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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.
dc.contributor.author Alper, Seth L.
dc.contributor.author Rudhard, York
dc.contributor.author Shmukler, Boris E.
dc.contributor.author Vicente García, Rubén, 1978-
dc.contributor.author Brugnara, Carlo
dc.contributor.author Trudel, Marie
dc.contributor.author Jentsch, Thomas J.
dc.contributor.author Hübner, Christian A.
dc.date.accessioned 2016-01-20T18:42:34Z
dc.date.available 2016-01-20T18:42:34Z
dc.date.issued 2007
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): 1708-1717. DOI 10.1172/jci30630
dc.identifier.issn 0021-9738
dc.identifier.uri http://hdl.handle.net/10230/25609
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.
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/pdf
dc.language.iso eng
dc.publisher American Society for Clinical Investigation
dc.relation.ispartof Journal of clinical investigation. 2007; 117(6): 1708-1717
dc.rights © American Society for Clinical Investigation
dc.subject.other Anemia
dc.subject.other Ratolins (Animals de laboratori)
dc.title Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1172/jci30630
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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