Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice
Cystatin C, a well‐established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood–brain barrier...
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description | Cystatin C, a well‐established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood–brain barrier (BBB) disruption by up‐regulating caveolin‐1 expression, thereby improving neurological outcomes in cerebral ischemic injury. Western blotting, immunohistochemistry, immunofluorescence staining, and immunoprecipitation were performed to investigate target proteins. Evans Blue and gelatin zymography were used to examine the effect of cystatin C on BBB disruption. Plasmid and small interfering RNA transfection was used to observe alterations in caveolin‐1 and occludin expression induced by changes in cystatin C expression. Intriguingly, our study showed that the expression of both cystatin C and caveolin‐1 was increased in middle cerebral artery occlusion‐injured mice, and pretreatment with exogenous cystatin C significantly increased caveolin‐1 expression, reduced Evans Blue leakage in the injured brain region, and decreased the enzymatic activity of matrix metallopeptidase‐9. Meanwhile, our study also showed that the over‐expression of cystatin C greatly enhanced caveolin‐1 expression, which later increased occludin expression in oxygen‐glucose deprivation‐exposed brain microvascular endothelial cells. The knockdown of cystatin C induced the opposite outcomes. These experimental results indicate a positive role for cystatin C in the regulation of caveolin‐1 and occludin expression in cerebral ischemic injury. Taken together, these data unveil a new mechanism of the regulation of caveolin‐1 expression by cystatin C in the maintenance of BBB integrity after ischemic brain injury and provide new clues for the identification of potential therapeutic strategies for stroke.
We report that Cystatin C reduces the permeability of the blood–brain barrier (BBB) by up‐regulating the expression of caveolin‐1 and occludin in ischemic brain injury. Enhancing the permeability of the BBB leads to increased MMP‐9 and the death of bEnd.3 cells, which can be counteracted by ameliorating the BBB disruption and might represent a new therapeutic strategy for cerebral ischemic injury. The diagram shows that pretreatment with cystatin C increases caveolin‐1 and occludin expression in ischemic brain injury (right side of diagram). Left side of the diagram: cerebral ischemia‐reperfusion‐i |
doi_str_mv | 10.1111/jnc.14894 |
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We report that Cystatin C reduces the permeability of the blood–brain barrier (BBB) by up‐regulating the expression of caveolin‐1 and occludin in ischemic brain injury. Enhancing the permeability of the BBB leads to increased MMP‐9 and the death of bEnd.3 cells, which can be counteracted by ameliorating the BBB disruption and might represent a new therapeutic strategy for cerebral ischemic injury. The diagram shows that pretreatment with cystatin C increases caveolin‐1 and occludin expression in ischemic brain injury (right side of diagram). Left side of the diagram: cerebral ischemia‐reperfusion‐induced injury increases cystatin C and caveolin‐1, which may be a compensatory reaction; but it fails to rescue the degradation of occludin.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1111/jnc.14894</identifier><identifier>PMID: 31603990</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>bEnd.3 ; Biomarkers ; Blood-brain barrier ; Brain injury ; Caveolin ; caveolin‐1 ; Cerebral blood flow ; Cystatin C ; Deprivation ; Disruption ; Endothelial cells ; Enzymatic activity ; Gelatin ; Head injuries ; Immunofluorescence ; Immunohistochemistry ; Immunoprecipitation ; Injury prevention ; Integrity ; Ischemia ; ischemic brain injury ; Matrix metalloproteinases ; Metalloproteinase ; Microvasculature ; Neuroprotection ; occludin ; Occlusion ; Renal function ; siRNA ; Stroke ; Transfection ; Traumatic brain injury ; Western blotting</subject><ispartof>Journal of neurochemistry, 2020-05, Vol.153 (3), p.413-425</ispartof><rights>2019 International Society for Neurochemistry</rights><rights>2019 International Society for Neurochemistry.</rights><rights>Copyright © 2020 International Society for Neurochemistry</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3884-390d9856274b70d18d32734c47985af4c18a07be5f4d9755abfd123bd791b8193</citedby><cites>FETCH-LOGICAL-c3884-390d9856274b70d18d32734c47985af4c18a07be5f4d9755abfd123bd791b8193</cites><orcidid>0000-0002-9258-671X ; 0000-0003-2255-9721</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjnc.14894$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjnc.14894$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31603990$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Bo</creatorcontrib><creatorcontrib>Xu, Junjie</creatorcontrib><creatorcontrib>Chang, Liuhui</creatorcontrib><creatorcontrib>Miao, Zhigang</creatorcontrib><creatorcontrib>Heang, Dara</creatorcontrib><creatorcontrib>Pu, Yuwei</creatorcontrib><creatorcontrib>Zhou, Xun</creatorcontrib><creatorcontrib>Zhang, Lingwei</creatorcontrib><creatorcontrib>Xie, Hong</creatorcontrib><title>Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>Cystatin C, a well‐established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood–brain barrier (BBB) disruption by up‐regulating caveolin‐1 expression, thereby improving neurological outcomes in cerebral ischemic injury. Western blotting, immunohistochemistry, immunofluorescence staining, and immunoprecipitation were performed to investigate target proteins. Evans Blue and gelatin zymography were used to examine the effect of cystatin C on BBB disruption. Plasmid and small interfering RNA transfection was used to observe alterations in caveolin‐1 and occludin expression induced by changes in cystatin C expression. Intriguingly, our study showed that the expression of both cystatin C and caveolin‐1 was increased in middle cerebral artery occlusion‐injured mice, and pretreatment with exogenous cystatin C significantly increased caveolin‐1 expression, reduced Evans Blue leakage in the injured brain region, and decreased the enzymatic activity of matrix metallopeptidase‐9. Meanwhile, our study also showed that the over‐expression of cystatin C greatly enhanced caveolin‐1 expression, which later increased occludin expression in oxygen‐glucose deprivation‐exposed brain microvascular endothelial cells. The knockdown of cystatin C induced the opposite outcomes. These experimental results indicate a positive role for cystatin C in the regulation of caveolin‐1 and occludin expression in cerebral ischemic injury. Taken together, these data unveil a new mechanism of the regulation of caveolin‐1 expression by cystatin C in the maintenance of BBB integrity after ischemic brain injury and provide new clues for the identification of potential therapeutic strategies for stroke.
We report that Cystatin C reduces the permeability of the blood–brain barrier (BBB) by up‐regulating the expression of caveolin‐1 and occludin in ischemic brain injury. Enhancing the permeability of the BBB leads to increased MMP‐9 and the death of bEnd.3 cells, which can be counteracted by ameliorating the BBB disruption and might represent a new therapeutic strategy for cerebral ischemic injury. The diagram shows that pretreatment with cystatin C increases caveolin‐1 and occludin expression in ischemic brain injury (right side of diagram). Left side of the diagram: cerebral ischemia‐reperfusion‐induced injury increases cystatin C and caveolin‐1, which may be a compensatory reaction; but it fails to rescue the degradation of occludin.</description><subject>bEnd.3</subject><subject>Biomarkers</subject><subject>Blood-brain barrier</subject><subject>Brain injury</subject><subject>Caveolin</subject><subject>caveolin‐1</subject><subject>Cerebral blood flow</subject><subject>Cystatin C</subject><subject>Deprivation</subject><subject>Disruption</subject><subject>Endothelial cells</subject><subject>Enzymatic activity</subject><subject>Gelatin</subject><subject>Head injuries</subject><subject>Immunofluorescence</subject><subject>Immunohistochemistry</subject><subject>Immunoprecipitation</subject><subject>Injury prevention</subject><subject>Integrity</subject><subject>Ischemia</subject><subject>ischemic brain injury</subject><subject>Matrix metalloproteinases</subject><subject>Metalloproteinase</subject><subject>Microvasculature</subject><subject>Neuroprotection</subject><subject>occludin</subject><subject>Occlusion</subject><subject>Renal function</subject><subject>siRNA</subject><subject>Stroke</subject><subject>Transfection</subject><subject>Traumatic brain injury</subject><subject>Western blotting</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp1kM1KxDAUhYMozji68AWk4EYXnclt0qZZSvGXQTeKy5K0qab0Z0xapTvfwTf0SczY0YXg3VzuuR-Hw0HoEPAc3CzKJpsDjTndQlOgDHwKId9GU4yDwCeYBhO0Z22JMUQ0gl00IRBhwjmeosdksJ3odOMlnq5Xpn1V1pNV2-af7x_SCPeQwhitjKebTj0Z3Q2eKLr1bbNnVevMGzHdlL0Z3PKcpvbRTiEqqw42e4YeLs7vkyt_eXd5nZwt_YzEMfUJxzmPwyhgVDKcQ5yTgBGaUeZUUdAMYoGZVGFBc87CUMgih4DInHGQMXAyQyejr4v-0ivbpbXLpapKNKrtbRoQHOIwogE49PgPWra9aVw6R_EQMKWEOup0pDLTWmtUka6MroUZUsDpuu3UtZ1-t-3Yo41jL2uV_5I_9TpgMQJvulLD_07pzW0yWn4Bul6Ijg</recordid><startdate>202005</startdate><enddate>202005</enddate><creator>Yang, Bo</creator><creator>Xu, Junjie</creator><creator>Chang, Liuhui</creator><creator>Miao, Zhigang</creator><creator>Heang, Dara</creator><creator>Pu, Yuwei</creator><creator>Zhou, Xun</creator><creator>Zhang, Lingwei</creator><creator>Xie, Hong</creator><general>Blackwell Publishing Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9258-671X</orcidid><orcidid>https://orcid.org/0000-0003-2255-9721</orcidid></search><sort><creationdate>202005</creationdate><title>Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice</title><author>Yang, Bo ; Xu, Junjie ; Chang, Liuhui ; Miao, Zhigang ; Heang, Dara ; Pu, Yuwei ; Zhou, Xun ; Zhang, Lingwei ; Xie, Hong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3884-390d9856274b70d18d32734c47985af4c18a07be5f4d9755abfd123bd791b8193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>bEnd.3</topic><topic>Biomarkers</topic><topic>Blood-brain barrier</topic><topic>Brain injury</topic><topic>Caveolin</topic><topic>caveolin‐1</topic><topic>Cerebral blood flow</topic><topic>Cystatin C</topic><topic>Deprivation</topic><topic>Disruption</topic><topic>Endothelial cells</topic><topic>Enzymatic activity</topic><topic>Gelatin</topic><topic>Head injuries</topic><topic>Immunofluorescence</topic><topic>Immunohistochemistry</topic><topic>Immunoprecipitation</topic><topic>Injury prevention</topic><topic>Integrity</topic><topic>Ischemia</topic><topic>ischemic brain injury</topic><topic>Matrix metalloproteinases</topic><topic>Metalloproteinase</topic><topic>Microvasculature</topic><topic>Neuroprotection</topic><topic>occludin</topic><topic>Occlusion</topic><topic>Renal function</topic><topic>siRNA</topic><topic>Stroke</topic><topic>Transfection</topic><topic>Traumatic brain injury</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Bo</creatorcontrib><creatorcontrib>Xu, Junjie</creatorcontrib><creatorcontrib>Chang, Liuhui</creatorcontrib><creatorcontrib>Miao, Zhigang</creatorcontrib><creatorcontrib>Heang, Dara</creatorcontrib><creatorcontrib>Pu, Yuwei</creatorcontrib><creatorcontrib>Zhou, Xun</creatorcontrib><creatorcontrib>Zhang, Lingwei</creatorcontrib><creatorcontrib>Xie, Hong</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Bo</au><au>Xu, Junjie</au><au>Chang, Liuhui</au><au>Miao, Zhigang</au><au>Heang, Dara</au><au>Pu, Yuwei</au><au>Zhou, Xun</au><au>Zhang, Lingwei</au><au>Xie, Hong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2020-05</date><risdate>2020</risdate><volume>153</volume><issue>3</issue><spage>413</spage><epage>425</epage><pages>413-425</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><abstract>Cystatin C, a well‐established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood–brain barrier (BBB) disruption by up‐regulating caveolin‐1 expression, thereby improving neurological outcomes in cerebral ischemic injury. Western blotting, immunohistochemistry, immunofluorescence staining, and immunoprecipitation were performed to investigate target proteins. Evans Blue and gelatin zymography were used to examine the effect of cystatin C on BBB disruption. Plasmid and small interfering RNA transfection was used to observe alterations in caveolin‐1 and occludin expression induced by changes in cystatin C expression. Intriguingly, our study showed that the expression of both cystatin C and caveolin‐1 was increased in middle cerebral artery occlusion‐injured mice, and pretreatment with exogenous cystatin C significantly increased caveolin‐1 expression, reduced Evans Blue leakage in the injured brain region, and decreased the enzymatic activity of matrix metallopeptidase‐9. Meanwhile, our study also showed that the over‐expression of cystatin C greatly enhanced caveolin‐1 expression, which later increased occludin expression in oxygen‐glucose deprivation‐exposed brain microvascular endothelial cells. The knockdown of cystatin C induced the opposite outcomes. These experimental results indicate a positive role for cystatin C in the regulation of caveolin‐1 and occludin expression in cerebral ischemic injury. Taken together, these data unveil a new mechanism of the regulation of caveolin‐1 expression by cystatin C in the maintenance of BBB integrity after ischemic brain injury and provide new clues for the identification of potential therapeutic strategies for stroke.
We report that Cystatin C reduces the permeability of the blood–brain barrier (BBB) by up‐regulating the expression of caveolin‐1 and occludin in ischemic brain injury. Enhancing the permeability of the BBB leads to increased MMP‐9 and the death of bEnd.3 cells, which can be counteracted by ameliorating the BBB disruption and might represent a new therapeutic strategy for cerebral ischemic injury. The diagram shows that pretreatment with cystatin C increases caveolin‐1 and occludin expression in ischemic brain injury (right side of diagram). Left side of the diagram: cerebral ischemia‐reperfusion‐induced injury increases cystatin C and caveolin‐1, which may be a compensatory reaction; but it fails to rescue the degradation of occludin.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>31603990</pmid><doi>10.1111/jnc.14894</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-9258-671X</orcidid><orcidid>https://orcid.org/0000-0003-2255-9721</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | bEnd.3 Biomarkers Blood-brain barrier Brain injury Caveolin caveolin‐1 Cerebral blood flow Cystatin C Deprivation Disruption Endothelial cells Enzymatic activity Gelatin Head injuries Immunofluorescence Immunohistochemistry Immunoprecipitation Injury prevention Integrity Ischemia ischemic brain injury Matrix metalloproteinases Metalloproteinase Microvasculature Neuroprotection occludin Occlusion Renal function siRNA Stroke Transfection Traumatic brain injury Western blotting |
title | Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice |
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