Urea and urine concentrating ability: new insights from studies in mice

Urea is the most abundant solute in the urine in humans (on a Western-type diet) and laboratory rodents. It is far more concentrated in the urine than in plasma and extracellular fluids. This concentration depends on the accumulation of urea in the renal medulla, permitted by an intrarenal recycling of urea among collecting ducts, vasa recta and thin descending limbs, all equipped with specialized, facilitated urea transporters (UTs) (UT-A1 and 3, UT-B, and UT-A2, respectively). UT-B null mice have been recently generated by targeted gene deletion. This review describes 1) the renal handling of urea by the mammalian kidney; 2) the consequences of UT-B deletion on urinary concentrating ability; and 3) species differences among mice, rats, and humans related to their very different body size and metabolic rate, leading to considerably larger needs to excrete and to concentrate urea in smaller species (urea excretion per unit body weight in mice is 5 times that in rats and 23 times that in humans). UT-B null mice have a normal glomerular filtration rate but moderately reduced urea clearance. They exhibit a 30% reduction in urine concentrating ability with a more severe defect in the capacity to concentrate urea (50%) than other solutes, despite a twofold enhanced expression of UT-A2. The urea content of the medulla is reduced by half, whereas that of chloride is almost normal. When given an acute urea load, UT-B null mice are unable to raise their urinary osmolality, urine urea concentration (Uurea), and the concentration of non-urea solutes, as do wild-type mice. When fed diets with progressively increasing protein content (10, 20, and 40%), they cannot prevent a much larger increase in plasma urea than wild-type mice because they cannot raise Uurea. In both wild-type and UT-B null mice, urea clearance was higher than creatinine clearance, suggesting the possibility that urea could be secreted in the mouse kidney, thus allowing more efficient excretion of the disproportionately high urea load. On the whole, studies in UT-B null mice suggest that recycling of urea by countercurrent exchange in medullary vessels plays a more crucial role in the overall capacity to concentrate urine than its recycling in the loops of Henle.