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| Item Type: | Article |
|---|---|
| Title: | Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice |
| Creators Name: | Rust, M.B., Alper, S.L., Rudhard, Y., Shmukler, B.E., Vicente, R., Brugnara, C., Trudel, M., Jentsch, T.J. and Huebner, C.A. |
| 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. |
| Keywords: | Sickle Cell Anemia, Base Sequence, DNA Primers, Animal Disease Models, Erythrocyte Volume, Erythrocytes, Sickle Hemoglobin, Ion Transport, Inbred C57BL Mice, Knockout Mice, Transgenic Mice, Symporters, Animals, Mice |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 117 |
| Number: | 6 |
| Page Range: | 1708-1717 |
| Date: | 1 June 2007 |
| Official Publication: | https://doi.org/10.1172/JCI30630 |
| PubMed: | View item in PubMed |
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