2002 Global Researcher Conference Proceeding
April 26 - 28, 2002
| Conference: | 2002 Global Researcher Conference |
|---|---|
| Title: | Defective urinary concentrating function in transgenic mice lacking urea transporter UT-B |
| Authors: | Yang, Baoxue; Bankir, Lise; Verkman, Alan S. |
| Institutions: | University of California, San Francisco, INSERM, Unit 872 - E2, University of California, S.F. |
In mammals, at least 5 facilitated urea transporters are expressed in the kidney. UT-A1 is expressed in the apical membrane of terminal inner medullary collecting duct (IMCD) cells and is thought to be involved in vasopressin-regulated urea permeability. UT-A2 is located in the late part of descending thin limbs of short and long loops of Henle and may facilitate intrarenal urea recycling. UT-A3 is most abundant in intracellular membranes and in the apical region of IMCD cells. The localization of UT-A4 in the kidney is unclear. UT-B is expressed in vasa recta of the kidney inner and outer medulla. These proteins should play a role in the urinary concentrating mechanism.
We recently generated transgenic mice lacking urea transporter UT-B by the gene targeting strategy. The UT-B null mice had grossly normal appearance, activity, and behavior. Urea permeability in erythrocytes from null mice was 45-fold lower than in those from wildtype mice. Urinary concentrating function was compared in the wildtype and UT-B null mice. The UT-B null mice were moderately polyuric, consuming and excreting about 50 % more fluid than litter-matched heterozygous and wildtype mice. Average urine osmolality in UT-B null mice (1532 ± 71 mosm/kg H2O) was significantly lower than that in wildtype mice (2056 ± 83 mosm/kg H2O). Urinary concentrating ability was measured in response to a 24-h water deprivation test. Urine osmolality in the UT-B null mice increased significantly (2403 ± 38 mosm/kg H2O), although to a significantly lesser extent than in wildtype mice (3438 ± 98 mosm/kg H2O). The urine-to-plasma ratio for osmolality (an index of overall concentrating capacity of the kidney) was lower by one-third in UT-B null mice compared to wildtype mice (4.0 ± 0.2 vs. 6.1 ± 0.4, P < 0.001). Plasma urea concentration was significantly higher, and urinary urea concentration was significantly lower in the UT-B-deficient mice. These opposing changes suggest that plasma urea increased because the kidney was less able to recycle urea and to concentrate urea in the urine. The urine-to-plasma ratio of urea concentration reflects the capacity of the kidney to concentrate urea above its level in body fluids. This ratio was markedly decreased in UT-B null mice, from 124 ± 9 to 61 ± 5. In contrast to the remarkably reduced urea concentrating ability in the UT-B null mice, the defect in the concentration of all solutes was more modest, suggesting that UT-B plays a greater role in enabling the kidney to concentrate urea than other solutes in the urine and affects the urinary concentrating ability.
The chemical compound urea is the principal end product of protein breakdown in the body. The urea is excreted by the kidney. UT-B is one of at least five proteins in the kidney that are thought to help the kidney absorb and excrete urea. Yang, et al., generated a line of mice that lacked UT-B and compared these mice to normal mice to see if UT-B helps the kidney excrete urea and concentrate urine properly.
The researchers found that compared to normal mice, UT-null mice:
- urinated more,
- had more dilute urine,
- scored lower on a major index of kidney concentrating capacity,
- had higher concentrations of blood plasma urea and lower concentrations of urinary urea.
These findings suggest that UT-B plays a significant role in helping the kidney concentrate urea and plays a role in the overall ability of the kidney to concentrate urine.