INVITED REVIEW
Gene structure of urea transporters
Serena M.
Bagnasco
Department of Pathology, Emory University School of
Medicine, Atlanta, Georgia 30322
 |
ABSTRACT |
Urea plays various roles in the
biology of diverse organisms. The past decade has produced new
information on the molecular structure of several urea transporters in
various species. Availability of DNA probes has revealed that the
presence of urea transporters is not confined to the mammalian kidney
but is also evident in testis and brain, raising new questions about
the possible physiological role of urea in these organs. Cloning of the
genes encoding the two closely related mammalian urea transporters UT-A
and UT-B has helped in identifying molecular mechanisms affecting
expression of urea transporters in the kidney, such as transcriptional
control for UT-A abundance. On the basis of analysis of genomic
sequences of individuals lacking the UT-B transporter, mutations have
been found that explain deficits in their capacity to concentrate
urine. More urea transporters are being characterized in marine
organisms and lower vertebrates, and studying the role and regulation
of urea transport from an evolutionary perspective can certainly enrich
our understanding of renal physiology.
urea; kidney; Kidd antigen; concentrating mechanism; osmoregulation
 |
INTRODUCTION |
UREA SERVES DIFFERENT PURPOSES in
different organisms. Urea represents a source of nitrogen for
microorganisms like yeasts and bacteria. Urea is present in high
concentrations in the tissues of marine elasmobranchs, where it serves
as an osmolyte to balance the high salinity of seawater. Excretion of
urea provides a good vehicle for eliminating waste products from
nitrogen metabolism in mammals. Although urea can diffuse slowly across
cell membranes along concentration gradients, in many cases a more
efficient and rapid movement of this solute is necessary. This can be
achieved by use of specific carriers, resulting in facilitated
diffusion or active transport. Urea transporters have now been cloned
and characterized in bacteria, yeasts, amphibians, marine organisms, and mammalians (Table 1). The urea
transporter genes described in Saccharomyces
cerevisiae (DUR3) (10), in
Helicobacter pylori (UreI ) (50),
and the ABC-type permeases in cyanobacteria (46) do not
have homologous counterparts in higher organisms, and only minimal
identity (20-25%) exists between the urea transporter genes of
Yersinia pseudotuberculosis (Yut), and
Brucella melitensis (8) and those in mammals
and lower vertebrates. However, substantial homology is emerging in the
structure of urea transporters described in mammals, amphibians, and
elasmobranch and teleost fishes. Two similar but distinct urea
transporters have been identified in rodents and humans: the UT-A urea
transporter, encoded by the Slc14A2 gene, and the UT-B urea
transporter, encoded by the Slc14A1 gene. The
organization of the Slc14A2 gene has now been elucidated in
rats (25), humans (2), and mice
(12). The genomic structure of the UT-B urea transporter,
encoded by the Slc14A1 gene, is also known
(23). These advances have made possible the identification of some important regulatory mechanisms involved in the long-term expression of these transporters (3, 25, 26, 31) and will
facilitate the study of how urea transporter expression is regulated in
other species.
 |
THE UT-A TRANSPORTER AND Slc14A2 GENE |
Most information on the UT-A transporter has been generated in
studies on urea transport in rat kidney, where three major transcripts
are detected by Northern hybridization in the medullary region of the
kidney: UT-A1 (4.0 kb), UT-A2 (2.9 kb), and UT-A3 (2.1 kb). The mRNA of
UT-A4 (2,584 bp) is present in very low abundance, and it is only
detectable by PCR. Additional mRNA isoforms are evident by Northern
hybridization: UT-A1b (3.5 kb), UT-A2b (2.5 kb), and UT-A3b (3.7 kb),
and they differ from the major UT-A transcripts by expressing
alternative 3'-untranslated sequences (UTR) (3). All of
these transcripts are localized in the medullary region of the kidney.
UT-A2 is expressed in the thin descending limb of Henle's loop (tDL),
and UT-A1 and UT-A3 are localized in the inner medullary collecting
duct (IMCD) (36, 43). There is also evidence that two
other UT-A isoforms are expressed in rat testis (11, 19),
one comprising 3.3 kb and the other 1.7 kb, the latter probably
representing the rat equivalent of mouse UT-A5. On the basis of Western
blot analysis, it has been proposed that the UT-A transporter may be
present in liver (21) and heart (9); however,
the specific UT-A mRNA species expressed in those organs have yet to be characterized.
The UT-A transporter is encoded by the Slc14A2 gene, which
was first cloned in rats (25). The rat gene is large,
extends for ~300 kb, and encodes all the known rat transcript
sequences with 24 exons (Fig. 1). The
Slc14A2 gene includes at least two promoters. A promoter in
the 5'-flanking region controls transcription of UT-A1, UT-A3, and
their 3'-UTR variants, as well as UT-A4. Another promoter in intron 12 controls transcription of UT-A2 and UT-A2b. Exon 13 includes the
transcription start of UT-A2 and is transcribed only in UT-A2 in rats
and mice. It is likely that additional promoters may be present in the
gene, which may regulate transcription of the testis UT-A isoforms, but
they have not yet been described. The murine Slc14A2 gene
has also been characterized (12) and appears very similar
to the rat gene, with two promoters, two large introns separating exons
2, 3, and 4, which encode the 5'-UTR sequence of UT-A1, UT-A3, and
UT-A4, respectively, and an additional exon in intron 5 from which the 5'-end of UT-A5 originates (the transcription start site of mUT-A5 has
not been described). In humans, only UT-A1 and UT-A2 have been cloned,
although Northern blot analysis shows a 2.2-kb mRNA consistent with
UT-A3 expression in the kidney (2). The human Slc14A2 gene is smaller than the rat and mouse genes, and
most of the 5'-UTR of UT-A1 is encoded by a single initial exon (Fig. 2). On the basis of the cloned cDNA
sequence, there is no evidence that the 5'-end of human UT-A2 is
encoded by a unique exon as in rodents or that a distinct promoter
controls its transcription. However, this possibility cannot be ruled
out until a specific transcription start site for human UT-A2 is
identified and the structure of its 5'-flanking genomic region is
known. The Slc14A2 gene is adjacent to the
Slc14A1 gene, which encodes the UT-B transporter, on
chromosome 18 in humans and mice (13, 29).

View larger version (13K):
[in this window]
[in a new window]
|
Fig. 1.
A: organization of the rat Slc14A2 gene
(scale: 10 kb). Vertical lines indicate the position of the exons
encoding urea transporter UT-A transcripts (B). PI and PII
indicate the 5' and 3' promoters, respectively. PI controls
transcription of UT-A1, UT-A1b, UT-A3, UT-A3b, and UT-A4. PII controls
transcription of UT-A2 and UT-A2b. B: splicing pattern of
the Slc14A2 gene generates different UT-A transcripts, shown
as boxed segments of rectangles (scale: 1 kb). A similar filling
pattern among transcripts indicates regions of homology. Nos.
underneath each segment indicate the first and last exon spliced
together to encode a particular segment of each transcript. The UT-A
isoforms designated b represent variants with a 3'-untranslated region
(UTR) different from that of the parent transcript. The 3'-UTRs of
UT-A1b and UT-A2b are provided by alternative use of exon 24, skipping
part of exon 23. The UT-A3b isoform has a longer 3'-UTR resulting from
extended transcription from exon 12.
|
|

View larger version (14K):
[in this window]
[in a new window]
|
Fig. 2.
Human Slc14A2 gene (A) and human
Slc14A1 gene (B; scale: 10 kb). Horizontal
brackets indicate the exons encoding individual transcripts.
Illustration of the splicing pattern of the Slc14A1 gene for
the UT-B transcripts is based on the original description of this gene
by Lucien et al. (23).
|
|
 |
THE UT-B TRANSPORTER AND Slc14A1 GENE |
The urea transporter UT-B (HUT11), which is
expressed in erythrocytes, was cloned in 1994 from human bone marrow
cells (30), encodes a protein that is 71% identical to
the UT-A2 protein, and corresponds to the Kidd blood group antigen
(29). By Northern hybridization, two mRNA species of 2.5 and 4.7 kb are present in the human kidney (30), and
transcripts of similar size (2.0 and 3.8 kb) have been found in mouse
brain, spleen, kidney, ureter, and urinary bladder (52)
and in rat testis (3.8 kb) (11). In the kidney, UT-B is
expressed in descending vasa recta (44, 51). The Kidd/UT-B
transporter is encoded by the Slc14A1 gene. The
Slc14A1 gene has been characterized in humans
(23). It is ~30 kb long, includes 11 exons, and encodes
two transcripts, arising from usage of different polyadenylation
signals, separated by ~2 kb in exon 11 (Fig. 2). The
Slc14A1 gene on chromosome 18, according to current maps of
the human genome (http://genome.ucsc.edu), could be separated by <100
kb from the human Slc14A2 gene. The close position of these
two genes and the considerable number of highly homologous splice
isoforms that they encode suggest a possible origin by duplication of
an ancestral gene.
Interestingly, individuals lacking the Kidd erythrocyte antigen show a
mild deficit (20%) in the ability to concentrate urine after water
deprivation (34). The cause of this deficit in Kidd null
subjects was recently linked to mutations in the Slc14A1 gene, resulting in a truncated UT-B protein unable to mediate urea
uptake when expressed in Xenopus laevis oocytes
(23). A relatively mild defect in urinary concentration
has been found in a recently created UT-B knockout mouse
(52), which lacks expression of the UT-B protein in vasa
recta. UT-B null mice show a selective impairment in the capacity to
concentrate urea in the urine and a 35% decrease in maximum urinary
concentration after water deprivation. Overall, these data suggest that
lack of UT-B expression in the kidney of Kidd null humans and UT-B knockout mice does not result in profound impairment of the urinary concentrating mechanism. It is not known whether in these conditions upregulation of the UT-A transporters may occur, but this possibility needs to be tested. Whether disruption of the UT-A transporter system
would have more dramatic consequences is not clear. No specific
condition has been identified so far that may be associated with
defective function of the UT-A transporter and/or with mutation of the
Slc14A2 gene in humans. Although instances of familial hyperazotemia with normal glomerular filtration rate have been described (16), a genetic analysis of those affected by
this syndrome is not available. Generation of UT-A
knockout/transgenic mice could clarify the role and importance of the
UT-A transporter in renal function.
 |
REGULATION OF UT-A AND UT-B TRANSPORTER EXPRESSION IN THE KIDNEY |
UT-A
After the characterization of the gene for the UT-A transporter,
it has been possible to identify transcriptional mechanisms regulating
UT-A expression in the kidney in various physiological settings.
Several conditions affecting the level of mRNA and/or protein abundance
of UT-A and UT-B in the kidney have been reported in different studies,
which are listed in Table 2.
Hydration is a very important physiological determinant of urinary
concentration and urea transport, and its effects on urea transporter
expression have been examined in several articles. Water restriction is
associated with production of highly concentrated urine, increased
content of sodium chloride and urea in the renal medullary
interstitium, and increased vasopressin levels (reviewed in Ref.
4). Increased interstitial urea content is due to
stimulation of the facilitated transport of this solute by the terminal
segment of IMCD and urea recycling by influx from the ascending vasa
recta into descending vasa recta and into the tDL to prevent escape into the renal venous circulation. It is therefore not surprising that
UT-A3 and UT-A2 mRNA levels are increased in the renal medulla during
water deprivation (UT-A1 does not change significantly) (3). This pattern is similar to the increased expression
of the inner medullary osmolyte sodium-myo-inositol
cotransporter (SMIT) and betaine-GABA cotransporter BGT-1 during
thirsting, which occurs in response to the increased extracellular
tonicity in the medullary interstitium (5, 15).
Upregulation of renal tonicity-responsive genes is usually
mediated by transcriptional activation via the binding of a
transactivating factor [tonicity enhancer binding protein
(TonEBP)/ NF-AT5] to a tonicity enhancer DNA sequence
(TonE/osmotic response element) (24, 41). Transcription of
UT-A1 and UT-A3 is controlled by the 5'-promoter of the UT-A gene
(promoter I), which includes a TonE sequence within 400 bp of the
transcription start site common to UT-A1 and UT-A3 (26). We showed that the activity of UT-A promoter I is stimulated by hypertonicity, through binding of TonEBP to TonE, similar to the medullary genes involved in osmoregulation (26). Thus
during water deprivation, increased extracellular tonicity activates transcription of UT-A1 and UT-A3 (and their 3'-UTR variants) by stimulation of UT-A promoter I. The regulation of UT-A1 in response to
hydration is obviously more difficult to study in humans than in
rodents, but it is likely to be similar. Within the initial 2-kb
5'-flanking sequence of the human gene are two closely spaced TonE
motifs at ~1.3 kb from the beginning of exon 1, suggesting that
hypertonicity may also stimulate expression of human UT-A1.
UT-A2 mRNA consistently increases in the inner medulla of dehydrated
animals. Transcription of UT-A2 is controlled by UT-A promoter II in
intron 12, which, unlike promoter I, has several cAMP response elements
(25). The activity of UT-A promoter II is stimulated by
cAMP and forskolin but not by hypertonicity (25). Vasopressin induces generation of cAMP by activation of the vasopressin V2 receptor. During water deprivation, higher levels of
vasopressin leading to increased intracellular cAMP could stimulate
transcription of UT-A2 by activating UT-A promoter II. The importance
of vasopressin for UT-A2 expression has been confirmed by analysis of
protein abundance (47) and is underscored by studies in
Brattleboro rats, which lack this hormone and in which UT-A2 mRNA is
usually undetectable even after thirsting, unless exogenous DDAVP, a
V2-receptor agonist, is given (37). Because
the V2 receptor is not present in the tDL, the exact
mechanism linking vasopressin to UT-A2 expression remains obscure and
will require further study. Similar responses to hypertonicity and cAMP
have been reported for the two promoters of the mouse UT-A gene
(12).
During water diuresis in rats, UT-A3 decreases in the inner medulla
compared with controls (UT-A1 does not change significantly), whereas
UT-A2 is significantly decreased in the outer medulla but does not
change in the inner medulla (3). It is likely that
dilution of the inner medullary osmotic gradient and absence of
vasopressin stimulation may dampen the activity of the two promoters,
reducing transcription.
Transcription also seems to play a substantial role in the
downregulation exerted by glucocorticoids on urea transport. Previous studies showed that urea fractional excretion increases in
adrenalectomized rats treated with dexamethasone for 3 days
(22) and that urea permeability of perfused IMCD segments
and UT-A1 protein abundance in the inner medullary tip decrease in
adrenalectomized rats treated with dexamethasone for 7 days
(27). Our laboratory recently demonstrated that rats
treated with stress doses of glucocorticoids for 3 days show an ~70%
decrease in UT-A1 and UT-A3 mRNA in the renal inner medulla
(31). In the same study, we show that this effect
correlates with 70% inhibition of UT-A promoter I activity by
dexamethasone, whereas the abundance of UT-A2 mRNA and the activity of
UT-A promoter II are not affected. This downregulation is not mediated
by glucocorticoid response elements, and the specific sequences in
promoter I involved in this response have not yet been identified. Thus
the decrease in UT-A1 protein induced by glucocorticoids can be
explained by reduced transcription of UT-A1. The role of mRNA stability
in modulating the abundance of UT-A transcripts in these conditions has
not been established.
The relative importance of transcriptional control vs.
posttranscriptional mechanisms in regulating UT-A abundance is not known, but the latter may be predominant in certain instances of
impaired urinary concentrating ability. An increase in the 117-kDa form
of the UT-A1 protein has been reported in rats when their ability to
concentrate urine is impaired after furosemide and water diuresis
(42). This is somewhat surprising in light of unchanged or
decreased UT-A1 mRNA reported in this condition and suggests that
increased translation efficiency and/or reduced protein degradation may
intervene to sustain the level of UT-A1 protein, in an attempt to
maximize urea transport and to preserve the medullary osmotic gradient
in the face of diuresis.
UT-B
Only a few studies have analyzed expression of the UT-B
transporter in the kidney. A weak correlation of UT-B mRNA abundance with urine osmolarity, without evidence of significant change after
infusion of DDAVP, was reported by Promeneur et al. (33). More recently, downregulation of the UT-B protein in rat inner medulla
has been reported after 6 days of treatment with DDAVP and with 6 days
of treatment with furosemide (45). In the original description of the Slc14A1 gene promoter region, there is no
evidence of TonE motifs or cAMP response element sequences, suggesting that hypertonicity and cAMP-mediated signals may not be important for
promoter activation (23). However, functional studies of UT-B promoter activity are needed to clarify the role of transcription (if any) in the regulation of the UT-B transporter expression.
 |
REGULATION OF UT-A AND UT-B TRANSPORTER EXPRESSION DURING
DEVELOPMENT OF THE KIDNEY AND OTHER ORGANS |
The expression of UT-A and UT-B and of other transporters
has been examined in the developing rat kidney (20). UT-A
begins to appear in IMCD and tDL after birth, and its intensity
increases afterward. UT-B is apparent in descending vasa recta of
20-day-old fetal kidneys, and its intensity also increases after birth.
These observations suggest that increased abundance of urea
transporters may be an important component for the maturation of
urinary concentrating ability by the developing kidney.
UT-A and UT-B transcripts are expressed in testis. However, not much is
known about the factors influencing testicular expression of the UT-A
and UT-B transporters. UT-A5 mRNA is detected in testis ~15 days
postpartum and reaches high expression ~25 days after birth
(14). The mechanisms regulating its expression, as well as
the promoter sequences controlling transcription of UT-A5, are still unknown.
UT-B has been detected in brain astrocytes (45), and UT-B
mRNA abundance has been found to be decreased in the brain of rats with
chronic renal failure induced by
nephrectomy
(17). These animals had high plasma urea levels, and
whether urea by itself has a depressive effect on UT-B remains to be determined.
 |
UREA TRANSPORTERS IN LOWER VERTEBRATES |
Fascinating progress is occurring in our understanding of the
physiological role of urea transport in elasmobranch and teleost fishes
and amphibians, and elucidation of the molecular structure of urea
transporters in lower organisms may greatly contribute to trace the
evolution of urea transporter systems.
Table 3 summarizes the degree of protein
homology of urea transporters cloned in lower vertebrates and mammalian
transporters (the homology of these transporters with the urea
transporter proteins in Y. pseudotuberculosis and B. melitensis is only 25-27%, and there is no similarity with
those of other microorganisms). Figure 3
shows the hydrophilicity plots of the urea transporters listed in Table
3 and illustrates the remarkable similarity in the predicted structural
configuration of these transporters in different species. All
transporters include two conserved amino acid sequences, WDLPVFTLPFN
and PVGXGQVXGCDNPW (X indicates conservative substitutions),
which are found in similar location within the peptide of different
transporters (Fig. 4), including UT-A3,
UT-A4, UT-A5, and UT-A1. However, only UT-B shows an ALE domain
(residues 205-207 in rat UT-B, residues 219-221 in human
UT-B), which may be considered a signature sequence for the UT-B
transporter. On the basis of structural analysis, it seems that
nonmammalian transporters show a slightly higher homology with UT-A,
more specifically with UT-A2, than with UT-B, and a phylogenetic
relationship between the elasmobranch urea transporter ShUT and UT-A2
has been previously suggested by Smith and Wright (40).
Similar considerations apply to the urea transporter of another
elasmobranch, the Atlantic stingray, leading to the hypothesis that the
urea transporters in elasmobranch and teleost fish and the mammalian
UT-A2 transporters may all derive from a common ancestral form and
that, among the mammalian urea transporters, UT-A2 may be the most
representative of the common ancestral form (18).

View larger version (36K):
[in this window]
[in a new window]
|
Fig. 3.
Hydrophilicity plots of urea transporter peptides in
lower vertebrates and mammalians (Kyte-Doolittle). The
protein sequences, predicted from the cDNAs listed in Table 1, are
aligned according to their respective size, indicated as no. of amino
acids (top).
|
|

View larger version (51K):
[in this window]
[in a new window]
|
Fig. 4.
Putative peptide sequences of lower vertebrates and
mammalian transporters aligned to show amino acid motifs (boxed areas)
WDLPVFTLPFN and PVGV/IGQV/IYGCDNPW, which are conserved among different
species, and the ALE motif, which appears to be present only in the
UT-B transporters. Nos. on the left, no. of amino acids in
each sequence.
|
|
The cDNAs, but not the genes encoding the transporters listed in Table
3, have been cloned. However, high-stringency Northern blot analysis
suggests that additional transcripts may exist for some of the urea
transporters described. In the bladder of Rana esculenta,
1.6- and 4.3-kb mRNA species have been detected (6). Two
mRNA species, 10 and 2.2 kb, have been reported in the kidney and brain
of Squalus achantias (40); two mRNA species of
1.8 and 3.5 kb are described in the gills of the gulf toadfish
(49). In addition to whUT-A2 (2.7 kb, 91% identical to
hUT-A2), a 4.0-kb transcript is expressed in the kidney of the
short-finned whale, possibly representing the cetacean counterpart of
UT-A1 (18). UT-A1 is the largest urea transporter cloned
so far, although there is evidence that a UT-B large transcript may
exist, and it will be very interesting to see whether any of the
elasmobranch and teleost large transcripts shows structural analogies
with UT-A1.
Not much is known about the regulation of urea transport and
transporter expression in lower vertebrates in different physiological states and in response to environmental changes. In the gills of the
gulf toadfish, urea excretion occurs through pulses that last from 0.5 to 3 h. This process apparently does not require variation in the
abundance of tUT mRNA in the gills, suggesting that the main regulatory
events are not acting at the mRNA level (49). Some
elasmobranch species can survive and reproduce in waters of different
salinities and adapt to these environmental changes by modifying renal
function and urea reabsorption (18). It is possible that
these changes in habitat may require a relatively long-term modulation
of the abundance of urea transporter, but it is hard to predict how
similar the mechanisms regulating these responses may be to those
operating in the mammalian kidney. This may become clearer once the
urea transporter genes in marine organisms are cloned and characterized.
 |
ACKNOWLEDGEMENTS |
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grants RO1-DK-53917 and PO1-DK-50268.
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
S. M. Bagnasco, WMRB Rm. 7105A, Dept. of Pathology, Emory
Univ. Medical School, 1639 Pierce Dr., Atlanta, GA 30322 (E-mail:
sbagnas{at}emory.edu).
10.1152/ajprenal.00260.2002
 |
REFERENCES |
1.
Ashkar, ZM,
Martial S,
Isozaki T,
Price SR,
and
Sands JM.
Urea transport in initial IMCD of rats fed a low-protein diet: functional properties and mRNA abundance.
Am J Physiol Renal Fluid Electrolyte Physiol
268:
F1218-F1223,
1995[Abstract/Free Full Text].
2.
Bagnasco, SM,
Peng T,
Janech MG,
Karakashian A,
and
Sands JM.
Cloning and characterization of the human urea transporter UT-A1 and mapping of the human Slc14a2 gene.
Am J Physiol Renal Physiol
281:
F400-F406,
2001[Abstract/Free Full Text].
3.
Bagnasco, SM,
Peng T,
Nakayama Y,
and
Sands JM.
Differential expression of individual UT-A urea transporter isoforms in rat kidney.
J Am Soc Nephrol
11:
1980-1986,
2000[Abstract/Free Full Text].
4.
Bankir, L.
Urea and the kidney.
In: The Kidney, edited by Brenner B,
and Rector RF.. New York: Saunders, 2000, p. 637-679.
5.
Cha, JH,
Woo SK,
Han YH,
Kim KH,
Handler JS,
Kim J,
and
Kwon HM.
Hydration status affects nuclear distribution of transcription factor tonicity-responsive enhancer binding protein in rat kidney.
J Am Soc Nephrol
12:
2221-2230,
2001[Abstract/Free Full Text].
6.
Couriaud, C,
Leroy C,
Simon M,
Silberstein C,
Bailly P,
Ripoche P,
and
Rousselet G.
Molecular and functional characterization of an amphibian urea transporter.
Biochim Biophys Acta
1421:
347-352,
1999[ISI][Medline].
7.
Couriaud, C,
Ripoche P,
and
Rousselet G.
Cloning and functional characterization of a rat urea transport: expression in the brain.
Biochim Biophys Acta
1309:
197-199,
1996[ISI][Medline].
8.
DelVecchio, VG,
Kapatral V,
Redkar RJ,
Patra G,
Mujer C,
Los T,
Ivanova N,
Anderson I,
Bhattacharyya A,
Lykidis A,
Reznik G,
Jablonski L,
Larsen N,
D'Souza M,
Bernal A,
Mazur M,
Goltsman E,
Selkov E,
Elzer PH,
Hagius S,
O'Callaghan D,
Letesson JJ,
Haselkorn R,
Kyrpides N,
and
Overbeek R.
The genome sequence of the facultative intracellular pathogen Brucella melitensis.
Proc Nat Acad Sci USA
99:
443-448,
2002[Abstract/Free Full Text].
9.
Duchesne, R,
Klein DJ,
Velotta JB,
Doran JJ,
Rouillard P,
Roberts BR,
McDonough AA,
and
Sands JM.
UT-A urea transporter protein in heart increased abundance during uremia, hypertension, and heart failure.
Circ Res
89:
139-145,
2001[Abstract/Free Full Text].
10.
ElBerry, HM,
Majmudar ML,
Cunningham TS,
Sumrada RA,
and
Cooper TG.
Regulation of the urea active transport gene (DUR3) in Saccharomyces cerevisiae.
J Bacteriol
175:
4688-4698,
1993[Abstract].
11.
Fenton, RA,
Cooper GJ,
Morris ID,
and
Smith CP.
Coordinated expression of UT-A and UT-B urea transporters in rat testis.
Am J Physiol Cell Physiol
282:
C1492-C1501,
2002[Abstract/Free Full Text].
12.
Fenton, RA,
Cottingham CA,
Stewart GS,
Howorth A,
Hewitt JA,
and
Smith CM.
Structure and characterization of the mouse UT-A gene (Slc14a2).
Am J Physiol Renal Physiol
282:
F630-F638,
2002[Abstract/Free Full Text].
13.
Fenton, RA,
Hewitt JE,
Howorth A,
Cottingham CA,
and
Smith CP.
The murine urea transporter genes Slc14a1 and Slc14a2 occur in tandem on chromosome 18.
Cytogenet Cell Genet
87:
95-96,
1999[ISI][Medline].
14.
Fenton, RA,
Howorth A,
Cooper GJ,
Meccariello R,
Morris ID,
and
Smith CP.
Molecular characterization of a novel UT-A urea transporter isoform (UT-A5) in testis.
Am J Physiol Cell Physiol
279:
C1425-C1431,
2000[Abstract/Free Full Text].
15.
Handler, JS,
and
Kwon HM.
Regulation of the myo-inositol and betaine cotransporters by tonicity.
Kidney Int
49:
1682-1683,
1996[ISI][Medline].
16.
Hsu, CH,
Kurtz TW,
Massari BSP,
Ponze SA,
and
Chang BS.
Familial azotemia.
N Engl J Med
298:
117-121,
1978[Abstract].
17.
Hu, MC,
Bankir L,
Michelet S,
Rousselet G,
and
Trinh-Trang-Tan MM.
Massive reduction of urea transporters in remnant kidney and brain of uremic rats.
Kidney Int
58:
1202-1210,
2000[ISI][Medline].
18.
Janech, MG,
Chen R,
Klein JD,
Nowak MW,
McFee W,
Paul RV,
Fitzgibbon WR,
and
Ploth DW.
Molecular and functional characterization of a urea transporter from the kidney of a short-finned pilot whale.
Am J Physiol Regul Integr Comp Physiol
282:
R1490-R1500,
2002[Abstract/Free Full Text].
19.
Karakashian, A,
Timmer RT,
Klein DJ,
Gunn RB,
Sands JM,
and
Bagnasco SM.
Cloning and characterization of two new isoforms of the rat kidney urea transporter: UT-A3 and UT-A4.
J Am Soc Nephrol
10:
230-237,
1999[Abstract/Free Full Text].
20.
Kim, YH,
Kim DU,
Han KH,
Jung JY,
Sands JM,
Knepper MA,
Madsen KM,
and
Kim J.
Expression of urea transporters in the developing rat kidney.
Am J Physiol Renal Physiol
282:
F530-F540,
2002[Abstract/Free Full Text].
21.
Klein, DJ,
Rouillard P,
Roberts BR,
and
Sands JM.
Acidosis mediates the upregulation of UT-A protein in livers from uremic rats.
J Am Soc Nephrol
13:
581-587,
2002[Abstract/Free Full Text].
22.
Knepper, MA,
Danielson RA,
Saidel GM,
and
Johnston KH.
Effects of dietary protein restriction and glucocorticoid administration on urea excretion in rats.
Kidney Int
8:
303-315,
1975[ISI][Medline].
23.
Lucien, N,
Sidoux-Walter F,
Olives B,
Moulds J,
Le Pennec PY,
Cartron J-P,
and
Bailly P.
Characterization of the gene encoding the human Kidd blood group/urea transporter protein.
J Biol Chem
273:
12973-12980,
1998[Abstract/Free Full Text].
24.
Miyakawa, HS,
Woo SK,
Dahl SC,
Handler JS,
and
Kwon HM.
Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity.
Proc Nat Acad Sci USA
96:
2538-2542,
1999[Abstract/Free Full Text].
25.
Nakayama, Y,
Naruse M,
Karakashian A,
Peng T,
Sands JM,
and
Bagnasco SM.
Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter.
Biochim Biophys Acta
1518:
19-26,
2001[ISI][Medline].
26.
Nakayama, Y,
Peng T,
Sands JM,
and
Bagnasco S.
The TonE/TonEBP pathway mediates tonicity-responsive regulation of UT-A urea transporter expression.
J Biol Chem
275:
38275-38280,
2000[Abstract/Free Full Text].
27.
Naruse, M,
Klein JD,
Ashkar ZM,
Jacobs JD,
and
Sands JM.
Glucocorticoids downregulate the rat vasopressin-regulated urea transporter in rat terminal inner medullary collecting ducts.
J Am Soc Nephrol
8:
517-523,
1997[Abstract].
28.
Olives, B,
Martial S,
Mattei MG,
Matassi G,
Rousselet G,
Ripoche P,
Cartron J-P,
and
Bailly P.
Molecular characterization of a new urea transporter in the human kidney.
FEBS Lett
386:
156-160,
1996[ISI][Medline].
29.
Olives, B,
Mattei MG,
Huet P,
Neau P,
Martial S,
Cartron J-P,
and
Bailly P.
Kidd blood group and urea transport function of human erythrocytes are carried by the same protein.
J Biol Chem
270:
15607-15610,
1995[Abstract/Free Full Text].
30.
Olives, B,
Neau P,
Bailly P,
Hediger MA,
Rousselet G,
Cartron J-P,
and
Ripoche P.
Cloning and functional expression of a urea transporter from human bone marrow cells.
J Biol Chem
269:
31649-31652,
1994[Abstract/Free Full Text].
31.
Peng, T,
Sands JM,
and
Bagnasco SM.
Glucocorticoids inhibit transcription and expression of the UT-A urea transporter gene.
Am J Physiol Renal Physiol
282:
F853-F858,
2002[Abstract/Free Full Text].
32.
Promeneur, D,
Bankir L,
Hu MC,
and
Trinh-Trang-Tan MM.
Renal tubular and vascular urea transporter: influence of antidiuretic hormone on messenger RNA expression in Brattleboro rats.
J Am Soc Nephrol
9:
1359-1366,
1998[Abstract].
33.
Promeneur, D,
Rousselet G,
Bankir L,
Bailly P,
Cartron J-P,
Ripoche P,
and
Trinh-Trang-Tan MM.
Evidence for distinct vascular and tubular urea transporters in the rat kidney.
J Am Soc Nephrol
7:
852-860,
1996[Abstract].
34.
Sands, JM,
Gargus JJ,
Froelich O,
Gunn RB,
and
Kokko JP.
Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport.
J Am Soc Nephrol
2:
1689-1696,
1992[Abstract].
35.
Sands, JM,
Timmer RT,
and
Gunn RB.
Urea transporters in kidney and erythrocytes.
Am J Physiol Renal Physiol
273:
F321-F339,
1997[Abstract/Free Full Text].
35a.
Sebbane, F,
Bury-Mone S,
Caillau K,
Browaeys-Poly E,
De Reuse H,
and
Simonet M.
The Yersinia pseudotuberculosis Yut protein, a new type of urea transporter homologous to eukaryotic channels and functionally interchangeable in vitro with the Helicobacter pylori UreI protein.
Mol Microbiol
45:
1165-1174,
2002[ISI][Medline].
36.
Shayakul, C,
Knepper MA,
Smith CP,
DiGiovanni SR,
and
Hediger MA.
Segmental localization of urea transporter mRNAs in rat kidney.
Am J Physiol Renal Physiol
272:
F654-F660,
1997[Abstract/Free Full Text].
37.
Shayakul, C,
Smith CP,
Mackenzie HS,
Lee WS,
Brown D,
and
Hediger MA.
Long-term regulation of urea transporter expression by vasopressin Brattleboro rats.
Am J Physiol Renal Physiol
278:
F620-F627,
2000[Abstract/Free Full Text].
38.
Shayakul, C,
Steel A,
and
Hediger MA.
Molecular cloning and characterization of the vasopressin-regulated urea transporter of rat kidney collecting ducts.
J Clin Invest
98:
2580-2587,
1996[Abstract/Free Full Text].
39.
Smith, CP,
Lee WS,
Martial S,
Knepper MA,
You G,
Sands JM,
and
Hediger MA.
Cloning and regulation of expression of the rat kidney urea transporter (rUT2).
J Clin Invest
96:
1556-1563,
1995[ISI][Medline].
40.
Smith, CP,
and
Wright PA.
Molecular characterization of an elasmobranch urea transporter.
Am J Physiol Regul Integr Comp Physiol
276:
R622-R626,
1999[Abstract/Free Full Text].
41.
Takenaka, M,
Preston AS,
Kwon ED,
and
Handler JS.
The tonicity-sensitive element that mediates increased transcription of the betaine transporter gene in response to hypertonic stress.
J Biol Chem
269:
29379-29381,
1994[Abstract/Free Full Text].
42.
Terris, J,
Ecelbarger CA,
Sands JM,
and
Knepper MA.
Long-term regulation of renal urea transporter protein expression in rat.
J Am Soc Nephrol
9:
729-736,
1998[Abstract].
43.
Terris, J,
Knepper MA,
and
Wade JB.
UT-A3: localization and characterization of an additional urea transporter isoform in the IMCD3.
Am J Physiol Renal Physiol
280:
F325-F332,
2001[Abstract/Free Full Text].
44.
Timmer, RT,
Klein DJ,
Bagnasco SM,
Doran JJ,
Verlander JW,
Gunn RB,
and
Sands JM.
Localization of the urea transporter UT-B protein in human and rat erythrocytes and tissues.
Am J Physiol Cell Physiol
281:
C1318-C1325,
2001[Abstract/Free Full Text].
45.
Trinh-Trang-Tan, MM,
Lasbennes F,
Gane P,
Roudier N,
Ripoche P,
Cartron J-P,
and
Bailly P.
UT-B1 proteins in rat: tissue distribution and regulation by antidiuretic hormone in kidney.
Am J Physiol Renal Physiol
283:
F912-F922,
2002[Abstract/Free Full Text].
46.
Valladares, A,
Montesinos ML,
Herrero A,
and
Flores E.
An ABC-type, high-affinity urea permease identified in cyanobacteria.
Mol Microbiol
43:
703-715,
2002[ISI][Medline].
47.
Wade, JB,
Lee AJ,
Liu J,
Ecelbarger CA,
Mitchell C,
Bradford AD,
Terris J,
Kim GH,
Kohl D,
and
Knepper MA.
UT-A2: a 55-kDa urea transporter in thin descending limb whose abundance is regulated by vasopressin.
Am J Physiol Renal Physiol
278:
F52-F62,
2000[Abstract/Free Full Text].
48.
Walsh, PJ,
Grosell M,
Goss GG,
Bergman HL,
Bergman AN,
Wilson P,
Laurent P,
Alper SL,
Smith CP,
Kamunde C,
and
Wood CM.
Physiological and molecular characterization of urea transport by the gills of the Lake Magadi tilapia (Alcolapia grahami).
J Exp Biol
204:
509-520,
2001[Abstract/Free Full Text].
49.
Walsh, PJ,
Heitz MJ,
Campbell CE,
Cooper GJ,
Medina M,
Wang YS,
Coss GG,
Vincek V,
Wood CM,
and
Smith CP.
Molecular characterization of a urea transporter in the gill of the gulf toadfish (Opsanus beta).
J Exp Biol
203:
2357-2364,
2000[Abstract/Free Full Text].
50.
Weeks, DL,
Eskandari S,
Scott DR,
and
Sachs G.
A H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization.
Science
287:
482-485,
2000[Abstract/Free Full Text].
51.
Xu, Y,
Olives B,
Bailly P,
Fischer E,
Ripoche P,
Ronco P,
and
Rondeau E.
Endothelial cells of the kidney vasa recta express the urea transporter HUT11.
Kidney Int
51:
138-146,
1997[ISI][Medline].
52.
Yang, B,
Bankir L,
Gillespie A,
Epstein CJ,
and
Verkman AS.
Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B.
J Biol Chem
277:
10633-10637,
2002[Abstract/Free Full Text].
53.
You, G,
Smith CP,
Kanai Y,
Lee WS,
Stelzner M,
and
Hediger MA.
Cloning and characterization of the vasopressin-regulated urea transporter.
Nature
365:
844-847,
1993[ISI][Medline].
Am J Physiol Renal Fluid Electrolyte Physiol 284(1):F3-F10
0363-6127/03 $5.00
Copyright © 2003 the American Physiological Society