Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter

Nakayama, Yushi; Naruse, Masahiro; Karakashian, Alexander A.; Peng, Tao; Sands, Jeff M.; Bagnasco, Serena M.

doi:10.1016/s0167-4781(00)00311-0

Cited by 68 publications

(68 citation statements)

References 20 publications

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“…1. Based on the previously identified structure of the UT-A gene, we decided to delete the promoter region and first noncoding exon (exon 13) of the UT-A2 gene, since all other UT-A2 exons are also present in UT-A1 (2), but UT-A2 is driven by a different promoter (14). Genomic Southern blot of mouse tail genomic DNA digested with EcoRI ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Impaired Urea Accumulation in the Inner Medulla of Mice Lacking the Urea Transporter UT-A2

Uchida

Sohara

Rai

et al. 2005

Molecular and Cellular Biology

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Urea transporter UT-A2, the major urea transporter of the thin descending limb of the loop of Henle in short loop nephrons, has been implicated in urea recycling in the medulla, thereby producing concentrated urine. To investigate the physiological role of UT-A2 in vivo, we generated UT-A2-selective knockout mice by deleting the UT-A2 promoter. Western analysis, immunohistochemistry, and quantitative reverse transcription-PCR were used to confirm the specific deletion of UT-A2 with preservation of other UT-A transporters. Compared to wild-type mice, differences in the urine outputs of UT-A2 ؊/؊ mice consuming a normal protein diet (20% protein) were not observed under normal conditions or with dehydration. Likewise, impairment of urea accumulation in the inner medulla of UT-A2 ؊/؊ mice was not observed. On a low-protein diet (4% protein), however, significantly reduced maximal urine osmolality was observed in dehydrated UT-A2 ؊/؊ mice compared to wild-type littermates (2,500 mosmol versus 3,450 mosmol, respectively). A significant reduction in urea accumulation in the inner medulla was also observed in UT-A2 ؊/؊ mice; however, differences in Na ؉ and Cl ؊ accumulation were not observed. Thus, UT-A2 is important for maintaining a high concentration of urea in the inner medulla when urea supply to the kidney is limited.

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Section: Resultsmentioning

confidence: 99%

“…Although UT-A2 shares several exons with UT-A1, transcription of UT-A2 is governed by a different promoter than UT-A1, UT-A3, or UT-A4 (2,14). Its intrarenal localization also differs from that of UT-A1, UT-A3, or UT-A4.…”

mentioning

confidence: 99%

Impaired Urea Accumulation in the Inner Medulla of Mice Lacking the Urea Transporter UT-A2

Uchida

Sohara

Rai

et al. 2005

Molecular and Cellular Biology

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“…In the present study, there did appear to be a urea-sensitive component to tUT mRNA expression; however, blood pH in toadfish infused with urea was not measured and thus it cannot be conclusively ruled out that acidosis was a contributing factor. An increased expression of UT-A2 transporters has also been shown to occur in response to the hydration state of the animal (Smith et al, 1995), with the increase in transcription resulting from the activation of the UT-A promoter by cAMP-dependent pathways (Nakayama et al, 2001). Changes in hydration status based on the volume loading experienced by both cortisol-infused and ureainfused fish would not explain the significant difference in tUT transcription measured between these two groups.…”

Section: D Mcdonald and Othersmentioning

confidence: 97%

Urea transporter and glutamine synthetase regulation and localization in gulf toadfish gill

McDonald

Vulesevic

Perry

et al. 2009

Journal of Experimental Biology

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SUMMARYThe goal of the present study was to investigate the role of circulating cortisol and urea in the transcriptional regulation of branchial glutamine synthetase (GS), which incorporates NH 3 into glutamate to form glutamine, and the toadfish urea transporter, tUT, which is involved in urea excretion across the gill of the gulf toadfish. GS (of which there are two isoforms, LGS and GGS) and tUT mRNA expression and activity were measured in toadfish exposed to treatments that would induce variable stress responses. In addition, the role of circulating urea in tUT regulation was investigated by infusing toadfish with urea alone or in combination with intraperitoneal injection of RU486, a corticosteroid type II receptor antagonist. There was a 4.8-fold upregulation in the mRNA expression of the gill-specific GS isoform (GGS) in response to cortisol infusion and a similar upregulation in the more ubiquitous isoform (LGS). Furthermore, there was a significant 1.9-fold and 3.3-fold upregulation in the mRNA expression of the toadfish urea transporter, tUT, in response to stress through crowding or exogenous cortisol loading through infusion, respectively. In addition, tUT was found to have a urea-sensitive component to transcriptional regulation that was independent of circulating cortisol concentrations. However, the changes measured in mRNA expression of GGS, LGS and tUT did not correspond with changes in protein activity. To determine the cell type(s) involved in glutamine production and urea excretion, we attempted to localize GGS, LGS and tUT using in situ hybridization. This study is the first to show that GGS and tUT expression appear to occur in gill mitochondria-rich cells of toadfish, suggesting that these cells play a combined glutamine production and urea excretion role, which may have implications for predator avoidance.

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“…There are two distinct but closely related urea transporter genes: UT-A (Slc14a2) and UT-B (Slc14a1) (15)(16)(17). Several urea transporter isoforms are derived from the UT-A gene via alternative splicing and alternative promotors ( Figure 2) (15).…”

Section: Urea Transportersmentioning

confidence: 99%

Urea and Renal Function in the 21st Century

Fenton¹,

Knepper²

2007

Journal of the American Society of Nephrology

115

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Since the turn of the 21st century, gene knockout mice have been created for all major urea transporters that are expressed in the kidney: the collecting duct urea transporters UT-A1 and UT-A3, the descending thin limb isoform UT-A2, and the descending vasa recta isoform UT-B. This article discusses the new insights that the results from studies in these mice have produced in the understanding of the role of urea in the urinary concentrating mechanism and kidney function. Following is a summary of the major findings: (1) Urea accumulation in the inner medullary interstitium depends on rapid transport of urea from the inner medullary collecting duct (IMCD) lumen via UT-A1 and/or UT-A3; (2) as proposed by Robert Berliner and colleagues in the 1950s, the role of IMCD urea transporters in water conservation is to prevent a urea-induced osmotic diuresis; (3) the absence of IMCD urea transport does not prevent the concentration of NaCl in the inner medulla, contrary to what would be predicted from the passive countercurrent multiplier mechanism in the form proposed by Kokko and Rector and Stephenson; (4) deletion of UT-B (vasa recta isoform) has a much greater effect on urinary concentration than deletion of UT-A2 (descending limb isoform), suggesting that the recycling of urea between the vasa recta and the renal tubules quantitatively is less important than classic countercurrent exchange; and (5) urea reabsorption from the IMCD and the process of urea recycling are not important elements of the mechanism of protein-induced increases in GFR. In addition, the clinical relevance of these studies is discussed, and it is suggested that inhibitors that specifically target collecting duct urea transporters have the potential for clinical use as potassium-sparing diuretics that function by creation of urea-dependent osmotic diuresis.

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Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter

Cited by 68 publications

References 20 publications

Impaired Urea Accumulation in the Inner Medulla of Mice Lacking the Urea Transporter UT-A2

Impaired Urea Accumulation in the Inner Medulla of Mice Lacking the Urea Transporter UT-A2

Urea transporter and glutamine synthetase regulation and localization in gulf toadfish gill

Urea and Renal Function in the 21st Century

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