Massive reduction of urea transporters in remnant kidney and brain of uremic rats

Abstract

Background. The facilitated urea transporters (UT), UT-A1, UT-A2, and UT-B1, are involved in intrarenal recycling of urea, an essential feature of the urinary concentrating mechanism, which is impaired in chronic renal failure (CRF). In this study, the expression of these UTs was examined in experimentally induced CRF. Methods. The abundance of mRNA was measured by Northern analysis and that of corresponding proteins by Western blotting in rats one and five weeks after 5/6 nephrectomy (Nx). Results. At five weeks, urine output was enhanced threefold with a concomitant decrease in urine osmolality. The marked rise in plasma urea concentration and fall in urinary urea concentration resulted in a 30-fold decrease in the urine/plasma (U/P) urea concentration ratio, while the U/P osmoles ratio fell only fourfold. A dramatic decrease in mRNA abundance for the three UTs was observed, bringing their level at five weeks to 1/10th or less of control values. Immunoblotting showed complete disappearance of the 97 and 117 kD bands of UT-A1, and considerable reduction of UT-A2 and UT-B1 in the renal medulla. Similar, but less intense, changes were observed at one-week post-Nx. In addition to the kidney, UT-B1 is also normally expressed in brain and testis. In the brain, its mRNA expression remained normal one-week post-Nx, but decreased to about 30% of normal at five-weeks post-Nx, whereas no change was seen in testis. Conclusions. (1) The decline in urinary concentrating ability seen in CRF is largely due to a major reduction of UTs involved in the process of urea concentration in the urine, while factors enabling the concentration of other solutes are less intensely affected. (2) The marked reduction of brain UT expression in CRF may be responsible for brain edema of dialysis disequilibrium syndrome observed in some patients after fast dialysis.