Alternative titles; symbols
HGNC Approved Gene Symbol: SLC14A2
Cytogenetic location: 18q12.3 Genomic coordinates (GRCh38): 18:45,167,963-45,683,688 (from NCBI)
In mammalian cells, urea is the chief end-product of nitrogen catabolism and plays an important role in the urinary concentration mechanism. Thus, the plasma membrane of erythrocytes and some renal epithelial cells exhibit an elevated urea permeability that is mediated by highly selective urea transporters. In mammals, 2 urea transporters have been identified: the renal tubular urea transporter, UT2, and the erythrocyte urea transporter, UT11 (SLC14A1; 613868) (summary by Olives et al., 1996).
By homology cloning from a human kidney library, Olives et al. (1996) isolated a cDNA clone sharing 61.1% and 89.9% sequence identity with the human erythroid (UT11) and rabbit urea (Ut2) transporters, respectively. Transcripts of this human UT2 homolog were restricted to the kidney, and the polypeptide was not immunoprecipitated with blood group Kidd-related antibodies.
Bagnasco et al. (2001) stated that there are at least 4 Uta splice variants expressed in rat kidney, and that the UT11 cDNA cloned by Olives et al. (1996) is homologous to rat Uta2. By RT-PCR of normal human kidney total RNA using primers designed from rat Uta1, followed by 5-prime and 3-prime RACE, Bagnasco et al. (2001) cloned UTA1. The deduced 920-amino acid protein has a calculated molecular mass of 101 kD. Hydropathy analysis detected several transmembrane regions. UTA1 has several putative phosphorylation sites within the intracellular domains, including 4 cAMP-dependent phosphorylation sites. Northern blot analysis detected transcripts of 6.5, 4.4, and 2.2 kb in the inner medulla but not in the cortex of human kidney. Western blot analysis detected endogenous UTA1 at an apparent molecular mass of 100 kD in human inner medulla. Transfected human embryonic kidney cells showed UTA1 at an apparent molecular mass of 97 kD.
Using functional expression studies in Xenopus oocytes, Olives et al. (1996) demonstrated that human UT2-mediated urea transport was not inhibited by p-chloromercuribenzene sulfonate, which, however, inhibited the urea flux mediated by human UT11. These findings demonstrated the existence of at least 2 distinct urea transporters in human tissues.
By expression studies in Xenopus oocytes, Bagnasco et al. (2001) determined that UTA1 supported Na(+)-independent and phloretin-inhibitable urea uptake. Due to only modest stimulation by cAMP, the authors concluded that vasopressin may have a limited role in the short-term regulation of UTA1-mediated urea transport within the human inner medullary collecting duct.
Fenton et al. (2002) found that activity of the mouse Uta-alpha promoter, which drives expression of Uta1 and Uta3, was activated by cAMP agonists and regulated by the tonicity of the culture medium. The Uta-beta promoter, which drives expression of Uta2, was activated by cAMP agonists, but not by tonicity. The levels of Uta2 and Uta3 mRNA were increased in thirsted mice compared with controls, indicating that the activities of both promoters are likely elevated during prolonged antidiuresis.
Bagnasco et al. (2001) determined that the SLC14A2 gene contains 20 exons and spans about 67.5 kb. The translation start codon for UTA1 is in exon 2, and the start codon for UTA2 is in exon 13. The region upstream of the UTA1 start codon contains 2 CAAT motifs, but no TATA box and no tonicity enhancer (TonE) motif, which mediates tonicity-responsive gene transcription. Bagnasco et al. (2001) noted that the human SLC14A2 gene is significantly smaller than the rat Slc14a2 gene and shows a different structural organization.
Fenton et al. (2002) determined that the mouse Slc14A2 gene contains 24 exons and spans more than 300 kb, similar to the rat gene. It has 2 distinct promoters: Uta-alpha, which lies 5-prime to exon 1, contains a well-defined TonE motif, and drives expression of Uta1 and Uta3, and Uta-beta, which lies within intron 13 and drives expression of Uta2, which has a translation start codon in exon 17.
By isotopic in situ hybridization, Olives et al. (1996) mapped the human UT2 gene to chromosome 18q12.1-q21.1. This is the same region as that for the Kidd/urea transporter SLC14A1, suggesting that the 2 genes evolved by duplication of a common ancestor.
Fenton et al. (2002) stated that the mouse Slc14a2 gene maps to chromosome 18 and is arranged in tandem with Slc14a1.
Genetic variation in proteins that determine sodium reabsorption and excretion significantly influences blood pressure. Ranade et al. (2001) investigated whether nucleotide variation in human UT2 could be associated with variation in blood pressure. Seven single-nucleotide polymorphisms (SNPs) were identified, including val227 to ile and ala357 to thr. Over 1,000 hypertensive and low-normotensive individuals of Chinese origin were genotyped. The ile227 and ala357 alleles were associated with low diastolic blood pressure in men but not women, with odds ratios 2.1 (95% confidence interval 1.5-2.7, P less than 0.001) and 1.5 (95% confidence interval 1.2-1.8, P less than 0.001), respectively. There was a similar trend for systolic blood pressure, and odds ratios for the ile227 and ala357 alleles were 1.7 (95% confidence interval 1.2-2.3, P = 0.002) and 1.3 (95% confidence interval 1.1-1.6, P = 0.007), respectively, in men.
By disrupting the mouse Uta-alpha promoter, Fenton et al. (2004) produced mice that lacked expression of Uta1 and Uta3. Homozygous-null mice appeared normal and were fertile. Inner medullary collecting ducts from these mice showed a complete absence of phloretin-sensitive or vasopressin-stimulated urea transport. After water restriction, the inner medullary tissue showed a marked depletion in urea. There were no significant differences in mean inner medullary Na(+) or Cl(-) concentrations between homozygous-null and wildtype mice.
Bagnasco, S. M., Peng, T., Janech, M. G., Karakashian, A., Sands, J. M. 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. [PubMed: 11502588] [Full Text: https://doi.org/10.1152/ajprenal.2001.281.3.F400]
Fenton, R. A., Chou, C.-L., Stewart, G. S., Smith, C. P., Knepper, M. A. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc. Nat. Acad. Sci. 101: 7469-7474, 2004. [PubMed: 15123796] [Full Text: https://doi.org/10.1073/pnas.0401704101]
Fenton, R. A., Cottingham, C. A., Stewart, G. S., Howorth, A., Hewitt, J. A., Smith, C. P. Structure and characterization of the mouse UT-A gene (Slc14a2). Am. J. Physiol. Renal Physiol. 282: F630-F638, 2002. [PubMed: 11880324] [Full Text: https://doi.org/10.1152/ajprenal.00264.2001]
Olives, B., Martial, S., Mattei, M.-G., Matassi, G., Rousselet, G., Ripoche, P., Cartron, J.-P., Bailly, P. Molecular characterization of a new urea transporter in the human kidney. FEBS Lett. 386: 156-160, 1996. [PubMed: 8647271] [Full Text: https://doi.org/10.1016/0014-5793(96)00425-5]
Ranade, K., Wu, K.-W., Hwu, C.-M., Ting, C.-T., Pei, D., Pesich, R., Hebert, J., Chen, Y.-D. I., Pratt, R., Olshen, R., Masaki, K., Risch, N., Cox, D. R., Botstein, D. Genetic variation in the human urea transporter-2 is associated with variation in blood pressure. Hum. Molec. Genet. 10: 2157-2164, 2001. [PubMed: 11590132] [Full Text: https://doi.org/10.1093/hmg/10.19.2157]