tubular injury and enhanced renal function without altering the inflammatory response and did reduce renal fibrin deposition. Administration of APC mutant lacking anticoagulant properties reduced renal damage and enhanced renal function. Blocking the anticoagulant and cytoprotective functions of endogenous APC resulted in elevated tubular damage and reduced tubular cell proliferation, however, without influencing renal function or the inflammatory response. Furthermore, blocking both the anticoagulant and cytoprotective effects of APC resulted in dramatic renal interstitial haemorrhage, indicative of impaired vascular integrity. Blocking only the anticoagulant function of APC did not result in interstitial bleeding. In conclusion, the renoprotective effect of APC during I/R is independent of its anticoagulant properties. |
|---|---|
| AbstractList | Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated protein C (APC) might be of importance in the pathogenesis of renal I/R. APC is a serine protease which has anticoagulant but also several anti-inflammatory and cytoprotective effects such as protection of endothelial barrier function. It was our objective to study the role of cytoprotective and anticoagulant functions of APC during renal I/R. C57BL/6j mice subjected to renal I/R were treated with intraperitoneally injected exogenous human APC, or two mutant forms of APC (200 µg/kg) which specifically lack anticoagulant or signalling properties. In a different experiment mice received specific monoclonal antibodies (20 mg/kg) that block the cytoprotective and/or anticoagulant properties of endogenous APC. Treatment with APC reduced tubular injury and enhanced renal function without altering the inflammatory response and did reduce renal fibrin deposition. Administration of APC mutant lacking anticoagulant properties reduced renal damage and enhanced renal function. Blocking the anticoagulant and cytoprotective functions of endogenous APC resulted in elevated tubular damage and reduced tubular cell proliferation, however, without influencing renal function or the inflammatory response. Furthermore, blocking both the anticoagulant and cytoprotective effects of APC resulted in dramatic renal interstitial haemorrhage, indicative of impaired vascular integrity. Blocking only the anticoagulant function of APC did not result in interstitial bleeding. In conclusion, the renoprotective effect of APC during I/R is independent of its anticoagulant properties.Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated protein C (APC) might be of importance in the pathogenesis of renal I/R. APC is a serine protease which has anticoagulant but also several anti-inflammatory and cytoprotective effects such as protection of endothelial barrier function. It was our objective to study the role of cytoprotective and anticoagulant functions of APC during renal I/R. C57BL/6j mice subjected to renal I/R were treated with intraperitoneally injected exogenous human APC, or two mutant forms of APC (200 µg/kg) which specifically lack anticoagulant or signalling properties. In a different experiment mice received specific monoclonal antibodies (20 mg/kg) that block the cytoprotective and/or anticoagulant properties of endogenous APC. Treatment with APC reduced tubular injury and enhanced renal function without altering the inflammatory response and did reduce renal fibrin deposition. Administration of APC mutant lacking anticoagulant properties reduced renal damage and enhanced renal function. Blocking the anticoagulant and cytoprotective functions of endogenous APC resulted in elevated tubular damage and reduced tubular cell proliferation, however, without influencing renal function or the inflammatory response. Furthermore, blocking both the anticoagulant and cytoprotective effects of APC resulted in dramatic renal interstitial haemorrhage, indicative of impaired vascular integrity. Blocking only the anticoagulant function of APC did not result in interstitial bleeding. In conclusion, the renoprotective effect of APC during I/R is independent of its anticoagulant properties. Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated protein C (APC) might be of importance in the pathogenesis of renal I/R. APC is a serine protease which has anticoagulant but also several anti-inflammatory and cytoprotective effects such as protection of endothelial barrier function. It was our objective to study the role of cytoprotective and anticoagulant functions of APC during renal I/R. C57BL/6j mice subjected to renal I/R were treated with intraperitoneally injected exogenous human APC, or two mutant forms of APC (200 µg/kg) which specifically lack anticoagulant or signalling properties. In a different experiment mice received specific monoclonal antibodies (20 mg/kg) that block the cytoprotective and/or anticoagulant properties of endogenous APC. Treatment with APC reduced tubular injury and enhanced renal function without altering the inflammatory response and did reduce renal fibrin deposition. Administration of APC mutant lacking anticoagulant properties reduced renal damage and enhanced renal function. Blocking the anticoagulant and cytoprotective functions of endogenous APC resulted in elevated tubular damage and reduced tubular cell proliferation, however, without influencing renal function or the inflammatory response. Furthermore, blocking both the anticoagulant and cytoprotective effects of APC resulted in dramatic renal interstitial haemorrhage, indicative of impaired vascular integrity. Blocking only the anticoagulant function of APC did not result in interstitial bleeding. In conclusion, the renoprotective effect of APC during I/R is independent of its anticoagulant properties. |
| Author | Jansen, Marcel P B Claessen, Nike Roelofs, Joris J T H Lattenist, Lionel Florquin, Sandrine Teske, Gwendoline Esmon, Charles T Meijers, Joost C M Rezaie, Alireza R |
| Author_xml | – sequence: 1 givenname: Lionel surname: Lattenist fullname: Lattenist, Lionel – sequence: 2 givenname: Marcel P B surname: Jansen fullname: Jansen, Marcel P B – sequence: 3 givenname: Gwendoline surname: Teske fullname: Teske, Gwendoline – sequence: 4 givenname: Nike surname: Claessen fullname: Claessen, Nike – sequence: 5 givenname: Joost C M surname: Meijers fullname: Meijers, Joost C M – sequence: 6 givenname: Alireza R surname: Rezaie fullname: Rezaie, Alireza R – sequence: 7 givenname: Charles T surname: Esmon fullname: Esmon, Charles T – sequence: 8 givenname: Sandrine surname: Florquin fullname: Florquin, Sandrine – sequence: 9 givenname: Joris J T H surname: Roelofs fullname: Roelofs, Joris J T H email: j.j.roelofs@amc.uva.nl organization: J. J. T. H. Roelofs, Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room M2-130, 1105 AZ Amsterdam, The Netherlands, Tel.: +31 20 56 65626, Fax: +31 20 56 69523, E-mail: j.j.roelofs@amc.uva.nl |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27052416$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNUE1LAzEQDVLRWr15lhw9uDbJ5muPpagVCl4qeFuy2aRGdrM1yQr996a0gpd5j_l4M2-uwMQP3gBwi9EjxhzNNyvMCiQKxCQ9A1PCuCi4rD4m__gFuCQCMUIxn4K00Mn9qGRauAtDMs7D5ZHpFKHaKudjgsF41UEX9acyvVPzYHYm2DG6wUPnv8awf8jY5mwOPsHBQncY98npQW3HLrODap5KzsRrcG5VF83NCWfg_flps1wV67eX1-ViXeiSiFSotsFYSctFgykhlS4ZwQ2XtBWtaowtWSUswiXnWtrsnuWSFLhUlGhqqSIzcH_Uzau_RxNT3WcPpsvnmGGMNZYIS06rUubWu1Pr2PSmrXfB9Srs679PkV9TLmtW |
| CitedBy_id | crossref_primary_10_1007_s12265_023_10445_y crossref_primary_10_1016_j_jtha_2022_10_012 crossref_primary_10_3390_ijms20071762 crossref_primary_10_1097_MOH_0000000000000364 crossref_primary_10_1080_00015385_2018_1494116 |
| ContentType | Journal Article |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1160/TH15-07-0584 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| EISSN | 2567-689X |
| ExternalDocumentID | 27052416 |
| Genre | Journal Article |
| GroupedDBID | CGR CUY CVF ECM EIF NPM 7X8 |
| ID | FETCH-LOGICAL-c327t-adb11a8f67b14229c3521b684d7dabef3597f01366c8f16056848713a42c4f4a2 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 10 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000379495000014&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 2567-689X |
| IngestDate | Thu Jul 10 17:49:47 EDT 2025 Thu Apr 03 07:09:11 EDT 2025 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 1 |
| Keywords | kidney Acute Kidney Injury ischaemia-reperfusion injury protein C haemostasis |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c327t-adb11a8f67b14229c3521b684d7dabef3597f01366c8f16056848713a42c4f4a2 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| PMID | 27052416 |
| PQID | 1801864938 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_1801864938 pubmed_primary_27052416 |
| PublicationCentury | 2000 |
| PublicationDate | 2016-Jul-04 |
| PublicationDateYYYYMMDD | 2016-07-04 |
| PublicationDate_xml | – month: 07 year: 2016 text: 2016-Jul-04 day: 04 |
| PublicationDecade | 2010 |
| PublicationPlace | Germany |
| PublicationPlace_xml | – name: Germany |
| PublicationTitle | Thrombosis and haemostasis |
| PublicationTitleAlternate | Thromb Haemost |
| PublicationYear | 2016 |
| Score | 2.2453618 |
| Snippet | Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 124 |
| SubjectTerms | Acute Kidney Injury - metabolism Acute Kidney Injury - pathology Acute Kidney Injury - prevention & control Animals Anticoagulants - metabolism Anticoagulants - therapeutic use Cell Proliferation Disease Models, Animal Fibrin - metabolism Humans Kidney - injuries Kidney - metabolism Kidney - pathology Male Mice Mice, Inbred C57BL Mutant Proteins - genetics Mutant Proteins - metabolism Mutant Proteins - therapeutic use Protein C - genetics Protein C - metabolism Protein C - therapeutic use Recombinant Proteins - genetics Recombinant Proteins - metabolism Recombinant Proteins - therapeutic use Reperfusion Injury - metabolism Reperfusion Injury - pathology Reperfusion Injury - prevention & control Signal Transduction |
| Title | Activated protein C protects against renal ischaemia/reperfusion injury, independent of its anticoagulant properties |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/27052416 https://www.proquest.com/docview/1801864938 |
| Volume | 116 |
| WOSCitedRecordID | wos000379495000014&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3NS8MwFA_qPHjxA7_mFxE8Gra0SdqeZAzHDjp2mNDbSJtEItjWtvPv9yXr9CQIXnpIeTS8vKS_vLz8fgjdUcMDQLEJybgShBmWEWkkJaFJDGw4QsWNvyj8FM1mcZom8y7h1nRllZs10S_UqsxdjnxAYSmNBUvC-KH6IE41yp2udhIa26gXApRxUR2lXoSOw_yHLqSbWncxHCymlPtCS-6oTH_Dk_6_Mjn4b48O0X6HKPFoHQJHaEsXx6gd5V63TCvsmRhsgce442RosHyVFmAhrrWztI2rnH-3jiuq0rVZuQQatsUbuPse22-d3BaXBltnXsCnSulE7KGxcun82vGynqCXyeNiPCWdwALJwyBqiVQZpTI2IvKpoCQHNEYzETMVKZlpE8JuwzhSN5HHBlzI4RVssELJghyGVQanaKcoC32OcMZoYLgCPKgCpsAQcENItYB2I6QRfXS7ceISAtidSshCl6tm-ePGPjpbj8SyWjNtLINoyAFiiIs_WF-iPQAzwo8wu0I9A9NXX6Pd_LO1TX3jIwOes_nzFzC8xv4 |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Activated+protein+C+protects+against+renal+ischaemia%2Freperfusion+injury%2C+independent+of+its+anticoagulant+properties&rft.jtitle=Thrombosis+and+haemostasis&rft.au=Lattenist%2C+Lionel&rft.au=Jansen%2C+Marcel+P+B&rft.au=Teske%2C+Gwendoline&rft.au=Claessen%2C+Nike&rft.date=2016-07-04&rft.issn=2567-689X&rft.eissn=2567-689X&rft.volume=116&rft.issue=1&rft.spage=124&rft_id=info:doi/10.1160%2FTH15-07-0584&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=2567-689X&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=2567-689X&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=2567-689X&client=summon |