At physiological expression levels the Kidd blood group/urea transporter protein is not a water channel

The Kidd (JK) blood group locus encodes a urea transporter that is expresse d on human red cells and on endothelial cells of the vasa recta in the kidn ey, Here, we report the identification in human erythroblasts of a novel cD NA, designated HUT11A, which encodes a protein identical to the previously reported erythroid HUT11 urea transporter, except for a Lys(44) --> Glu sub stitution and a Val-Gly dipeptide deletion after proline 227, which leads t o a polypeptide of 389 residues versus 391 in HUT11. Genomic typing by poly merase chain reaction and transcript analysis by ribonuclease protection as say demonstrated that HUT11A encodes the true Kidd blood group/urea transpo rter protein, which carries only 2 Val-Gly motifs. Upon expression at high levels in Xenopus oocytes, the physiological Kidd/urea transporter HUT11A c onferred a rapid transfer of urea (which was insensitive to p-chloromercuri benzene sulfonate or phloretin), a high water permeability, and a selective uptake of small solutes including amides and diols, but not glycerol and m eso-erythritol. However, at plasma membrane expression levels close to the level observed in the red cell membrane, HUT11A-mediated water transport an d small solutes uptake were absent and the urea transport was poorly inhibi ted by p-chloromercuribenzene sulfonate, but strongly inhibited by phloreti n. These findings show that, at physiological expression levels, the HUT11A transporter confers urea permeability but not water permeability, and that the observed water permeability is a feature of the red cell urea transpor ter when expressed at unphysiological high levels.