Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma
The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to iden...
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| Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2009-06, Vol.53 (6), p.1077-1082 |
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| creator | Cousin, Christelle Bracquart, Diane Contrepas, Aurelie Corvol, Pierre Muller, Laurent Nguyen, Genevieve |
| description | The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the followingLoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin. |
| doi_str_mv | 10.1161/HYPERTENSIONAHA.108.127258 |
| format | Article |
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We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the followingLoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.</description><identifier>ISSN: 0194-911X</identifier><identifier>EISSN: 1524-4563</identifier><identifier>DOI: 10.1161/HYPERTENSIONAHA.108.127258</identifier><identifier>PMID: 19380613</identifier><identifier>CODEN: HPRTDN</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Analysis of Variance ; Animals ; Arterial hypertension. Arterial hypotension ; Biochemistry, Molecular Biology ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cells, Cultured ; Cellular Biology ; CHO Cells ; Cricetinae ; Cricetulus ; Cytoplasm - metabolism ; Embryonic Stem Cells ; Endocrine kidney. Renin-angiotensin-aldosterone system ; Fluorescent Antibody Technique ; Fundamental and applied biological sciences. Psychology ; Furin - pharmacology ; Humans ; Life Sciences ; Medical sciences ; mRNA Cleavage and Polyadenylation Factors - metabolism ; Polymerase Chain Reaction ; Probability ; Rats ; Renin - drug effects ; Renin - metabolism ; RNA, Messenger - analysis ; Sensitivity and Specificity ; Solubility ; Transfection ; Vertebrates: endocrinology</subject><ispartof>Hypertension (Dallas, Tex. 1979), 2009-06, Vol.53 (6), p.1077-1082</ispartof><rights>2009 American Heart Association, Inc.</rights><rights>2009 INIST-CNRS</rights><rights>Attribution - NonCommercial - NoDerivatives</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6538-b896c781b97efd524369df083926f463e06497349cb6204a713c5e9b919ee4f63</citedby><cites>FETCH-LOGICAL-c6538-b896c781b97efd524369df083926f463e06497349cb6204a713c5e9b919ee4f63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3687,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21539891$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19380613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02157586$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Cousin, Christelle</creatorcontrib><creatorcontrib>Bracquart, Diane</creatorcontrib><creatorcontrib>Contrepas, Aurelie</creatorcontrib><creatorcontrib>Corvol, Pierre</creatorcontrib><creatorcontrib>Muller, Laurent</creatorcontrib><creatorcontrib>Nguyen, Genevieve</creatorcontrib><title>Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma</title><title>Hypertension (Dallas, Tex. 1979)</title><addtitle>Hypertension</addtitle><description>The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the followingLoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Arterial hypertension. Arterial hypotension</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cells, Cultured</subject><subject>Cellular Biology</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cytoplasm - metabolism</subject><subject>Embryonic Stem Cells</subject><subject>Endocrine kidney. Renin-angiotensin-aldosterone system</subject><subject>Fluorescent Antibody Technique</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Furin - pharmacology</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Medical sciences</subject><subject>mRNA Cleavage and Polyadenylation Factors - metabolism</subject><subject>Polymerase Chain Reaction</subject><subject>Probability</subject><subject>Rats</subject><subject>Renin - drug effects</subject><subject>Renin - metabolism</subject><subject>RNA, Messenger - analysis</subject><subject>Sensitivity and Specificity</subject><subject>Solubility</subject><subject>Transfection</subject><subject>Vertebrates: endocrinology</subject><issn>0194-911X</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkNFq2zAUhsXYWNNurzDEYNBeONOxZFnqRSGEpAmENiQdtFdGVo6XtIodJDulbz8bhw52tSuho-8T__kJ-Q5sCCDh5-xpOVk9TO7W8_u70Ww0BKaGEKdxoj6QASSxiEQi-UcyYKBFpAEez8h5CM-MgRAi_UzOQHPFJPABeV5Xrskd0mnl97QqaL1Fern01dUKy11JV2jxUFee3mKJ3tS4ofkbnZe1Nxada5zxdOzQHM1v7F6mjW-teaBrtB47vL0unQl784V8KowL-PV0XpBf08nDeBYt7m_n49EisjLhKsqVljZVkOsUi027DZd6UzDFdSwLITkyKXTKhba5jJkwKXCboM41aERRSH5Brvp_t8ZlB7_bG_-WVWaXzUaLrJuxGJI0UfIILXvds9ZXIXgs3gVgWVd29k_Z7Vxlfdmt_K2XD02-x81f9dRuC_w4ASZY4wpvSrsL71wbg2uluxQ3PfdauRp9eHHNK_psi8bV2_9J8gfICZvU</recordid><startdate>200906</startdate><enddate>200906</enddate><creator>Cousin, Christelle</creator><creator>Bracquart, Diane</creator><creator>Contrepas, Aurelie</creator><creator>Corvol, Pierre</creator><creator>Muller, Laurent</creator><creator>Nguyen, Genevieve</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</general><general>American Heart Association</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>1XC</scope></search><sort><creationdate>200906</creationdate><title>Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma</title><author>Cousin, Christelle ; Bracquart, Diane ; Contrepas, Aurelie ; Corvol, Pierre ; Muller, Laurent ; Nguyen, Genevieve</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6538-b896c781b97efd524369df083926f463e06497349cb6204a713c5e9b919ee4f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Arterial hypertension. Arterial hypotension</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Cardiology. Vascular system</topic><topic>Cells, Cultured</topic><topic>Cellular Biology</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cytoplasm - metabolism</topic><topic>Embryonic Stem Cells</topic><topic>Endocrine kidney. Renin-angiotensin-aldosterone system</topic><topic>Fluorescent Antibody Technique</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Furin - pharmacology</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Medical sciences</topic><topic>mRNA Cleavage and Polyadenylation Factors - metabolism</topic><topic>Polymerase Chain Reaction</topic><topic>Probability</topic><topic>Rats</topic><topic>Renin - drug effects</topic><topic>Renin - metabolism</topic><topic>RNA, Messenger - analysis</topic><topic>Sensitivity and Specificity</topic><topic>Solubility</topic><topic>Transfection</topic><topic>Vertebrates: endocrinology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cousin, Christelle</creatorcontrib><creatorcontrib>Bracquart, Diane</creatorcontrib><creatorcontrib>Contrepas, Aurelie</creatorcontrib><creatorcontrib>Corvol, Pierre</creatorcontrib><creatorcontrib>Muller, Laurent</creatorcontrib><creatorcontrib>Nguyen, Genevieve</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>Hyper Article en Ligne (HAL)</collection><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cousin, Christelle</au><au>Bracquart, Diane</au><au>Contrepas, Aurelie</au><au>Corvol, Pierre</au><au>Muller, Laurent</au><au>Nguyen, Genevieve</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma</atitle><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle><addtitle>Hypertension</addtitle><date>2009-06</date><risdate>2009</risdate><volume>53</volume><issue>6</issue><spage>1077</spage><epage>1082</epage><pages>1077-1082</pages><issn>0194-911X</issn><eissn>1524-4563</eissn><coden>HPRTDN</coden><abstract>The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the followingLoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>19380613</pmid><doi>10.1161/HYPERTENSIONAHA.108.127258</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Hypertension (Dallas, Tex. 1979), 2009-06, Vol.53 (6), p.1077-1082 |
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| source | MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | Analysis of Variance Animals Arterial hypertension. Arterial hypotension Biochemistry, Molecular Biology Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cells, Cultured Cellular Biology CHO Cells Cricetinae Cricetulus Cytoplasm - metabolism Embryonic Stem Cells Endocrine kidney. Renin-angiotensin-aldosterone system Fluorescent Antibody Technique Fundamental and applied biological sciences. Psychology Furin - pharmacology Humans Life Sciences Medical sciences mRNA Cleavage and Polyadenylation Factors - metabolism Polymerase Chain Reaction Probability Rats Renin - drug effects Renin - metabolism RNA, Messenger - analysis Sensitivity and Specificity Solubility Transfection Vertebrates: endocrinology |
| title | Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma |
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