Urea-selective Concentrating Defect in Transgenic Mice Lacking Urea Transporter UT-B

Abstract

Urea transporter UT-B has been proposed to be the major urea transporter in erythrocytes and kidney-descending vasa recta. The mouse UT-B cDNA was isolated and encodes a 384-amino acid urea-transporting glycoprotein expressed in kidney, spleen, brain, ureter, and urinary bladder. The mouse UT-B gene was analyzed, and UT-B knockout mice were generated by targeted gene deletion of exons 3-6. The survival and growth of UT-B knockout mice were not different from wild-type littermates. Urea permeability was 45-fold lower in erythrocytes from knockout mice than from those in wild-type mice. Daily urine output was 1.5-fold greater in UT-B-deficient mice (p < 0.01), and urine osmolality (U osm ) was lower (1532 ؎ 71 versus 2056 ؎ 83 mosM/ kgH 2 O, mean ؎ S.E., p < 0.001). After 24 h of water deprivation, U osm (in mosM/kgH 2 O) was 2403 ؎ 38 in UT-B null mice and 3438 ؎ 98 in wild-type mice (p < 0.001). Plasma urea concentration (P urea ) was 30% higher, and urine urea concentration (U urea ) was 35% lower in knockout mice than in wild-type mice, resulting in a much lower U urea /P urea ratio (61 ؎ 5 versus 124 ؎ 9, p < 0.001). Thus, the capacity to concentrate urea in the urine is more severely impaired than the capacity to concentrate other solutes. Together with data showing a disproportionate reduction in the concentration of urea compared with salt in homogenized renal inner medullas of UT-B null mice, these data define a novel "ureaselective" urinary concentrating defect in UT-B null mice. The UT-B null mice generated for these studies should also be useful in establishing the role of facilitated urea transport in extrarenal organs expressing UT-B.

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

“…People lacking UT-B1 are unable to concentrate their urine .800 mOsm/kg H 2 O, even after water deprivation and vasopressin administration (23). UT-B1 knockout mice also have a reduced maximal urine concentrating ability compared with wild-type mice (24). These data suggest that urea transport in red blood cells is important for efficient countercurrent exchange, which is necessary for maximal urinary concentration (25).…”

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

“…Plasma levels of urea were not different between genotypes (Table 1), but urinary urea concentration (AC6 Ϫ/Ϫ : 0.51 Ϯ 0.04 versus WT: 1.1 Ϯ 0.07 mol/L, n ϭ 8; P Ͻ 0.05) was reduced in the same proportion as urinary osmolality ( Figure 1A). As observed for the total osmoles, the urine-toplasma ratio for urea was reduced by approximately 60% in AC6 Ϫ/Ϫ versus WT mice, indicating that, in contrast to mice lacking the urea transporter UT-B, 20 …”

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

“…In particular, the possible role of urea metabolism in relation to pathogen resistance has been briefly mentioned above as a possible explanation for selection at this locus, but current knowledge on this issue is too limited to warrant extensive speculation. Moreover, consistent with the biological function of SLC14A1, Kidd-null subjects and knockout mice display mild urinary concentrating defects and greater urine output (Sands et al 1992;Yang et al 2002). This observation raises the possibility that, together with pathogen-driven selection, the transporter might also have adapted to climatic variables, possibly driven, for example, by the necessity to spare water in hot dry climates.…”