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Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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ABSTRACT |
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Facilitated urea transporters (UTs) are responsible for urea accumulation in the renal inner medulla of the mammalian kidney and therefore play a central role in the urinary concentrating process. Recently, the cDNAs encoding three members of the UT family, UT1, UT2, and UT3 have been cloned. These transporters are expressed in different structures of the mammalian kidney. In rat, UT1 resides in the apical membrane of terminal inner medullary collecting ducts, where it mediates vasopressin-regulated urea reabsorption. UT2 and UT3 are located in descending thin limbs of Henle's loop and descending vasa recta, respectively, and participate in urinary recycling processes, which minimize urea escape from the inner medulla. UT1 and UT2 are regulated independently and respond differently to changes in dietary protein content and hydration state. Identification and characterization of these urea transporters advances our understanding of the molecular basis and regulation of the urinary concentrating mechanism.
mammalian kidney; inner medullary collecting duct; vasopressin
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ARTICLE |
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Abstract
Article
References
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UREA IS THE MAJOR end product of nitrogen metabolism in mammals, and its transport in kidney plays an important role in urinary concentration (1, 5, 9, 12, 21). Urea formed in the liver via the urea cycle enters the circulation and is mostly excreted by the kidneys. Accumulation of urea in the kidney medulla contributes to the corticopapillary osmolality gradient, which provides the driving force for water reabsorption (see Fig. 3). In the past decade, carrier-mediated urea transport has been extensively studied in kidney inner medulla and red blood cells. Perfusion studies with isolated inner medullary collecting duct (IMCD) have shown that urea moves across the plasma membrane via a vasopressin-sensitive, phloretin-inhibitable transport mechanism (3, 10). A similar facilitated transport process has also been observed in red blood cells (11).
Molecular Cloning of Urea Transporters
The first molecular identification of a urea transporter (UT) has been achieved by expression cloning in Xenopus oocytes in our laboratory (31). The 3.1-kb cDNA encoding a 397-amino acid protein, designated UT2, was isolated by screening a rabbit medullary cDNA library for the uptake of [14C]urea. When expressed in oocytes, UT2 stimulates a large increase in urea uptake, which is inhibited by phloretin and urea analogs. The transporter is highly selective for urea, since it does not accept other noncharged small molecules such as water and glycerol. UT2 is the first member of a new protein family, and hydropathy analysis indicated that it has two extended hydrophobic stretches interspersed with relatively short hydrophilic regions (Fig. 1A).
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Northern analysis of rabbit kidney revealed two UT transcripts with distinct expression patterns within the kidney. Subsequent studies involving homology screening of a rat kidney cDNA library demonstrated that there are two related kidney-specific urea transporter isoforms in rat, UT2 (2.9 kb) (25) and UT1 (4.0 kb) (24). Rat UT2 encodes a 43-kDa protein with 88% amino acid sequence identity to that of rabbit UT2. In contrast, rat UT1 encodes an 86-kDa protein that consists of two internally homologous halves linked by a hydrophilic connecting segment (Fig. 1B). The amino terminal half of rat UT1 is 67% identical to rat UT2, whereas the carboxy-terminal half is identical to rat UT2. Preliminary studies of rat genomic DNA indicated that both UT1 and UT2 are the products of a single gene by utilization of different exon groups at the 5' terminus. Notably, urea uptake mediated by rat UT1, but not by rat UT2, in Xenopus oocytes is enhanced two- to fourfold in the presence of cAMP agonists, and its stimulation is inhibited by inhibition of protein kinase A (PKA) (24). The data indicate that rat UT1 is activated by stimulation of PKA as a result of the effect of vasopressin, which stimulates urea transport in the IMCD (28, 30).
A third isoform has been cloned from human bone marrow (HUT11) (17) and rat kidney (UT3) (20, 29). In rat, UT3 is expressed in kidney inner and outer medulla, testis, brain, bone marrow, and spleen. UT3 is a 384-amino acid protein, which has 62% identity to rat UT2. UT3 has the same membrane topology as UT2 and exhibits functional characteristics similar to UT1 and UT2. A summary of the properties of rat urea transporter isoforms is provided in Table 1.
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Urea uptake by UT3 is sensitive to the mercurial compound p-chloromercuribenzene sulfonate (pCMBS), which is consistent with findings observed in mammalian erythrocytes (11). Interestingly, rat UT2 is totally resistant to pCMBS. Analysis of pCMBS-reactive residues of UT3 by a scanning mutagenesis approach may provide valuable information on the urea binding/translocation site. Chromosomal localization of human homolog HUT11 and Western analysis of human erythrocyte membranes showed that HUT11 encodes the Kidd (JK) blood type antigen (16).
Physiological Roles of Urea Transporters
Northern analysis and in situ hybridization (24, 25) were initially used to localize UT1 and UT2 transcripts in the rat kidney. UT1 mRNA is exclusively expressed in the inner medulla, especially in its terminal portion, whereas UT2 mRNA is mainly expressed in the outer medulla (Figs. 2 and 3). Segmental localization of each transcript was further determined by RT-PCR analysis in microdissected kidney structures (23). This study showed that UT1 mRNA is located in the IMCD, and UT2 mRNA is located in the late part of descending thin limbs of short and long loops of Henle. Recently, a polyclonal antibody against the carboxy-terminal amino acids 379-397 of rat UT2, which recognizes both UT1 and UT2 proteins, was prepared to examine the UT protein localization in the rat kidney (14). Immunocytochemistry revealed remarkable staining in the IMCD, and in the terminal part of descending thin limbs of loops of Henle. In situ hybridization revealed that the UT2 signal mostly resides in the second part of descending thin limbs of short loops of Henle (Figs. 2 and 3). In IMCD cells, UT protein was detected in the apical plasma membrane and in subapical intracellular vesicles (14).
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The lack of staining in the basolateral membrane of IMCD cells suggests that a different urea transporter exists on the basolateral side of IMCD cells, as has been observed in perfused tubule studies (27). Together with oocyte expression data, our findings revealed that UT1 is the vasopressin-regulated apical urea transporter involved in reabsorption of the bulk of urea in the terminal IMCD (24). On the other hand, UT2 is expressed in the descending thin limbs of loops of Henle and provides a pathway for urea reentry into descending thin limbs, a process called urea recycling, which limits the escape of urea from the renal medulla and enhances the corticopapillary osmolality gradient (Fig. 3).
In contrast to UT1 and UT2, expression of UT3 in kidney does not occur in nephron segments but in descending vasa recta, papillary surface epithelium, and the transitional epithelium of the ureter (Figs. 2 and 3). The expression of UT3 in vascular structures is in accordance with in vitro microperfusion studies showing a phloretin-sensitive urea transport activity in descending vasa recta (18, 19). Thus these data suggest that UT3 is involved in countercurrent exchange between ascending and descending vasa recta, a process that also serves to enhance the corticopapillary osmolality gradient (Fig. 3).
We also found expression of UT3 in astrocytes and ependymal cells in rat brain and in Sertoli cells in seminiferous tubules in testis (2, 29). The function of UT3 expression in brain and testis appears to be related to the formation of polyamines in these tissues. Polyamines are positively charged molecules that are critically involved in cell division and proliferation and in the modulation of the function of N-methyl-D-aspartate (NMDA) glutamate receptors. Polyamines are primarily synthesized from ornithine, the synthesis of which generates urea as a byproduct. UT3 expression in astrocytes may be involved in the regulation and dispersal of high urea levels in the brain (29). Similarly, UT3 expression by Sertoli cells in testis may allow the exit of urea from these cells during polyamine synthesis.
Regulation of Urea Transporters
The regulation of urea transporters has been studied under acute and chronic conditions. Acute regulation by vasopressin has been extensively investigated by perfusion studies (8, 30) and was speculated to involve phosphorylation and/or vesicle shuttle trafficking of urea transporter molecules. Studies under chronic conditions (long-term regulation) have recently shown that expression levels of UT1 and UT2 are regulated independently in response to changes of water and nitrogen balance (25).Acute regulation. In the IMCD, vasopressin acts by stimulating cAMP production via basolateral V2 receptors, and subsequent activation of PKA increases the urea permeability (Fig. 4). Time course analysis of urea transport in the IMCD revealed that vasopressin causes a rapid rise in urea permeability in the first 5 min and a slow secondary rise at 20-25 min (28). This suggests that there may be multiple steps involved in the stimulation of urea transporters by vasopressin, including activation by posttranslational modification such as phosphorylation by PKA (direct phosphorylation) and trafficking of urea transporter-containing vesicles into the apical membrane (vesicle trafficking), analogous to the vasopressin-regulated water channel aquaporin AQP2 (1a, 13) (see Fig. 4). Since preincubation with vasopressin or cAMP agonists stimulates urea uptake in the IMCD to the same degree as preincubation of UT1-expressing Xenopus oocytes with cAMP agonists, it is reasonable to use this expression system to explore the basic mechanism underlying acute-phase UT1 regulation. Our preliminary studies indicate that UT1 protein expression on the oocyte plasma membranes is not altered after incubation with cAMP agonists despite a two- to fivefold increase in urea uptake (22). These data suggest that stimulation of urea uptake in oocytes expressing UT1 is mediated by in situ modification of the membrane proteins, presumably by direct phosphorylation. Site-directed mutagenesis of seven potential PKA phosphorylation sites in UT1 is now under investigation. Recently, an acute effect of vasopressin on surface expression of urea transporters in rat IMCD cell suspensions was reported (6). In agreement with this, no change in the surface expression of urea transporter protein was observed after treatment with vasopressin both by biotinylation techniques and immunocytochemistry. Further studies are required to elucidate the exact mechanism of short-term regulation of the collecting duct urea permeability by vasopressin, including the role of urea transporter protein detected in subcellular vesicles (14).
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Long-term regulation. To investigate the longterm regulation of UTs, we first studied the effect of dehydration in Sprague-Dawley rats following a 3-day water restriction (25). Although UT1 mRNA levels in the kidney inner medulla was not elevated, a large increase in UT2 mRNA levels was observed, along with a spreading of the message toward the upper part of the outer stripe of the outer medulla and the basal part of the inner medulla. A similar increase in UT2 mRNA was also seen in Brattleboro rats after continuous infusion with vasopressin for 1 wk (26). Although the functional role of UT2 transcript upregulation in this region has not been clearly defined, it is likely that this serves as a mechanism to maintain high levels of urea and increased hypertonicity in the inner medulla during water restriction.
Regulation of urea transporters in kidney is also important for body nitrogen homeostasis, and urea transport must therefore respond to changes in dietary protein intake. During a low-protein diet, increased urea reabsorption is expected to occur to conserve nitrogen in the body. In rats fed a low-protein diet (8%) for 4 wk, UT1 mRNA was found to be upregulated in the terminal IMCD (25), whereas UT2 mRNA levels were not affected. The data are consistent with the reported observation in isolated kidney tubules that dietary protein restriction increases a phloretin-inhibitable urea transporter in the IMCD (7). Taken together, our data indicate that long-term regulation of UT1 is independent and distinct from UT2. The different segmental regulation of urea transporters may be mediated by different circulating hormonal factors (i.e., dehydration by vasopressin, protein restriction by glucocorticoids). However, it is likely that long-term regulation is controlled by multiple factors, in combination with local regulatory signals. Unlike UT1 and UT2, UT3 appears to be constitutively expressed in kidney (30). Interestingly, UT3 expression in brain is upregulated during neurotoxic injury in gliotic astrocytes (2). This upregulation of UT3 may be related to increased polyamine formation during injury.
Conclusion
After the first molecular identification of a urea transporter in 1993 (31), substantial progress has been achieved in the past 5 years toward the understanding of the role of urea transporters in the urinary concentrating process. Three urea transporter isoforms are located in different structures of rat kidney, and their expression is regulated differently. The regulation of UT1 and UT2 allows the kidney to adapt to physiological stresses such as dehydration and starvation. Further studies, including identification of the urea transporter in the basolateral surface and analysis of the regulatory processes at the molecular levels (i.e., phosphorylation, membrane trafficking) will lead to a better understanding of the roles of urea transporters in fine-tuning urinary concentration and maintaining nitrogen balance.| |
ACKNOWLEDGEMENTS |
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We acknowledge Drs. Guofeng You, Craig P. Smith, and Angela Steel for their contribution to this work.
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FOOTNOTES |
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1 This report is the first in a series of minireviews, which are based on a symposium on the urinary concentrating mechanism, held at Experimental Biology '97 in New Orleans, LA.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-46289 (to M. A. Hediger), a National Kidney Foundation Fellowship (to H. Tsukaguchi), and by the Siriraj-China Medical Board, Mahidol University, Thailand (to C. Shayakul).
Present address of C. Shayakul: Molecular Medicine and Renal Units, Beth Israel and Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.
Address for reprint requests: M. A. Hediger, Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, Boston, MA 02115.
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subunit,
activation of adenylyl cyclase, production of cAMP, and stimulation of
protein kinase A (PKA). Two potential mechanisms for UT1 activation by
PKA are indicated by increasing the insertion of vesicles containing
the urea transporters (a, broken line)
and by direct phosphorylation of urea transporters molecules
(b). Current experimental evidence
suggests that mechanism b is mainly
involved in UT1 activation.