P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3
Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain uncle...
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| Veröffentlicht in: | Toxicology and applied pharmacology 2014-11, Vol.281 (1), p.1-10 |
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| creator | Zhang, Yuanyuan Yuan, Fahuan Cao, Xuejiao Zhai, Zhifang GangHuang Du, Xiang Wang, Yiqin zhang, Jingbo Huang, Yunjian Zhao, Jinghong Hou, Weiping |
| description | Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease.
•The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity.•P2X7R blockade significantly attenuated the cisplatin-induced renal injury.•P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue.•P2X7R blockade reduced levels of oxidative stress and apoptosis in renal tissue.•P2X7R blockade may be a novel adjunctive therapy strategy for this disease. |
| doi_str_mv | 10.1016/j.taap.2014.09.016 |
| format | Article |
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•The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity.•P2X7R blockade significantly attenuated the cisplatin-induced renal injury.•P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue.•P2X7R blockade reduced levels of oxidative stress and apoptosis in renal tissue.•P2X7R blockade may be a novel adjunctive therapy strategy for this disease.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2014.09.016</identifier><identifier>PMID: 25308879</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; Acute Kidney Injury - chemically induced ; Acute Kidney Injury - metabolism ; Acute Kidney Injury - prevention & control ; ANIMAL TISSUES ; Animals ; Antineoplastic agents ; APOPTOSIS ; Biological and medical sciences ; Caspase 3 - metabolism ; Caspase-3 ; CHEMOTHERAPY ; Cisplatin - toxicity ; Cisplatin-induced nephrotoxicity ; COMPARATIVE EVALUATIONS ; Dose-Response Relationship, Drug ; GENES ; IN VIVO ; Inflammasomes - antagonists & inhibitors ; Inflammasomes - metabolism ; INFLAMMATION ; INJURIES ; KIDNEYS ; Male ; Medical sciences ; MICE ; Mice, Inbred C57BL ; NLRP3 inflammasome ; OXIDATION ; Oxidative stress ; Oxidative Stress - drug effects ; Oxidative Stress - physiology ; P2X7R ; Pharmacology. Drug treatments ; Purinergic P2X Receptor Antagonists - pharmacology ; Purinergic P2X Receptor Antagonists - therapeutic use ; Pyridines - pharmacology ; Pyridines - therapeutic use ; RECEPTORS ; Receptors, Purinergic P2X7 - metabolism ; STRESSES ; Tetrazoles - pharmacology ; Tetrazoles - therapeutic use ; Toxicology</subject><ispartof>Toxicology and applied pharmacology, 2014-11, Vol.281 (1), p.1-10</ispartof><rights>2014 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-f707aa154d4108af2208ca01c49dac2e64333493b8b9a2acbcf42e255ff78db43</citedby><cites>FETCH-LOGICAL-c513t-f707aa154d4108af2208ca01c49dac2e64333493b8b9a2acbcf42e255ff78db43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.taap.2014.09.016$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=29025777$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25308879$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22439903$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Yuanyuan</creatorcontrib><creatorcontrib>Yuan, Fahuan</creatorcontrib><creatorcontrib>Cao, Xuejiao</creatorcontrib><creatorcontrib>Zhai, Zhifang</creatorcontrib><creatorcontrib>GangHuang</creatorcontrib><creatorcontrib>Du, Xiang</creatorcontrib><creatorcontrib>Wang, Yiqin</creatorcontrib><creatorcontrib>zhang, Jingbo</creatorcontrib><creatorcontrib>Huang, Yunjian</creatorcontrib><creatorcontrib>Zhao, Jinghong</creatorcontrib><creatorcontrib>Hou, Weiping</creatorcontrib><title>P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease.
•The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity.•P2X7R blockade significantly attenuated the cisplatin-induced renal injury.•P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue.•P2X7R blockade reduced levels of oxidative stress and apoptosis in renal tissue.•P2X7R blockade may be a novel adjunctive therapy strategy for this disease.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Acute Kidney Injury - chemically induced</subject><subject>Acute Kidney Injury - metabolism</subject><subject>Acute Kidney Injury - prevention & control</subject><subject>ANIMAL TISSUES</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>APOPTOSIS</subject><subject>Biological and medical sciences</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase-3</subject><subject>CHEMOTHERAPY</subject><subject>Cisplatin - toxicity</subject><subject>Cisplatin-induced nephrotoxicity</subject><subject>COMPARATIVE EVALUATIONS</subject><subject>Dose-Response Relationship, Drug</subject><subject>GENES</subject><subject>IN VIVO</subject><subject>Inflammasomes - antagonists & inhibitors</subject><subject>Inflammasomes - metabolism</subject><subject>INFLAMMATION</subject><subject>INJURIES</subject><subject>KIDNEYS</subject><subject>Male</subject><subject>Medical sciences</subject><subject>MICE</subject><subject>Mice, Inbred C57BL</subject><subject>NLRP3 inflammasome</subject><subject>OXIDATION</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - physiology</subject><subject>P2X7R</subject><subject>Pharmacology. Drug treatments</subject><subject>Purinergic P2X Receptor Antagonists - pharmacology</subject><subject>Purinergic P2X Receptor Antagonists - therapeutic use</subject><subject>Pyridines - pharmacology</subject><subject>Pyridines - therapeutic use</subject><subject>RECEPTORS</subject><subject>Receptors, Purinergic P2X7 - metabolism</subject><subject>STRESSES</subject><subject>Tetrazoles - pharmacology</subject><subject>Tetrazoles - therapeutic use</subject><subject>Toxicology</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU-LFDEQxRtR3NnRL-BBAiLswR4r6fR0B_Yii_9gQQ8KewvV6eqdjN1Jm2QG5xv5Mc0wo970FCh-9SrvvaJ4xmHFga9fb1cJcV4J4HIFapVHD4oFB7Uuoaqqh8UCQPISoL27KC5j3AKAkpI_Li5EXUHbNmpR_Pws7hoWyNCcfGDd6M037InNwScyKTK8R-tiYsbGecRkXWldvzPUM0fzJlP-hzU2HZh1bLKGWHdgPZlAGK27Z2lDDE2ye5ssReaHzA0jThNGPxEzfpq9I5fiK5aF-nxgTyymQDGfdj0zGGeMVFZPikcDjpGent9l8fXd2y83H8rbT-8_3ry5LU3Nq1QODTSIvJa95NDiIAS0BoEbqXo0gtYyRyNV1bWdQoGmM4MUJOp6GJq272S1LF6cdH1MVsdsjczGeOdyGloIWSmV010WVycq5_R9RzHpyUZD44iO_C5q3gI0INYg_o-uZQNcVA1kVJxQE3yMgQY9BzthOGgO-li53upj5fpYuQal8ygvPT_r77qJ-j8rvzvOwMszgNHgOAR0ucy_nAJRN02TuesTRznevaVwdE8uV23D0Xzv7b_-8QsCxczr</recordid><startdate>20141115</startdate><enddate>20141115</enddate><creator>Zhang, Yuanyuan</creator><creator>Yuan, Fahuan</creator><creator>Cao, Xuejiao</creator><creator>Zhai, Zhifang</creator><creator>GangHuang</creator><creator>Du, Xiang</creator><creator>Wang, Yiqin</creator><creator>zhang, Jingbo</creator><creator>Huang, Yunjian</creator><creator>Zhao, Jinghong</creator><creator>Hou, Weiping</creator><general>Elsevier Inc</general><general>Elsevier</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>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20141115</creationdate><title>P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3</title><author>Zhang, Yuanyuan ; Yuan, Fahuan ; Cao, Xuejiao ; Zhai, Zhifang ; GangHuang ; Du, Xiang ; Wang, Yiqin ; zhang, Jingbo ; Huang, Yunjian ; Zhao, Jinghong ; Hou, Weiping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-f707aa154d4108af2208ca01c49dac2e64333493b8b9a2acbcf42e255ff78db43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Acute Kidney Injury - chemically induced</topic><topic>Acute Kidney Injury - metabolism</topic><topic>Acute Kidney Injury - prevention & control</topic><topic>ANIMAL TISSUES</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>APOPTOSIS</topic><topic>Biological and medical sciences</topic><topic>Caspase 3 - metabolism</topic><topic>Caspase-3</topic><topic>CHEMOTHERAPY</topic><topic>Cisplatin - toxicity</topic><topic>Cisplatin-induced nephrotoxicity</topic><topic>COMPARATIVE EVALUATIONS</topic><topic>Dose-Response Relationship, Drug</topic><topic>GENES</topic><topic>IN VIVO</topic><topic>Inflammasomes - antagonists & inhibitors</topic><topic>Inflammasomes - metabolism</topic><topic>INFLAMMATION</topic><topic>INJURIES</topic><topic>KIDNEYS</topic><topic>Male</topic><topic>Medical sciences</topic><topic>MICE</topic><topic>Mice, Inbred C57BL</topic><topic>NLRP3 inflammasome</topic><topic>OXIDATION</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - physiology</topic><topic>P2X7R</topic><topic>Pharmacology. Drug treatments</topic><topic>Purinergic P2X Receptor Antagonists - pharmacology</topic><topic>Purinergic P2X Receptor Antagonists - therapeutic use</topic><topic>Pyridines - pharmacology</topic><topic>Pyridines - therapeutic use</topic><topic>RECEPTORS</topic><topic>Receptors, Purinergic P2X7 - metabolism</topic><topic>STRESSES</topic><topic>Tetrazoles - pharmacology</topic><topic>Tetrazoles - therapeutic use</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Yuanyuan</creatorcontrib><creatorcontrib>Yuan, Fahuan</creatorcontrib><creatorcontrib>Cao, Xuejiao</creatorcontrib><creatorcontrib>Zhai, Zhifang</creatorcontrib><creatorcontrib>GangHuang</creatorcontrib><creatorcontrib>Du, Xiang</creatorcontrib><creatorcontrib>Wang, Yiqin</creatorcontrib><creatorcontrib>zhang, Jingbo</creatorcontrib><creatorcontrib>Huang, Yunjian</creatorcontrib><creatorcontrib>Zhao, Jinghong</creatorcontrib><creatorcontrib>Hou, Weiping</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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Yuanyuan</au><au>Yuan, Fahuan</au><au>Cao, Xuejiao</au><au>Zhai, Zhifang</au><au>GangHuang</au><au>Du, Xiang</au><au>Wang, Yiqin</au><au>zhang, Jingbo</au><au>Huang, Yunjian</au><au>Zhao, Jinghong</au><au>Hou, Weiping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2014-11-15</date><risdate>2014</risdate><volume>281</volume><issue>1</issue><spage>1</spage><epage>10</epage><pages>1-10</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease.
•The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity.•P2X7R blockade significantly attenuated the cisplatin-induced renal injury.•P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue.•P2X7R blockade reduced levels of oxidative stress and apoptosis in renal tissue.•P2X7R blockade may be a novel adjunctive therapy strategy for this disease.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>25308879</pmid><doi>10.1016/j.taap.2014.09.016</doi><tpages>10</tpages></addata></record> |
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| ispartof | Toxicology and applied pharmacology, 2014-11, Vol.281 (1), p.1-10 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | 60 APPLIED LIFE SCIENCES Acute Kidney Injury - chemically induced Acute Kidney Injury - metabolism Acute Kidney Injury - prevention & control ANIMAL TISSUES Animals Antineoplastic agents APOPTOSIS Biological and medical sciences Caspase 3 - metabolism Caspase-3 CHEMOTHERAPY Cisplatin - toxicity Cisplatin-induced nephrotoxicity COMPARATIVE EVALUATIONS Dose-Response Relationship, Drug GENES IN VIVO Inflammasomes - antagonists & inhibitors Inflammasomes - metabolism INFLAMMATION INJURIES KIDNEYS Male Medical sciences MICE Mice, Inbred C57BL NLRP3 inflammasome OXIDATION Oxidative stress Oxidative Stress - drug effects Oxidative Stress - physiology P2X7R Pharmacology. Drug treatments Purinergic P2X Receptor Antagonists - pharmacology Purinergic P2X Receptor Antagonists - therapeutic use Pyridines - pharmacology Pyridines - therapeutic use RECEPTORS Receptors, Purinergic P2X7 - metabolism STRESSES Tetrazoles - pharmacology Tetrazoles - therapeutic use Toxicology |
| title | P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3 |
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