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Blood Cells Mol Dis. 2019 Nov 25;81:102389. doi: 10.1016/j.bcmd.2019.102389. [Epub ahead of print]

Genetic disruption of KCC cotransporters in a mouse model of thalassemia intermedia.

Author information

1
Renal Division and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States of America; Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America.
2
Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA 02115, United States of America; Department of Pathology, Harvard Medical School, Boston, MA 02115, United States of America.
3
Department of Laboratory Medicine, UCSF, San Francisco, CA, United States of America.
4
Renal Division and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States of America.
5
Quest Diagnostics, San Juan Capistrano, CA, United States of America.
6
Quest Diagnostics, Marlborough, MA, United States of America.
7
Dept. of Medicine, Universita Verona and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy.
8
Institute of Physiological Chemistry, Philipps-Universität Marburg, Marburg, Germany.
9
Institute of Human Genetics, Universitatsklinikum Jena, Jena, Germany.
10
Department of Medicine, Harvard Medical School, Boston, MA 02215, United States of America; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA 02115, United States of America.
11
Renal Division and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States of America; Department of Pathology, Harvard Medical School, Boston, MA 02115, United States of America. Electronic address: salper@bidmc.harvard.edu.

Abstract

β-thalassemia (β-Thal) is caused by defective β-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulating red blood cells. The hypochromic thalassemic red cells exhibit increased cell dehydration in association with elevated K+ leak and increased K-Cl cotransport activity, each of which has been linked to globin chain imbalance and related oxidative stress. We therefore tested the effect of genetic inactivation of K-Cl cotransporters KCC1 and KCC3 in a mouse model of β-thalassemia intermedia. In the absence of these transporters, the anemia of β-Thal mice was ameliorated, in association with increased MCV and reductions in CHCM and hyperdense cells, as well as in spleen size. The resting K+ content of β-Thal red cells was greatly increased, and Thal-associated splenomegaly slightly decreased. Lack of KCC1 and KCC3 activity in Thal red cells reduced red cell density and improved β-Thal-associated osmotic fragility. We conclude that genetic inactivation of K-Cl cotransport can reverse red cell dehydration and partially attenuate the hematologic phenotype in a mouse model of β-thalassemia.

KEYWORDS:

K(+) efflux; Osmotic fragility; Red cell density; Spleen

PMID:
31835175
DOI:
10.1016/j.bcmd.2019.102389

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