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

Rust, M.B.; Alper, S.L.; Rudhard, Y.; Shmukler, B.E.; Vicente, R.; Brugnara, C.; Trudel, M.; Jentsch, T.J.; Huebner, C.A.

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

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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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