Renal Phenotype of UT-A Urea Transporter Knockout Mice

Fenton, Robert A.; Flynn, Anneliese; Shodeinde, Adetola; Smith, Craig P.; Schnermann, Jürgen; Knepper, Mark A.

doi:10.1681/asn.2005010031

Cited by 113 publications

(127 citation statements)

References 44 publications

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“…It was shown recently in transgenic mice with a selective deficiency in UT-B (the urea transporter protein expressed in descending vasa recta and red blood cells) that lack of UT-B in normal conditions leads to a 44% elevation in plasma urea and to a 25% decrease in urea clearance (29). Recently, it was suggested that just like for uric acid, an active urea secretion does exist somewhere along the renal tubule (1,30). An age-related decrease in urea secretion could be another possible mechanism to explain our findings.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Increase in Plasma Urea Level and Decrease in Fractional Urea Excretion

Musch

Verfaillie

Decaux

2006

Clinical Journal of the American Society of Nephrology

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This study confirms in humans an age-related increase in plasma urea levels (r ‫؍‬ 0.62; P < 0.001; y ‫؍‬ 0.229x ؉ 18.26) and no correlation between plasma creatinine and age (r ‫؍‬ 0.06; NS). Fractional urea excretion (FE urea) decreases with age (r ‫؍‬ ؊0.41; P < 0.001; y ‫؍‬ ؊0.226x ؉ 55). Comparing urea and creatinine clearances, measured in 19 young and in 15 old women, a larger decrease of urea clearance (؊56%) compared with the creatinine clearance (؊43%) was observed as expected, explaining the lower FE urea in the elderly. In old women, the daily urea excretion was 27% and the daily creatinine excretion was 42% lower than in young women. An age-related decrease of same magnitude in both creatinine production and creatinine clearance explains why plasma creatinine remains stable with increasing age. The observation of a more important decrease in urea clearance (56%) than in urea production (27%) in older women led to an expected increase in plasma urea of 29%. These observations incited a comparison of biochemical profiles from younger and older patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Young patients with SIADH present lower mean plasma urea (18 ؎ 8 mg/dl) and higher mean FE urea (58 ؎ 14%), compared with both young control subjects (mean plasma urea 27 ؎ 7 mg/dl; mean FE urea 46 ؎ 10%) and old patients with SIADH (mean plasma urea 29 ؎ 8 mg/dl; mean FE urea 44 ؎ 15%). Physicians must realize that frankly low plasma urea values and high FE urea values can be expected only in young patients with SIADH, whereas old patients with SIADH will present values of plasma urea and FE urea in the same range than young control subjects. However, old patients with SIADH show still lower mean plasma urea values and higher mean FE urea values, compared with old control subjects (mean plasma urea 39 ؎ 8 mg/dl; mean FE urea 36 ؎ 9%), in whom plasma urea values between 40 and 50 mg/dl must be considered as usual.Clin J Am Soc Nephrol 1: 909 -914, 2006. doi: 10.2215/CJN.00320106 B oth plasma urea and fractional urea excretion (FE urea) are considered as useful biochemical parameters in the differential diagnosis of salt-depleted hyponatremic and patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (1-3). Hyponatremia in SIADH is usually associated with a low plasma urea as a result of a high FE urea (4), whereas in hyponatremia that is caused by salt depletion (SD), plasma urea usually is increased as a result of an abnormal low FE urea (5) (prerenal uremia). Unfortunately, the usefulness of plasma urea and FE urea in discriminating SIADH and SD is limited by an important degree of "overlapping" values. In earlier work (6), we noted that plasma urea values Ͼ30 mg/dl were observed in 82% of patients with SD, whereas plasma urea values Ͻ30 mg/dl were seen in 79% of patients with SIADH. Eighty-two percent of the patients with salt-depleted hyponatremic presented FE urea values Ͻ50%, but only 52% of the patients with SIADH showed FE urea values Ͼ50...

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Section: Discussionmentioning

confidence: 99%

Age-Related Increase in Plasma Urea Level and Decrease in Fractional Urea Excretion

Musch

Verfaillie

Decaux

2006

Clinical Journal of the American Society of Nephrology

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“…For testing of this hypothesis, the urinary concentrating function of UT-A1/3 Ϫ/Ϫ mice on three different levels of dietary protein intake was examined in a series of metabolic cage studies ( Figure 4) (37,42). With free access to water, UT-A1/3 Ϫ/Ϫ mice that were fed either a standard-protein (20% protein by weight) or high-protein (40%) diet had a significantly greater fluid intake and urine flow than wild-type controls, resulting in a decreased urine osmolality.…”

Section: Role Of Imcd Urea Transporters In the Urinary Concentrating mentioning

confidence: 99%

“…The conclusion from these data is that the role of IMCD urea transporters in water conservation is to prevent a urea-induced osmotic diuresis. Adapted from data in references (37,42).…”

Section: Accumulation Of Nacl In the Inner Medulla: Role Of Imcd Ureamentioning

confidence: 99%

Urea and Renal Function in the 21st Century

Fenton¹,

Knepper²

2007

Journal of the American Society of Nephrology

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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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“…The renal countercurrent mechanisms involve intrarenal urea recycling facilitated by urea transporters (UTs) expressed in renal tubule epithelial cells (UT-A, encoded by the SLc14A2 gene) and renal vasa recta microvessels (UT-B, encoded by the SLc14A1 gene). [3][4][5][6][7] Phenotype analysis of knockout mice lacking UT-B 8,9 or various UT-A isoforms [10][11][12] has provided evidence for the involvement of UTs in the urinary concentrating mechanism, subject to the caveat that gene knockout may produce off-target effects such as compensatory changes in the expression of non-UT transport proteins. 13,14 Although UT function has been studied mainly in the kidney, UTs are also expressed in erythrocytes as well as the testis, brain, heart, and urinary bladder.…”

mentioning

confidence: 99%

Triazolothienopyrimidine Inhibitors of Urea Transporter UT-B Reduce Urine Concentration

Yao

Anderson

Zhang

et al. 2012

Journal of the American Society of Nephrology

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Urea transport (UT) proteins facilitate the concentration of urine by the kidney, suggesting that inhibition of these proteins could have therapeutic use as a diuretic strategy. We screened 100,000 compounds for UT-B inhibition using an optical assay based on the hypotonic lysis of acetamide-loaded mouse erythrocytes. We identified a class of triazolothienopyrimidine UT-B inhibitors; the most potent compound, UTB inh -14, fully and reversibly inhibited urea transport with IC 50 values of 10 nM and 25 nM for human and mouse UT-B, respectively. UTB inh -14 competed with urea binding at an intracellular site on the UT-B protein. UTB inh -14 exhibited low toxicity and high selectivity for UT-B over UT-A isoforms. After intraperitoneal administration of UTB inh -14 in mice to achieve predicted therapeutic concentrations in the kidney, urine osmolality after administration of 1-deamino-8-D-arginine-vasopressin was approximately 700 mosm/kg H 2 O lower in UTB inh -14-treated mice than vehicle-treated mice. UTB inh -14 also increased urine output and reduced urine osmolality in mice given free access to water. UTB inh -14 did not reduce urine osmolality in UT-B knockout mice. In summary, these data provide proof of concept for the potential utility of UT inhibitors to reduce urinary concentration in high-vasopressin, fluid-retaining conditions. The diuretic mechanism of UT inhibitors may complement the action of conventional diuretics, which target sodium transport.

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Renal Phenotype of UT-A Urea Transporter Knockout Mice

Cited by 113 publications

References 44 publications

Age-Related Increase in Plasma Urea Level and Decrease in Fractional Urea Excretion

Age-Related Increase in Plasma Urea Level and Decrease in Fractional Urea Excretion

Urea and Renal Function in the 21st Century

Triazolothienopyrimidine Inhibitors of Urea Transporter UT-B Reduce Urine Concentration

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