Urea Transport in the Kidney

Abstract

Urea transport proteins were initially proposed to exist in the kidney in the late 1980s when studies of urea permeability revealed values in excess of those predicted by simple lipid-phase diffusion and paracellular transport. Less than a decade later, the first urea transporter was cloned. Currently, the SLC14A family of urea transporters contains two major subgroups: SLC14A1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14A2, the UT-A group with six distinct isoforms described to date. In the kidney, UT-A1 and UT-A3 are found in the inner medullary collecting duct; UT-A2 is located in the thin descending limb, and UT-B is located primarily in the descending vasa recta; all are glycoproteins. These transporters are crucial to the kidney's ability to concentrate urine. UT-A1 and UT-A3 are acutely regulated by vasopressin. UT-A1 has also been shown to be regulated by hypertonicity, angiotensin II, and oxytocin. Acute regulation of these transporters is through phosphorylation. Both UT-A1 and UT-A3 rapidly accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long-term regulation involves altering protein abundance in response to changes in hydration status, low protein diets, adrenal steroids, sustained diuresis, or antidiuresis. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new animal models are being developed to study these transporters and search for active urea transporters. Here we introduce urea and describe the current knowledge of the urea transporter proteins, their regulation, and their role in the kidney.

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

“…In general, 30%-50% of the filtered load of urea is excreted. The urea concentration increases in the first 75% of the proximal convoluted tubule, where it reaches a value approximately 50% higher than plasma (11). This increase results from the removal of water, secondary to salt transport, and is maintained throughout the remainder of the proximal tubule.…”

“…The urea transporter (UT)-A1 protein is expressed in the apical plasma membrane of the terminal inner medullary collecting duct (IMCD) (10)(11)(12). It consists of 12 transmembranespanning domains connected by a cytoplasmic loop (Figures 2 and 3) (13).…”

“…UT-A3 is the N-terminal half of UT-A1 and is also expressed in the IMCD, primarily in the basolateral membrane, but can be detected in the apical membrane after vasopressin stimulation (14,15). UT-A2 is the C-terminal half of UT-A1 and is expressed in the thin descending limb (11,(15)(16)(17). UT-A4 is the N-terminal 25% of UT-A1 spliced to the C-terminal 25% (11).…”

“…UT-A2 is the C-terminal half of UT-A1 and is expressed in the thin descending limb (11,(15)(16)(17). UT-A4 is the N-terminal 25% of UT-A1 spliced to the C-terminal 25% (11). UT-B1 protein is expressed in red blood cells (11,16,17) and in nonfenestrated endothelial cells that are characteristic of descending vasa recta, especially in those that are external to collecting duct clusters (18).…”

“…The difference is that short-looped nephrons lack a thin ascending limb ( Figure 4). All portions of short loops are permeable to urea, but the direction and magnitude of urea movement varies with the diuretic state of the animal (11). The urea concentration in the early distal tubule (at the end of the loop) can reach 7 times the plasma concentration in antidiuretic rats, higher than the concentration at the start of the loop.…”