Genetic loss of KCa3.1 causes subtle erythrocyte macrocytosis and progressive splenomegaly

Abstract

KCa3.1, also known as Gardos channel in erythrocytes, is considered to be a major regulator of red blood cell (RBC) volume by mediating K+ efflux. However, the functional importance of KCa3.1 in RBC in vivo is still incompletely understood. Here we used KCa3.1‐/‐ mice to investigate the consequences of KCa3.1 deficiency for RBC metrics, functions and sequestration. RBCs of KCa3.1‐/‐ mice of all ages were mildly macrocytic but their biconcave appearance preserved. RBCs number, total hemoglobin and hematocrit were unchanged in the adult KCa3.1‐/‐ mice and increased in the premature KCa3.1‐/‐ mice. Filterability, Ca2+ dependent volume decrease and osmotic tolerance of RBCs lacking KCa3.1 were noticeably reduced when compared to RBC of wt‐mice. Deformability to increasing shear stress was unchanged. Strikingly, KCa3.1‐/‐ mice developed progressive splenomegaly which was considerable 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. Injections of the KCa3.1‐blocker TRAM‐34 also produced mild splenomegaly in wt‐mice. We conclude that genetic deficit of erythroid KCa3.1 causes mild RBC macrocytosis, presumably leading to reduced filterability, and impairs volume regulation. These RBC defects result in mild but progressive splenomegaly.