title: Disruption of the Gardos channel (KCa3.1) in mice causes subtle erythrocyte macrocytosis and progressive splenomegaly.
abstract: Gardos channel, the erythrocyte Ca(2+)-activated K(+) channel (K(Ca)3.1), is considered a major regulator of red blood cell (RBC) volume by mediating efflux of potassium and thus cell dehydration and shrinkage. However, the functional importance of K(Ca)3.1 in RBC in vivo is incompletely understood. Here, we used K(Ca)3.1(-/-)-mice to investigate the consequences of K(Ca)3.1 deficiency for RBC indices, functions, and sequestration. RBCs of K(Ca)3.1(-/-)-mice of all ages were mildly macrocytic but their biconcave appearance being preserved. RBC number, total hemoglobin, and hematocrit were unchanged in the adult K(Ca)3.1(-/-)-mice and increased in the premature K(Ca)3.1(-/-)-mice. Filterability, Ca(2+)-dependent volume decrease and osmotic tolerance of RBCs lacking K(Ca)3.1 were noticeably reduced when compared to RBC of wild-type littermates. Deformability to increasing shear stress was unchanged. Strikingly, K(Ca)3.1(-/-)-mice developed progressive splenomegaly which was considerable ( approximately 200% of controls) in the >6-month-old mice and was paralleled by increased iron deposition in the aged mice presumably as a consequence of enhanced RBC sequestration. Daily injections of the K(Ca)3.1-blocker TRAM-34 (120 mg/kg) also produced mild splenomegaly in wild-type mice. We conclude that genetic deficit of erythroid K(Ca)3.1 causes mild RBC macrocytosis, presumably leading to reduced filterability, and impairs volume regulation. These RBC defects result in mild but progressive splenomegaly.
authors.affiliation: Department of Internal Medicine-Nephrology, Faculty of Medicine, Philipps-University, 35033 Marburg, Germany.
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgic
authors.forename: Brajesh P
authors.initials: BP
authors.lastname: Kaistha
authors.forename: Steffen
authors.initials: S
authors.lastname: Paschen
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kaistha
authors.forename: Christoph
authors.initials: C
authors.lastname: Busch
authors.forename: Han
authors.initials: H
authors.lastname: Si
authors.forename: Kernt
authors.initials: K
authors.lastname: Köhler
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size; D004906:Erythrocyte Count; D004907:Erythrocyte Deformability / Q000187:drug effects*; D004909:Erythrocyte Indices / Q000187:drug effects; D004912:Erythrocytes; D005434:Flow Cytometry; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency / Q000502:physiology*; D007501:Iron / Q000378:metabolism; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D013163:Splenomegaly / Q000209:etiology*
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; C411671:TRAM 34; D007501:Iron