Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

UT (Urea Transporter)

  • Mitsi A. Blount
  • Janet D. Klein
  • Jeff M. Sands
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_199


Historical Background

Since 1934, it has been understood that urea plays a key role in the generation of concentrated urine (reviewed in Klein et al. 2011). Functional measurements of urea transport in the kidney inner medullary collecting duct (IMCD), performed in the 1980s, provided evidence for the existence of urea transporter proteins (reviewed in Klein et al. 2011). Currently, two families of urea transporters have been cloned: SLC14A1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14A2, the UT-A group with six distinct isoforms described to date (reviewed in Klein et al. 2011) (Table 1). In the kidney, UT-A1 and UT-A3 are expressed in the IMCD; UT-A2 is expressed in the thin descending limb (tDL); and UT-B is located primarily in the descending vasa recta and red blood cells (Fig. 1). Although the exact location has yet to be determined, UT-A4 is expressed in rat kidney medulla but not in the mouse medulla (reviewed in Klein et al. 2011).
UT (Urea Transporter), Table 1

Regulation and location of the known urea transporters. Original citations are reviewed in Klein et al. (2011)



RNA (kb)

Protein (kDa)













Bovine rumen




4.0 (3.5)



IMCD (medullab)



2.9 (2.5)



tDL, liver (medullab, heart)



2.1 (3.7)



IMCD (medullab)














aHuman RNA form with additional 3′ untranslated regions

bExact tubular location unknown

cCloned from rat only

dCloned from mouse only

eCloned from human only

fAlso expressed in several other tissues and endothelial cells

UT (Urea Transporter), Fig. 1

Location of the renal urea transporters. UT-A2 is found in the thin descending limbs of Henle’s loop in the inner stripe of the outer medulla. UT-A1 and UT-A3 are expressed in the IMCD. UT-A1 is primarily found in the cytosol and the apical membrane of the cell, whereas UT-A3 is located in the cytosol and the basolateral membrane of the IMCD. UT-B is located primarily in the descending vasa recta and red blood cells

The UT-A family of urea transporters currently consists of six protein isoforms. The four renal isoforms are shown in Fig. 2. UT-A1 is the largest protein containing 12 transmembrane helices. Helices 6 and 7 are connected by a large intracellular loop that is crucial to the functional properties of UT-A1 (Blount et al. 2008; Klein et al. 2010). UT-A3 is the N-terminal half of UT-A1, while UT-A2 is the C-terminal half of UT-A1. UT-A4 is the N-terminal quarter of UT-A1 spliced to the C-terminal quarter. Although the need for the multiple isoforms of UT-A is not completely understood, the crystal structure of a bacterial urea-conducting channel, dvUT, suggested that these transporters may require some sort of oligomeric organization to function (Levin et al. 2009); however, no evidence for an oligomer of UT-A1 and UT-A3 is detected in rat IMCD (Klein et al. 2016b).
UT (Urea Transporter), Fig. 2

Four renal isoforms of UT-A. This schematic demonstrates that UT-A1 is the largest protein transcribed from the UT-A gene containing 12 transmembrane helices. UT-A3 is the N-terminal half of UT-A1 and UT-A2 is the C-terminal half of UT-A1. UT-A4 is the N-terminal quarter of UT-A1 spliced to the C-terminal quarter. Loop regions shown in blue are intracellular, whereas those highlighted in orange are extracellular. Transmembrane structure prediction was based on the GES-scale (Goldman Engelman Steitz) analysis of the primary structure which employs hydropathy calculations in combination with helical probabilities

The UT-B gene can produce two isoforms, UT-B1 and UT-B2, each of which is tissue specific. Despite the expression of two distinct transcripts (4.4 and 2 kb) cloned for the human UT-B1 transporter, both appear to encode for a single 43 kDa protein. Sequence alignment with other urea transporters shows that UT-B1 shares more than 60% identity with UT-A2. Additionally, hydrophilicity profiles indicate that UT-B1 and UT-A2 proteins show similar topology (reviewed in Klein et al. 2011). Another isoform of UT-B, UT-B2, is expressed in the bovine rumen but has not yet been detected in humans. Interestingly, UT-B2 is not regulated by vasopressin, cAMP, calcium, or protein kinases.

Acute Regulation of Urea Transport by Vasopressin

When the body is dehydrated, vasopressin (also known as antidiuretic hormone) is released (Fig. 3). When vasopressin is increased, the hormone binds to the V2 vasopressin receptor, located on the basolateral membrane of the IMCD, and activates the heterotrimeric G protein, Gsα. Activation of the G protein stimulates adenylyl cyclase to synthesize cAMP. The increase of intracellular cAMP stimulates several downstream proteins including protein kinase A (PKA) and Epac (exchange protein directly activated by cAMP). Both are involved in the vasopressin-mediated increase in urea permeability (reviewed in Klein et al. 2011). Vasopressin also increases urea flux in freshly isolated IMCD cell suspensions, UT-A1-MDCK cells, UT-A1-mIMCD3 cells, and mUT-A3-MDCK cells (reviewed in Klein et al. 2011). The acute effect of vasopressin on UT-A2 is still not understood. One group of studies showed that vasopressin and cAMP increased urea flux in mUT-A2-MDCK cells; however, other work found that treatment with cAMP or forskolin did not increase urea transport via UT-A2 (reviewed in Klein et al. 2011). cAMP-treated oocytes that have been injected with UT-A2 fail to display increased urea flux (reviewed in Klein et al. 2011). Further work will be needed to address the acute regulation of UT-A2 by vasopressin. The acute regulation of UT-A1 and UT-A3 has been studied in great detail, which is further discussed below.
UT (Urea Transporter), Fig. 3

Vasopressin signaling in the IMCD. When increased, vasopressin binds to the vasopressin receptor type 2, V2, located on the basolateral cell membrane and activates the heterotrimeric G protein, Gsα. Activation of the G protein stimulates adenylyl cyclase (AC) to synthesize cAMP. Increased cAMP can activate two downstream targets, Epac and PKA; both have been shown to affect urea transporter function. Increased levels of cAMP lead to direct phosphorylation of UT-A1 and UT-A3. Direct phosphorylation of UT-A1 is required for apical membrane insertion. UT-A3 membrane accumulation is also increased in the presence of high cAMP levels

Vasopressin-Stimulated Phosphorylation

An in silico analysis of the amino acid sequence of the urea transporter reveals a large number of consensus phosphorylation sites for a variety of kinases including several PKA consensus phosphorylation sites for both UT-A1 and UT-A3 (Fig. 4). In rat terminal IMCDs, vasopressin increases the phosphorylation of both UT-A1 and UT-A3, with a similar time-course and dose-response for that observed in the vasopressin-stimulated increase in urea permeability in perfused rat terminal IMCDs (reviewed in Klein et al. 2011). Vasopressin, acting through cAMP, stimulates Epac, which also increases urea permeability and UT-A1 phosphorylation in rat IMCDs (Wang et al. 2009).
UT (Urea Transporter), Fig. 4

Consensus phosphorylation sites in human UT-A1. The human UT-A1 sequence was analyzed using the NetPhosK 1.0 Server. Arrows indicate predicted sites with a greater than 50% of phosphorylation by the indicated kinase

Vasopressin stimulation results in the phosphorylation of UT-A1 at both S486 and S499 in rat kidney, which corresponds to S477 and S490 in human UT-A1 (Blount et al. 2008). Both of these residues are located in the large intracellular loop that is unique to UT-A1. Studies show that attaching the loop region of UT-A1 (aa 460–532) that contains S486 and S499 to UT-A2 confers vasopressin sensitivity to UT-A2 (reviewed in Klein et al. 2011) confirming the importance of these phosphorylation sites. Epac does not increase UT-A1 phosphorylation at either S486 or S499; the Epac-stimulated phosphorylation site in UT-A1 has not been determined (Hoban et al. 2015). Site-directed mutagenesis revealed that neither of the two PKA consensus sites (S85 or S92) in mouse is involved in vasopressin-induced phosphorylation (reviewed in Klein et al. 2011); however, vasopressin does increase phosphorylation at S84 in rat UT-A1 and UT-A3 (Hwang et al. 2010). The vasopressin-stimulated phosphorylation site in human UT-A3 has not been determined as S84 is not conserved in the human sequence. Satavaptan, a selective inhibitor of the V2 receptor, blocks V2-mediated activation of basophilic kinases and V2-mediated inhibition of proline-directed kinases (Hoffert et al. 2014).

Vasopressin-Stimulated Plasma Membrane Accumulation

Vasopressin increases the plasma membrane accumulation of UT-A1 and UT-A3 in IMCDs from normal rats but not from either vasopressin-deficit Brattleboro rats or water diuretic rats (Klein et al. 2006; Blount et al. 2007). When forskolin is used to stimulate cAMP instead of vasopressin, the plasma membrane accumulation of UT-A1 is increased in IMCDs from normal and diuretic rats (Klein et al. 2006). Activating Epac also increases UT-A1 plasma membrane accumulation in rat IMCDs (Wang et al. 2009).

UT-A1 apical plasma membrane accumulation is increased by vasopressin or forskolin in UT-A1-MDCK cells and UT-A1-mIMCD3 cells (reviewed in Klein et al. 2011). Mutation of both of the PKA sites in UT-A1, S486 or S499, eliminates vasopressin stimulation of UT-A1 apical plasma membrane accumulation and urea transport. Interestingly, increased membrane insertion of UT-A1 requires that both PKA sites are functional as mutation of either S486 or S499 individually has no effect on cAMP-mediated UT-A1 trafficking (Blount et al. 2008). Polyclonal antibodies that specifically detect UT-A1 phosphorylated at either the S486 or the S499 site were used to confirm that vasopressin increases UT-A1 accumulation in the apical plasma membrane and that both the S486-phospho-UT-A1 and S499-phospho-UT-A1 forms are primarily detected in the apical plasma membrane (Klein et al. 2010; Hoban et al. 2015). Vasopressin stimulates UT-A1 phosphorylation at both S486 and S499 with a similar time course (Hoban et al. 2015). 14–3-3γ binds to UT-A1, and this binding is stimulated by PKA (Feng et al. 2015). 14–3-3γ binding decreases urea transport and increases UT-A1 ubiquitination and degradation by interacting with MDM2, an E3 ubiquitin ligase, MDM2 (Feng et al. 2015). Thus, PKA activation both increases UT-A1 phosphorylation and leads to its degradation following its binding of 14–3-3γ, providing a feedback mechanism to return UT-A1 function to its basal state following stimulation by vasopressin (Feng et al. 2015).

Acute Regulation of Urea Transport by Hyperosmolality

Depending upon the hydration status of an animal, the osmolality of the renal medulla varies over a wide range. Increasing osmolality rapidly increases urea permeability in rat terminal IMCDs, even in the absence of vasopressin, suggesting that hyperosmolality is an independent regulator of urea transport. Increasing osmolality has an additive stimulatory effect on urea permeability when vasopressin is present. Both phloretin and thiourea inhibit hyperosmolality-stimulated urea permeability. Hyperosmolality, like vasopressin, increases urea permeability by increasing the Vmax rather than the Km. However, these two agonists stimulate urea permeability through different signaling pathways: hyperosmolality via increases in intracellular calcium and PKC; and vasopressin via increases in cAMP and PKA activity. These various aspects of hyperosmolar influences on urea permeability are reviewed in Klein et al. (2011).

Hyperosomolality, like vasopressin, increases the phosphorylation and the plasma membrane accumulation of both UT-A1 and UT-A3 (Blessing et al. 2008). More specifically, UT-A1 is phosphorylated by PKCα (Klein et al. 2012; Wang et al. 2013). PKCα phosphorylates UT-A1 at S494 (Blount et al. 2015). A polyclonal antibody that specifically detects UT-A1 phosphorylated at the S494 site was used to confirm that activators of PKC, phorbol dibutyrate and hypertonicity, increase UT-A1 phosphorylation at S494, while activators of either PKA or Epac do not (Blount et al. 2015). The apical plasma membrane accumulation of UT-A1 is increased by activation of both PKA and PKC, but not by PKC alone (Blount et al. 2015). These findings suggest PKC-mediated phosphorylation of UT-A1 at S494 may increase vasopressin-stimulated urea transport by enhancing UT-A1 retention in the apical plasma membrane (Blount et al. 2015). Activation of PKCα also increases UT-A1 sialylation and UT-A1 accumulation in the apical plasma membrane (Li et al. 2015). The effect of PKCα on UT-A1 sialylation is mediated by Src kinase (Li et al. 2015). The effects of vasopressin and tonicity are compared in Table 2.
UT (Urea Transporter), Table 2

Comparison of vasopressin and hyperosmolality in the IMCD. Original citations are reviewed in Klein et al. (2011)




Signaling pathway

cAMP and adenylyl cyclase

Intracellular calcium and PKCα


Phloretin, thiourea

Phloretin, thiourea








Increases UT-A1 and UT-A3

Increases UT-A1 and UT-A3

Plasma membrane accumulation

Increases UT-A1 and UT-A3

Increases UT-A1 and UT-A3

UT-A Promoter I activity

No effect of cAMP (and no consensus CRE)

Increases via TonE and TonEBP

Acute Regulation of Urea Transport by Other Factors

In addition to vasopressin regulation of urea permeability, several other hormones and cAMP-independent pathways have been shown to affect urea transporter function. Angiotensin II increases both vasopressin-stimulated urea permeability and UT-A1 phosphorylation in rat terminal IMCDs via a PKC-mediated effect, although the exact PKC isoform has not been determined. Angiotensin II does not affect urea permeability in the absence of vasopressin (reviewed in Klein et al. (2011)). Increased levels of glucagon, another hormone that activates the production of cAMP, were shown to have varied effects on urea transport in different studies (reviewed in Klein et al. (2011)). In one study, glucagon decreased urea permeability in perfused rat terminal IMCDs and UT-A1 protein abundance by stimulating a PKC signaling pathway, while in other studies, glucagon did not alter basal or vasopressin-stimulated urea permeability, nor cAMP production, in either the initial or terminal IMCD (reviewed in Klein et al. (2011)). Oxytocin stimulates urea permeability by binding to V2-receptors and increasing cAMP production. Alpha-2 adrenergic agonists, such as clonidine and epinephrine, inhibit vasopressin-stimulated urea permeability in the rat terminal IMCD. Likewise, furosemide and amphotericin B also inhibit vasopressin-stimulated urea permeability; however, neither atrial natriuretic peptide nor insulin alters urea permeability in perfused rat terminal IMCDs (reviewed in Klein et al. (2011)). Recent studies demonstrate that adenosine monophosphate kinase (AMPK) can directly phosphorylate UT-A1 and metformin, an AMPK activator, increases urea permeability in perfused rat terminal IMCDs. Interestingly, stimulation of AMPK does not increase apical plasma membrane accumulation of UT-A1. This suggests that AMPK phosphorylates, and in turn activates, the UT-A1 transporters already present in the membrane to increase urea permeability (Klein et al. 2016a). These collective findings suggest that there are many other complex signaling cascades involved in urea transporter function that remain to be elucidated.

Long-Term Regulation of Urea Transport by Vasopressin

Vasopressin may also exert long-term regulation of UT-A1 and UT-A3 through changes in protein abundance. Two approaches that have been used to vary vasopressin levels in animals are (1) altering endogenous vasopressin levels by altering hydration status and (2) administering exogenous vasopressin, or dDAVP, a V2-selective vasopressin receptor agonist, to induce a constant high level of vasopressin.


Treating Brattleboro rats (which lack endogenous vasopressin) with vasopressin for 5 days decreases UT-A1 protein abundance in the inner medulla. Similarly, terminal IMCDs from water-loaded (3 days) rats have higher basal and higher vasopressin-stimulated urea permeabilities and increased UT-A1 expression by immunohistochemistry than from rats given water ad libitum. The changes in UT-A1 protein abundance in response to changes in vasopressin levels or hydration state do not appear to be regulated by transcription (reviewed in Klein et al. (2011)). When vasopressin is administered to Brattleboro rats for a longer period of time (12 days), UT-A1 protein abundance is significantly increased. Similarly, water-loaded (2 weeks) rats have significant decreases in UT-A1 protein abundance. The delayed increase in UT-A1 protein abundance following vasopressin administration to Brattleboro rats is consistent with the time course for the increase in inner medullary urea concentration (reviewed in Klein et al. (2011)). Analysis of the UT-A promoter I may explain this time course since it does not contain a cAMP response element (CRE) in the 1.3 kb that has been cloned and thus cAMP does not increase promoter I activity. However, a tonicity enhancer element (TonE) is present in the UT-A promoter I and hyperosmolality increases promoter activity. Thus, increasing vasopressin may initially increase the transcription of the Na-K-2Cl co-transporter, NKCC2/BSC1, in the thick ascending limb. Higher expression of NKCC2/BSC1 results in an increase in NaCl reabsorption which will, in turn, increase inner medullary osmolality, causing increased UT-A1 transcription through TonE (reviewed in Klein et al. (2011)).

UT-A2 and UT-A3

The mRNA abundances of UT-A2, UT-A2b, UT-A3, and UT-A3b are decreased in the inner medulla of 3 day water-loaded rats and increased in (1) 3 day water restricted rats and mice, (2) rats receiving dDAVP for 3 weeks, and (3) Brattleboro rats treated with vasopressin for 1 week (reviewed in Klein et al. (2011)). Expression of UT-A2 and UT-A3 protein is decreased in 3 day water-loaded rats without a change in the subcellular distribution of either urea transporter. UT-A2 protein abundance is increased by 7 days of dDAVP administration to Brattleboro rats. UT-A2 regulation could involve transcriptional mechanisms stimulated by vasopressin since UT-A2 is under the control of UT-A promoter II, which contains a CRE element and its promoter activity is increased by cAMP (reviewed in Klein et al. (2011)). UT-A3, like UT-A1, is under the control of UT-A promoter I, which contains TonE. Tonicity-responsive transcription of UT-A3 would explain the increased UT-A3 protein abundance observed in water deprived rats (reviewed in Klein et al. (2011)).

Urea Transporter Knockout Mice

Within the last decade, several animal models have been developed to examine the role of the urea transporters in vivo. Each was shown to have urine concentrating defects supporting the hypothesis that urea transporters must be present for proper urine concentration (reviewed in Klein et al. (2011)). The significant findings are discussed in detail below.

UT-A1/UT-A3 Knockout Mice.

Mice lacking both UT-A1 and UT-A3 have reduced urine concentrating ability, reduced inner medullary interstitial urea content, and lack of vasopressin-stimulated urea transport in their IMCD (reviewed in Fenton and Knepper (2007)). These mice are able to concentrate their urine almost as well as wild-type mice when both are fed a low-protein diet, supporting the hypothesis that IMCD urea transport contributes to urine concentrating ability by preventing urea-induced osmotic diuresis (reviewed in Fenton and Knepper (2007)). Inner medullary tissue urea content was markedly reduced following water restriction, but there was no measurable difference in NaCl content between UT-A1/UT-A3 knockout mice and wild-type mice (reviewed in Fenton and Knepper (2007)). This finding has been interpreted both as being inconsistent with the predictions of the passive mechanism and supporting it (reviewed in Fenton and Knepper (2007); Klein et al. (2011)).

UT-A3 Knockout Mice

To determine the effect of UT-A1 in the absence of UT-A3, a mouse expressing only UT-A1 was created by transgenic restoration of UT-A1 into the UT-A1/UT-A3 knockout mouse (Klein et al. 2016b). These mice with UT-A1 but lacking UT-A3 have normal values for basal urea permeability in the IMCD, but in contrast to IMCDs from wild-type mice, vasopressin does not stimulate urea permeability (Klein et al. 2016b). Interestingly, urine concentrating ability is restored in these mice with only UT-A1 expressed (Klein et al. 2016b).

UT-A2 Knockout Mice

Mice lacking UT-A2 mice have a reduced urine concentrating ability (reviewed in Fenton and Knepper 2007; Klein et al. 2011). The reduction in urine concentrating ability is less severe than in the UT-A1/UT-A3 knockout mice and likely results from impairment of urea recycling (reviewed in Fenton and Knepper 2007; Klein et al. 2011).

UT-B1 Knockout Mice

Mice lacking UT-B1 have impaired urine concentrating ability, achieving a maximal urine osmolality of 2400 mOsm/kg H2O as compared to 3400 in a wild-type mouse (reviewed in Fenton and Knepper 2007; Klein et al. 2011). This phenotype is similar to humans lacking UT-B1, the Kidd antigen, who are unable to concentrate their urine above 800 mOsm/kg H2O, even following overnight water deprivation and exogenous vasopressin administration (reviewed in Klein et al. 2011). These findings support the hypothesis that urea transport in red blood cells is necessary to preserve the efficiency of countercurrent exchange (reviewed in Fenton and Knepper 2007; Klein et al. 2011).

UT-B1/UT-A2 Knockout Mice

A mouse lacking both UT-B1 and UT-A2 was generated to investigate the relationship between urea handling by these two transporters, since they are located in adjacent structures in the medulla and since knockout of UT-B1 results in increased UT-A2 in UT-B1 knockout mice (reviewed in Klein et al. 2011). In contrast to what was expected, UT-A2 deletion appeared to partially correct the concentrating defect in mice with only UT-B1 knocked out (Lei et al. 2011). These findings suggest that UT-A2 may function to move urea during the transition from diuresis to antidiuresis in an acute response, rather than playing a role in maintaining urea concentration during the normal steady state (Lei et al. 2011).


Urea plays a critical role in the urinary concentrating mechanism and, therefore, in the regulation of the body’s water balance. The kidney needs to be able to regulate urea excretion in order to vary urine osmolality and maintain (or restore) plasma osmolality within (to) the normal range. Functional data suggested that urea transport in the IMCD was mediated by specific urea transporter proteins. Subsequent molecular approaches resulted in the cloning of two gene families for facilitated urea transporters, UT-A and UT-B. Since the identification of the four UT-A renal isoforms and UT-B in the vasa recta, great strides have been made toward the understanding of the regulatory signaling mechanisms that control urea permeability. Vasopressin and hypertonicity regulate UT-A1 and UT-A3 by changes in phosphorylation as well as by changes in plasma membrane accumulation. In addition to acute regulation by vasopressin, urea transporter protein abundance is regulated by chronic vasopressin exposure. Genetically engineered mice that lack any of the urea transporter proteins show that urea transporters play a critical role in the urine concentrating mechanism. Further use of advancing technology including the generation of transgenic animals and proteomic data will continue to elucidate the complex signaling cascades that regulate the urine concentration mechanism.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Mitsi A. Blount
    • 1
  • Janet D. Klein
    • 1
  • Jeff M. Sands
    • 1
  1. 1.Renal Division, Department of Medicine, and Department of PhysiologyEmory UniversityAtlantaUSA