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

MB Rust, SL Alper, Y Rudhard… - The Journal of …, 2007 - Am Soc Clin Investig
MB Rust, SL Alper, Y Rudhard, BE Shmukler, R Vicente, C Brugnara, M Trudel, TJ Jentsch
The Journal of clinical investigation, 2007Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation