INVITED REVIEWGene structure of urea transporters - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:23 |只看该作者 |倒序浏览 |打印

作者：Serena M.Bagnasco作者单位：Department of Pathology, Emory University School ofMedicine, Atlanta, Georgia 30322 # Z" _6 Z! K) k, c0 m

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      【摘要】: s2 c( n/ O0 i. d) I7 ]
   Urea plays various roles in thebiology of diverse organisms. The past decade has produced newinformation on the molecular structure of several urea transporters invarious species. Availability of DNA probes has revealed that thepresence of urea transporters is not confined to the mammalian kidneybut is also evident in testis and brain, raising new questions aboutthe possible physiological role of urea in these organs. Cloning of thegenes encoding the two closely related mammalian urea transporters UT-Aand UT-B has helped in identifying molecular mechanisms affectingexpression of urea transporters in the kidney, such as transcriptionalcontrol for UT-A abundance. On the basis of analysis of genomicsequences of individuals lacking the UT-B transporter, mutations havebeen found that explain deficits in their capacity to concentrateurine. More urea transporters are being characterized in marineorganisms and lower vertebrates, and studying the role and regulationof urea transport from an evolutionary perspective can certainly enrichour understanding of renal physiology.
      【关键词】 urea kidney Kidd antigen concentrating mechanism osmoregulation+ |7 F2 \" `& H5 R) n" x
   INTRODUCTION
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UREA SERVES DIFFERENT PURPOSES indifferent organisms. Urea represents a source of nitrogen formicroorganisms like yeasts and bacteria. Urea is present in highconcentrations in the tissues of marine elasmobranchs, where it servesas an osmolyte to balance the high salinity of seawater. Excretion ofurea provides a good vehicle for eliminating waste products fromnitrogen metabolism in mammals. Although urea can diffuse slowly acrosscell membranes along concentration gradients, in many cases a moreefficient and rapid movement of this solute is necessary. This can beachieved by use of specific carriers, resulting in facilitateddiffusion or active transport. Urea transporters have now been clonedand characterized in bacteria, yeasts, amphibians, marine organisms, and mammalians (Table 1 ). The ureatransporter genes described in Saccharomycescerevisiae ( DUR3 ) ( 10 ), in Helicobacter pylori ( UreI ) ( 50 ),and the ABC-type permeases in cyanobacteria ( 46 ) do nothave homologous counterparts in higher organisms, and only minimalidentity (20-25%) exists between the urea transporter genes of Yersinia pseudotuberculosis ( Yut ), and Brucella melitensis ( 8 ) and those in mammalsand lower vertebrates. However, substantial homology is emerging in thestructure of urea transporters described in mammals, amphibians, andelasmobranch and teleost fishes. Two similar but distinct ureatransporters have been identified in rodents and humans: the UT-A ureatransporter, encoded by the Slc14A2 gene, and the UT-B ureatransporter, encoded by the Slc14A1 gene. Theorganization of the Slc14A2 gene has now been elucidated inrats ( 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 willfacilitate the study of how urea transporter expression is regulated inother species.! H  q$ ~3 I% ~/ B- \5 }7 U
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Table 1. Urea transporters/ X) K* X. B2 Z. W& l( H5 f6 _

THE UT-A TRANSPORTER AND Slc14A2 GENE
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Most information on the UT-A transporter has been generated instudies on urea transport in rat kidney, where three major transcriptsare detected by Northern hybridization in the medullary region of thekidney: UT-A1 (4.0 kb), UT-A2 (2.9 kb), and UT-A3 (2.1 kb). The mRNA ofUT-A4 (2,584 bp) is present in very low abundance, and it is onlydetectable by PCR. Additional mRNA isoforms are evident by Northernhybridization: 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 expressingalternative 3'-untranslated sequences (UTR) ( 3 ). All ofthese 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 collectingduct (IMCD) ( 36, 43 ). There is also evidence that twoother UT-A isoforms are expressed in rat testis ( 11, 19 ),one comprising 3.3 kb and the other 1.7 kb, the latter probablyrepresenting the rat equivalent of mouse UT-A5. On the basis of Westernblot analysis, it has been proposed that the UT-A transporter may bepresent in liver ( 21 ) and heart ( 9 ); however,the specific UT-A mRNA species expressed in those organs have yet to be characterized.
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The UT-A transporter is encoded by the Slc14A2 gene, whichwas first cloned in rats ( 25 ). The rat gene is large,extends for ~300 kb, and encodes all the known rat transcriptsequences with 24 exons (Fig. 1 ). The Slc14A2 gene includes at least two promoters. A promoter inthe 5'-flanking region controls transcription of UT-A1, UT-A3, andtheir 3'-UTR variants, as well as UT-A4. Another promoter in intron 12 controls transcription of UT-A2 and UT-A2b. Exon 13 includes thetranscription start of UT-A2 and is transcribed only in UT-A2 in ratsand mice. It is likely that additional promoters may be present in thegene, which may regulate transcription of the testis UT-A isoforms, butthey have not yet been described. The murine Slc14A2 genehas also been characterized ( 12 ) and appears very similarto the rat gene, with two promoters, two large introns separating exons2, 3, and 4, which encode the 5'-UTR sequence of UT-A1, UT-A3, andUT-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 hasnot been described). In humans, only UT-A1 and UT-A2 have been cloned,although Northern blot analysis shows a 2.2-kb mRNA consistent withUT-A3 expression in the kidney ( 2 ). The human Slc14A2 gene is smaller than the rat and mouse genes, andmost of the 5'-UTR of UT-A1 is encoded by a single initial exon (Fig. 2 ). On the basis of the cloned cDNAsequence, there is no evidence that the 5'-end of human UT-A2 isencoded by a unique exon as in rodents or that a distinct promotercontrols its transcription. However, this possibility cannot be ruledout until a specific transcription start site for human UT-A2 isidentified and the structure of its 5'-flanking genomic region isknown. The Slc14A2 gene is adjacent to the Slc14A1 gene, which encodes the UT-B transporter, onchromosome 18 in humans and mice ( 13, 29 ).

Fig. 1. A : organization of the rat Slc14A2 gene(scale: 10 kb). Vertical lines indicate the position of the exonsencoding urea transporter UT-A transcripts ( B ). PI and PIIindicate the 5' and 3' promoters, respectively. PI controlstranscription of UT-A1, UT-A1b, UT-A3, UT-A3b, and UT-A4. PII controlstranscription of UT-A2 and UT-A2b. B : splicing pattern ofthe Slc14A2 gene generates different UT-A transcripts, shownas boxed segments of rectangles (scale: 1 kb). A similar fillingpattern among transcripts indicates regions of homology. Nos.underneath each segment indicate the first and last exon splicedtogether to encode a particular segment of each transcript. The UT-Aisoforms designated b represent variants with a 3'-untranslated region(UTR) different from that of the parent transcript. The 3'-UTRs ofUT-A1b and UT-A2b are provided by alternative use of exon 24, skippingpart of exon 23. The UT-A3b isoform has a longer 3'-UTR resulting fromextended transcription from exon 12.
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Fig. 2. Human Slc14A2 gene ( A ) and human Slc14A1 gene ( B; scale: 10 kb). Horizontalbrackets indicate the exons encoding individual transcripts.Illustration of the splicing pattern of the Slc14A1 gene forthe UT-B transcripts is based on the original description of this geneby Lucien et al. ( 23 ).2 r- R6 B3 V1 r6 L
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THE UT-B TRANSPORTER AND Slc14A1 GENE

The urea transporter UT-B (HUT11), which isexpressed in erythrocytes, was cloned in 1994 from human bone marrowcells ( 30 ), encodes a protein that is 71% identical tothe 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 ), andtranscripts of similar size (2.0 and 3.8 kb) have been found in mousebrain, spleen, kidney, ureter, and urinary bladder ( 52 )and in rat testis (3.8 kb) ( 11 ). In the kidney, UT-B isexpressed in descending vasa recta ( 44, 51 ). The Kidd/UT-Btransporter is encoded by the Slc14A1 gene. The Slc14A1 gene has been characterized in humans( 23 ). It is ~30 kb long, includes 11 exons, and encodestwo transcripts, arising from usage of different polyadenylationsignals, separated by ~2 kb in exon 11 (Fig. 2 ). The Slc14A1 gene on chromosome 18, according to current maps ofthe human genome ( http://genome.ucsc.edu ), could be separated by Slc14A2 gene. The close position of thesetwo genes and the considerable number of highly homologous spliceisoforms that they encode suggest a possible origin by duplication ofan ancestral gene.

Interestingly, individuals lacking the Kidd erythrocyte antigen show amild deficit (20%) in the ability to concentrate urine after waterdeprivation ( 34 ). The cause of this deficit in Kidd nullsubjects was recently linked to mutations in the Slc14A1 gene, resulting in a truncated UT-B protein unable to mediate ureauptake when expressed in Xenopus laevis oocytes( 23 ). A relatively mild defect in urinary concentrationhas been found in a recently created UT-B knockout mouse( 52 ), which lacks expression of the UT-B protein in vasarecta. UT-B null mice show a selective impairment in the capacity toconcentrate urea in the urine and a 35% decrease in maximum urinaryconcentration after water deprivation. Overall, these data suggest thatlack 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 systemwould have more dramatic consequences is not clear. No specificcondition has been identified so far that may be associated withdefective 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 bythis syndrome is not available. Generation of UT-Aknockout/transgenic mice could clarify the role and importance of theUT-A transporter in renal function.6 K6 H3 q4 r, L# ?7 ~- \; f

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 regulatingUT-A expression in the kidney in various physiological settings.8 k7 X' x9 x; d
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Several conditions affecting the level of mRNA and/or protein abundanceof UT-A and UT-B in the kidney have been reported in different studies,which are listed in Table 2.

Table 2. UT-A and UT-B mRNA and/or protein expression in renal inner medulla: B  q6 J* h/ }* n! \7 p

Hydration is a very important physiological determinant of urinaryconcentration and urea transport, and its effects on urea transporterexpression have been examined in several articles. Water restriction isassociated with production of highly concentrated urine, increasedcontent of sodium chloride and urea in the renal medullaryinterstitium, and increased vasopressin levels (reviewed in Ref. 4 ). Increased interstitial urea content is due tostimulation of the facilitated transport of this solute by the terminalsegment of IMCD and urea recycling by influx from the ascending vasarecta into descending vasa recta and into the tDL to prevent escape into the renal venous circulation. It is therefore not surprising thatUT-A3 and UT-A2 mRNA levels are increased in the renal medulla duringwater deprivation (UT-A1 does not change significantly) ( 3 ). This pattern is similar to the increased expressionof the inner medullary osmolyte sodium- myo -inositolcotransporter (SMIT) and betaine-GABA cotransporter BGT-1 duringthirsting, which occurs in response to the increased extracellulartonicity in the medullary interstitium ( 5, 15 ).Upregulation of renal tonicity-responsive genes is usuallymediated by transcriptional activation via the binding of atransactivating factor [tonicity enhancer binding protein(TonEBP)/ NF-AT5] to a tonicity enhancer DNA sequence(TonE/osmotic response element) ( 24, 41 ). Transcription ofUT-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 thetranscription 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 ). Thusduring 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 tohydration is obviously more difficult to study in humans than inrodents, but it is likely to be similar. Within the initial 2-kb5'-flanking sequence of the human gene are two closely spaced TonEmotifs at ~1.3 kb from the beginning of exon 1, suggesting thathypertonicity may also stimulate expression of human UT-A1.5 l, w# U) @  F3 j6 |/ j

UT-A2 mRNA consistently increases in the inner medulla of dehydratedanimals. Transcription of UT-A2 is controlled by UT-A promoter II inintron 12, which, unlike promoter I, has several cAMP response elements( 25 ). The activity of UT-A promoter II is stimulated bycAMP and forskolin but not by hypertonicity ( 25 ). Vasopressin induces generation of cAMP by activation of the vasopressin V 2 receptor. During water deprivation, higher levels ofvasopressin leading to increased intracellular cAMP could stimulatetranscription of UT-A2 by activating UT-A promoter II. The importanceof vasopressin for UT-A2 expression has been confirmed by analysis ofprotein abundance ( 47 ) and is underscored by studies inBrattleboro rats, which lack this hormone and in which UT-A2 mRNA isusually undetectable even after thirsting, unless exogenous DDAVP, aV 2 -receptor agonist, is given ( 37 ). Becausethe V 2 receptor is not present in the tDL, the exactmechanism linking vasopressin to UT-A2 expression remains obscure andwill require further study. Similar responses to hypertonicity and cAMPhave been reported for the two promoters of the mouse UT-A gene( 12 ).# H1 \4 W" C3 W; m  F1 q% {; D
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During water diuresis in rats, UT-A3 decreases in the inner medullacompared with controls (UT-A1 does not change significantly), whereasUT-A2 is significantly decreased in the outer medulla but does notchange in the inner medulla ( 3 ). It is likely thatdilution of the inner medullary osmotic gradient and absence ofvasopressin stimulation may dampen the activity of the two promoters,reducing transcription.

Transcription also seems to play a substantial role in thedownregulation exerted by glucocorticoids on urea transport. Previous studies showed that urea fractional excretion increases inadrenalectomized rats treated with dexamethasone for 3 days( 22 ) and that urea permeability of perfused IMCD segmentsand UT-A1 protein abundance in the inner medullary tip decrease inadrenalectomized rats treated with dexamethasone for 7 days( 27 ). Our laboratory recently demonstrated that ratstreated with stress doses of glucocorticoids for 3 days show an ~70辌rease in UT-A1 and UT-A3 mRNA in the renal inner medulla( 31 ). In the same study, we show that this effectcorrelates with 70% inhibition of UT-A promoter I activity bydexamethasone, whereas the abundance of UT-A2 mRNA and the activity ofUT-A promoter II are not affected. This downregulation is not mediatedby glucocorticoid response elements, and the specific sequences inpromoter I involved in this response have not yet been identified. Thusthe decrease in UT-A1 protein induced by glucocorticoids can beexplained by reduced transcription of UT-A1. The role of mRNA stabilityin modulating the abundance of UT-A transcripts in these conditions hasnot 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 ofimpaired urinary concentrating ability. An increase in the 117-kDa formof the UT-A1 protein has been reported in rats when their ability toconcentrate urine is impaired after furosemide and water diuresis( 42 ). This is somewhat surprising in light of unchanged ordecreased UT-A1 mRNA reported in this condition and suggests thatincreased translation efficiency and/or reduced protein degradation mayintervene to sustain the level of UT-A1 protein, in an attempt tomaximize urea transport and to preserve the medullary osmotic gradientin the face of diuresis.! h0 }7 i8 v5 A5 j* o  R, ^

UT-B
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Only a few studies have analyzed expression of the UT-Btransporter in the kidney. A weak correlation of UT-B mRNA abundance with urine osmolarity, without evidence of significant change afterinfusion of DDAVP, was reported by Promeneur et al. ( 33 ). More recently, downregulation of the UT-B protein in rat inner medullahas been reported after 6 days of treatment with DDAVP and with 6 daysof treatment with furosemide ( 45 ). In the original description of the Slc14A1 gene promoter region, there is noevidence of TonE motifs or cAMP response element sequences, suggesting that hypertonicity and cAMP-mediated signals may not be important forpromoter 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.- ?( D6 R; @* P6 g9 p7 ~* S

REGULATION OF UT-A AND UT-B TRANSPORTER EXPRESSION DURINGDEVELOPMENT OF THE KIDNEY AND OTHER ORGANS
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The expression of UT-A and UT-B and of other transportershas been examined in the developing rat kidney ( 20 ). UT-Abegins to appear in IMCD and tDL after birth, and its intensityincreases afterward. UT-B is apparent in descending vasa recta of20-day-old fetal kidneys, and its intensity also increases after birth.These observations suggest that increased abundance of ureatransporters may be an important component for the maturation ofurinary concentrating ability by the developing kidney.

UT-A and UT-B transcripts are expressed in testis. However, not much isknown about the factors influencing testicular expression of the UT-Aand UT-B transporters. UT-A5 mRNA is detected in testis ~15 dayspostpartum and reaches high expression ~25 days after birth( 14 ). The mechanisms regulating its expression, as well asthe promoter sequences controlling transcription of UT-A5, are still unknown.

UT-B has been detected in brain astrocytes ( 45 ), and UT-BmRNA abundance has been found to be decreased in the brain of rats withchronic renal failure induced by 5 6 nephrectomy( 17 ). These animals had high plasma urea levels, andwhether urea by itself has a depressive effect on UT-B remains to be determined.; x) E  W( S. H# i8 y8 E
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UREA TRANSPORTERS IN LOWER VERTEBRATES' \2 l: f3 k" u/ k! j% e
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Fascinating progress is occurring in our understanding of thephysiological role of urea transport in elasmobranch and teleost fishesand amphibians, and elucidation of the molecular structure of ureatransporters in lower organisms may greatly contribute to trace theevolution of urea transporter systems./ n) F8 U1 C: X% g; K9 f
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Table 3 summarizes the degree of proteinhomology of urea transporters cloned in lower vertebrates and mammaliantransporters (the homology of these transporters with the ureatransporter proteins in Y. pseudotuberculosis and B. melitensis is only 25-27%, and there is no similarity withthose 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 structuralconfiguration of these transporters in different species. Alltransporters include two conserved amino acid sequences, WDLPVFTLPFNand PVGXGQVXGCDNPW (X indicates conservative substitutions),which are found in similar location within the peptide of differenttransporters (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 humanUT-B), which may be considered a signature sequence for the UT-Btransporter. On the basis of structural analysis, it seems thatnonmammalian transporters show a slightly higher homology with UT-A,more specifically with UT-A2, than with UT-B, and a phylogeneticrelationship between the elasmobranch urea transporter ShUT and UT-A2has been previously suggested by Smith and Wright ( 40 ).Similar considerations apply to the urea transporter of anotherelasmobranch, the Atlantic stingray, leading to the hypothesis that theurea transporters in elasmobranch and teleost fish and the mammalianUT-A2 transporters may all derive from a common ancestral form andthat, among the mammalian urea transporters, UT-A2 may be the mostrepresentative of the common ancestral form ( 18 ).

Table 3. Protein homology of urea transporters in lower vertebrates andmammals5 Q  i9 s) Q2 N' E; h

Fig. 3. Hydrophilicity plots of urea transporter peptides inlower vertebrates and mammalians (Kyte-Doolittle). Theprotein sequences, predicted from the cDNAs listed in Table 1, arealigned according to their respective size, indicated as no. of aminoacids ( top ).5 B$ A7 G# i1 G' L$ J4 u

Fig. 4. Putative peptide sequences of lower vertebrates andmammalian transporters aligned to show amino acid motifs (boxed areas)WDLPVFTLPFN and PVGV/IGQV/IYGCDNPW, which are conserved among differentspecies, and the ALE motif, which appears to be present only in theUT-B transporters. Nos. on the left, no. of amino acids ineach sequence., Z* q* M( ~+ G1 z  F
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The cDNAs, but not the genes encoding the transporters listed in Table 3, have been cloned. However, high-stringency Northern blot analysissuggests that additional transcripts may exist for some of the ureatransporters described. In the bladder of Rana esculenta,1.6- and 4.3-kb mRNA species have been detected ( 6 ). TwomRNA species, 10 and 2.2 kb, have been reported in the kidney and brainof Squalus achantias ( 40 ); two mRNA species of1.8 and 3.5 kb are described in the gills of the gulf toadfish( 49 ). In addition to whUT-A2 (2.7 kb, 91% identical tohUT-A2), a 4.0-kb transcript is expressed in the kidney of theshort-finned whale, possibly representing the cetacean counterpart ofUT-A1 ( 18 ). UT-A1 is the largest urea transporter clonedso far, although there is evidence that a UT-B large transcript mayexist, and it will be very interesting to see whether any of theelasmobranch and teleost large transcripts shows structural analogieswith UT-A1.1 p2 o* V# k0 @+ P

Not much is known about the regulation of urea transport andtransporter expression in lower vertebrates in different physiological states and in response to environmental changes. In the gills of thegulf toadfish, urea excretion occurs through pulses that last from 0.5 to 3 h. This process apparently does not require variation in theabundance of tUT mRNA in the gills, suggesting that the main regulatoryevents are not acting at the mRNA level ( 49 ). Someelasmobranch species can survive and reproduce in waters of differentsalinities and adapt to these environmental changes by modifying renalfunction and urea reabsorption ( 18 ). It is possible thatthese changes in habitat may require a relatively long-term modulationof the abundance of urea transporter, but it is hard to predict howsimilar the mechanisms regulating these responses may be to thoseoperating in the mammalian kidney. This may become clearer once theurea transporter genes in marine organisms are cloned and characterized.
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ACKNOWLEDGEMENTS
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This work was supported by National Institute of Diabetes andDigestive and Kidney Diseases Grants RO1-DK-53917 and PO1-DK-50268.
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