Urea transport and clinical potential of urearetics

Klein, Janet D.; Sands, Jeff M.

doi:10.1097/mnh.0000000000000252

Cited by 25 publications

(16 citation statements)

References 65 publications

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“…In addition, UT-B inhibitors are being developed for diuretic targeting and may overcome the side effects, such as hypernatremia of conventional diuretics because UT-B inhibitors usually do not change serum sodium, chlorine or potassium levels. Therefore, UT-B inhibitors may be particularly useful in reducing circulation volume in patients with congestive heart failure [35].…”

Section: Ut-b Proteinsmentioning

confidence: 99%

Physiological functions of urea transporter B

Liu

et al. 2019

Pflugers Arch - Eur J Physiol

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Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.

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Section: Ut-b Proteinsmentioning

confidence: 99%

Physiological functions of urea transporter B

Liu

et al. 2019

Pflugers Arch - Eur J Physiol

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“…The concentration of urea in uremic patients sweat is increased significantly. Urea transporters (UTs) are widely expressed in the kidney and red blood cells of human and other mammal animals, encoded by Slc14a2 (UT-A) and Slc14a1 (UT-B), which mediate urea flux across cellular membranes of inner medullary collecting duct cells, playing a major role in the urinary concentrating mechanism [ 19 , 20 ]. Of the UTs, the UT-A family are mostly restricted in renal tubular epithelia, while UT-B1 is also abundantly expressed in red cells.…”

Section: Discussionmentioning

confidence: 99%

The Expression of AQP5 and UTs in the Sweat Glands of Uremic Patients

Xie

Jin

Feng

et al. 2017

BioMed Research International

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Purpose To research the distribution and quantitative changes of UT-A1, UT-B1, and AQP5 in uremic skin tissue. Methods 34 cases of uremic patients (UP) and 11 controls were recruited. Immunohistochemistry, immunofluorescence, RT-PCR, and Western Blot were used to identify the proteins in sweat glands. Results AQP5, UT-A1, and UT-B1 were expressed and localized in human skin basal lines, skin sweat glands, and sweat ducts, both in UP and controls. Compared to controls, AQP5 mRNA abundance was significantly decreased in UP (P < 0.01), and, with the decrease of eGFR, the AQP5 expression was significantly decreased (P < 0.05). By contrast, UT-A1 and UT-B1 mRNA abundance was significantly increased in the skin of UP compared with the control (P < 0.01), and, with the decrease of eGFR, the AQP5 expression was significantly increased (P < 0.05). We found that the gene changes were coincident with the corresponding target proteins. The urea transporter subtypes, UT-A1 and UT-B1, were expressed in the skin basal cell layer and exocrine sweat glands. The abundance of UT-A1 and UT-B1 in uremic sweat glands was significantly increased in UP, while the expression of AQP5 was decreased. Conclusion Elimination of urea through the skin by producing sweat is a potential therapeutic strategy for renal failure patients.

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“…1–6 Unlike available diuretics, UT inhibition disrupts the renal countercurrent mechanisms, which are required for the generation of a concentrated urine, producing a diuretic response with relative salt-sparing. Evidence for this mechanism comes from studies in transgenic mice lacking various UTs, 7–13 from mathematical modeling of urinary concentration, 14 and from rodent studies with administration of UT inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1

Lee¹,

Çil²,

Diez‐Cecilia

et al. 2018

J. Med. Chem.

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Urea transporter A (UT-A) isoforms encoded by the Slc14a2 gene are expressed in kidney tubule epithelial cells, where they facilitate urinary concentration. UT-A1 inhibition is predicted to produce a unique salt-sparing diuretic action in edema and hyponatremia. Here we report the discovery of 1,2,4-triazoloquinoxalines and the analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4-triazolo[4,3-a]quinoxaline-substituted benzenesulfonamide linked by an aryl ether, rapidly and reversibly inhibited UT-A1 urea transport by a noncompetitive mechanism with IC50 ≈ 150 nM; the IC50 was ~2 µM for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding site on the UT-A1 cytoplasmic domain. In vitro metabolism showing quinoxaline ring oxidation prompted the synthesis of metabolically stable 7,8-difluoroquinoxaline analogue 8bl, which when administered to rats produced marked diuresis and reduced urinary osmolality. 8bl has substantially improved UT-A1 inhibition potency and metabolic stability compared with prior compounds.

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Urea transport and clinical potential of urearetics

Cited by 25 publications

References 65 publications

Physiological functions of urea transporter B

Physiological functions of urea transporter B

The Expression of AQP5 and UTs in the Sweat Glands of Uremic Patients

Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1

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