Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue
Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized th...
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| description | Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo. |
| doi_str_mv | 10.1371/journal.pone.0024276 |
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The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0024276</identifier><identifier>PMID: 21918686</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Annexin A5 - therapeutic use ; Annexins ; Aorta ; Apoptosis ; Binding sites ; Biology ; Cancer ; Cellular stress response ; Chemotherapy ; Dosimetry ; Gelatinase ; Heart diseases ; In vivo methods and tests ; Inflammation ; Injuries ; Ischemia ; Kidney - drug effects ; Kidney - metabolism ; Kidney transplantation ; Kidneys ; Leukocytes ; Life sciences ; Lipocalin ; Male ; Medical research ; Medicine ; Mice ; Muscles ; Nuclear medicine ; Organs ; Pharmacology ; Phosphatidylserine ; Phosphatidylserines - metabolism ; Proteins ; Renal function ; Reperfusion ; Reperfusion Injury - metabolism ; Reperfusion Injury - prevention & control ; Rodents ; Studies ; Surgery ; Tissues ; Toxicology ; Transcription ; Translocation ; Transplantation</subject><ispartof>PloS one, 2011-08, Vol.6 (8), p.e24276</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Wever et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Wever et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-8c689e9437d89d504c17d6c442c417458721cf225b88c541190635dcce82dc493</citedby><cites>FETCH-LOGICAL-c691t-8c689e9437d89d504c17d6c442c417458721cf225b88c541190635dcce82dc493</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/PMC3168880/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168880/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21918686$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wever, Kimberley E</creatorcontrib><creatorcontrib>Wagener, Frank A D T G</creatorcontrib><creatorcontrib>Frielink, Cathelijne</creatorcontrib><creatorcontrib>Boerman, Otto C</creatorcontrib><creatorcontrib>Scheffer, Gert J</creatorcontrib><creatorcontrib>Allison, Anthony</creatorcontrib><creatorcontrib>Masereeuw, Rosalinde</creatorcontrib><creatorcontrib>Rongen, Gerard A</creatorcontrib><title>Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo.</description><subject>Animals</subject><subject>Annexin A5 - therapeutic use</subject><subject>Annexins</subject><subject>Aorta</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cellular stress response</subject><subject>Chemotherapy</subject><subject>Dosimetry</subject><subject>Gelatinase</subject><subject>Heart diseases</subject><subject>In vivo methods and tests</subject><subject>Inflammation</subject><subject>Injuries</subject><subject>Ischemia</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney transplantation</subject><subject>Kidneys</subject><subject>Leukocytes</subject><subject>Life sciences</subject><subject>Lipocalin</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Muscles</subject><subject>Nuclear medicine</subject><subject>Organs</subject><subject>Pharmacology</subject><subject>Phosphatidylserine</subject><subject>Phosphatidylserines - metabolism</subject><subject>Proteins</subject><subject>Renal function</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - metabolism</subject><subject>Reperfusion Injury - prevention & control</subject><subject>Rodents</subject><subject>Studies</subject><subject>Surgery</subject><subject>Tissues</subject><subject>Toxicology</subject><subject>Transcription</subject><subject>Translocation</subject><subject>Transplantation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkluL1DAcxYso7rr6DUQLguDDjLm1SV-EZb0NLCx4ew2Z5N9Ohk5Sk1R2v70Zp7NMQUH6kCb5nZP09BTFc4yWmHL8duvH4FS_HLyDJUKEEV4_KM5xQ8miJog-PHk_K57EuEWooqKuHxdnBDdY1KI-L_x7q5yDW-vKIfgEOsVSdcq6mMoA2b-0UW9gZ1WeDhDaMVrvSuu2Y7grlTNlUqGDrBo2Pg4blay56yME6yBm7CjXZbIxjvC0eNSqvP9sGi-K7x8_fLv6vLi--bS6urxe6LrBaSF0LRpoGOVGNKZCTGNuas0Y0QxzVglOsG4JqdZC6Iph3KCaVkZrEMRo1tCL4uXBd-h9lFNWUWKKeEMo5iQTqwNhvNrKIdidCnfSKyv_LPjQSRWS1T1IwltRmwoQAcYQhaYC3CqjiDYgOF9nr3fTaeN6B0aDS0H1M9P5jrMb2flfkuJaCIGywavJIPifI8T0jytPVKfyraxrfTbTuxyxvGQ8O2V2_-nLv1D5Mfv_kNvS2rw-E7yZCTKT4DZ1aoxRrr5--X_25secfX3CbkD1aRN9P6bcoDgH2QHUwccYoL1PDiO5L_sxDbkvu5zKnmUvTlO_Fx3bTX8D6zr77Q</recordid><startdate>20110830</startdate><enddate>20110830</enddate><creator>Wever, Kimberley E</creator><creator>Wagener, Frank A D T G</creator><creator>Frielink, Cathelijne</creator><creator>Boerman, Otto C</creator><creator>Scheffer, Gert J</creator><creator>Allison, Anthony</creator><creator>Masereeuw, Rosalinde</creator><creator>Rongen, Gerard A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110830</creationdate><title>Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue</title><author>Wever, Kimberley E ; Wagener, Frank A D T G ; Frielink, Cathelijne ; Boerman, Otto C ; Scheffer, Gert J ; Allison, Anthony ; Masereeuw, Rosalinde ; Rongen, Gerard A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-8c689e9437d89d504c17d6c442c417458721cf225b88c541190635dcce82dc493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Annexin A5 - 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The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21918686</pmid><doi>10.1371/journal.pone.0024276</doi><tpages>e24276</tpages><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Annexin A5 - therapeutic use Annexins Aorta Apoptosis Binding sites Biology Cancer Cellular stress response Chemotherapy Dosimetry Gelatinase Heart diseases In vivo methods and tests Inflammation Injuries Ischemia Kidney - drug effects Kidney - metabolism Kidney transplantation Kidneys Leukocytes Life sciences Lipocalin Male Medical research Medicine Mice Muscles Nuclear medicine Organs Pharmacology Phosphatidylserine Phosphatidylserines - metabolism Proteins Renal function Reperfusion Reperfusion Injury - metabolism Reperfusion Injury - prevention & control Rodents Studies Surgery Tissues Toxicology Transcription Translocation Transplantation |
| title | Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T01%3A50%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Diannexin%20protects%20against%20renal%20ischemia%20reperfusion%20injury%20and%20targets%20phosphatidylserines%20in%20ischemic%20tissue&rft.jtitle=PloS%20one&rft.au=Wever,%20Kimberley%20E&rft.date=2011-08-30&rft.volume=6&rft.issue=8&rft.spage=e24276&rft.pages=e24276-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0024276&rft_dat=%3Cgale_plos_%3EA476881309%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1307923172&rft_id=info:pmid/21918686&rft_galeid=A476881309&rft_doaj_id=oai_doaj_org_article_27f86d5e02e4403e95e1fada2cde877b&rfr_iscdi=true |