Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice

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• dc.contributor.author Rust, Marco B.ca
• dc.contributor.author Alper, Seth L.ca
• dc.contributor.author Rudhard, Yorkca
• dc.contributor.author Shmukler, Boris E.ca
• dc.contributor.author Vicente García, Rubén, 1978-ca
• dc.contributor.author Brugnara, Carloca
• dc.contributor.author Trudel, Marieca
• dc.contributor.author Jentsch, Thomas J.ca
• dc.contributor.author Hübner, Christian A.ca
• dc.date.accessioned 2016-01-20T18:42:34Z
• dc.date.available 2016-01-20T18:42:34Z
• dc.date.issued 2007
• dc.description.abstract K-Cl cotransport activity in rbc is a major determinant of rbc volume and density. Pathologic activation of erythroid K-Cl cotransport activity in sickle cell disease contributes to rbc dehydration and cell sickling. To address the roles of individual K-Cl cotransporter isoforms in rbc volume homeostasis, we disrupted the Kcc1 and Kcc3 genes in mice. As rbc K-Cl cotransport activity was undiminished in Kcc1(-/-) mice, decreased in Kcc3(-/-) mice, and almost completely abolished in mice lacking both isoforms, we conclude that K-Cl cotransport activity of mouse rbc is mediated largely by KCC3. Whereas rbc of either Kcc1(-/-) or Kcc3(-/-) mice were of normal density, rbc of Kcc1(-/-)Kcc3(-/-) mice exhibited defective volume regulation, including increased mean corpuscular volume, decreased density, and increased susceptibility to osmotic lysis. K-Cl cotransport activity was increased in rbc of SAD mice, which are transgenic for a hypersickling human hemoglobin S variant. Kcc1(-/-)Kcc3(-/-) SAD rbc lacked nearly all K-Cl cotransport activity and exhibited normalized values of mean corpuscular volume, corpuscular hemoglobin concentration mean, and K(+) content. Although disruption of K-Cl cotransport rescued the dehydration phenotype of most SAD rbc, the proportion of the densest red blood cell population remained unaffected.ca
• dc.description.sponsorship This work was supported by grants from the Deutsche Forschungsgemeinschaft to T.J. Jentsch and C.A. Hübner, by NIH grants HL077765 and HL15157 (Boston Comprehensive Sickle Cell Center) to S.L. Alper and C. Brugnara, and from the Canadian Institutes of Health Research to M. Trudel
• dc.format.mimetype application/pdfca
• dc.identifier.citation Rust MB, Alper SL, Rudhard Y, Shmukler BE, Vicente R, Brugnara C et al. Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. Journal of clinical investigation. 2007;117(6):1708-17. DOI: 10.1172/jci30630ca
• dc.identifier.doi http://dx.doi.org/10.1172/jci30630
• dc.identifier.issn 0021-9738
• dc.identifier.uri http://hdl.handle.net/10230/25609
• dc.language.iso engca
• dc.publisher American Society for Clinical Investigationca
• dc.relation.ispartof Journal of clinical investigation. 2007;117(6):1708-17
• dc.rights © American Society for Clinical Investigationca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Anemiaca
• dc.subject.other Ratolins (Animals de laboratori)ca
• dc.title Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD miceca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca