Functional asymmetry of the urea transporter UT-B in human red blood cells.

We studied urea, thiourea, and methylurea transport and interaction in human red blood cells (RBCs) under conditions of self-exchange (SE), net efflux (NE), and net influx (NI) at pH 7.2. We combined four methods, a four-centrifuge technique, the Millipore-Swinnex filtering technique, the continuous flow tube method, and a continuous pump method to measure the transport of the 14C-labeled compounds. Under SE conditions, both urea and thiourea show perfect Michaelis-Menten kinetics with half-saturation constants, K½,SE (mM), of ≈300 (urea) and ≈20 (thiourea). The solutes show no concentration-dependent saturation under NE conditions. Under NI conditions, transport displays saturation or self-inhibition kinetics with a K½,NI (mM) of ≈210 (urea) and ≈20 (thiourea). Urea, thiourea, and methylurea are competitive inhibitors of the transport of analog solutes. This study supports the hypothesis that the three compounds share the same urea transport system (UT-B). UT-B functions asymmetrically as it saturates from the outside only under SE and NI conditions, whereas it functions as a high-capacity channel-like transporter under NE conditions. When the red blood cell enters the urea-rich kidney tissue, self-inhibition reduces the urea uptake in the cell. When the cell leaves the kidney, the channel-like function of UT-B implies that intracellular urea rapidly equilibrates with external urea. The net result is that the cell during the passage in the kidney capillaries carries urea to the kidney to be excreted while the urea transfer from the kidney via the bloodstream is minimized.NEW & NOTEWORTHY The kinetics of urea transport in red blood cells was determined by means of a combination of four methods that ensures a high time resolution. In the present study, we disclose that the urea transporter UT-B functions highly asymmetric being channel-like with no saturation under conditions of net efflux and saturable under conditions of net influx and self-exchange in the concentration range 1-1,000 mM (pH 7.2 and 25-38 °C).

A potential link between AQP3 and SLC14A1 gene expression level and clinical parameters of maintenance hemodialysis patients.

BACKGROUND: The transport of water and urea through the erythrocyte membrane is facilitated by aquaporins such as aquaglyceroporin (AQP3), and type B urea transporters (UT-B). As they may play an important role in osmotic balance of maintenance hemodialysis (HD) patients, the aim of the present study was to determine whether any relationship exists between the expression of their genes and the biochemical / clinical parameters in HD patients. METHODS: AQP3 and UT-B (SLC14A1) gene expression was evaluated using RT-qPCR analysis in 76 HD patients and 35 participants with no kidney failure. RESULTS: The HD group demonstrated significantly higher median expression of AQP3 and UT-B (Z = 2.16; P = 0.03 and Z = 8.82; p < 0.0001, respectively) than controls. AQP3 negatively correlated with pre-dialysis urea serum concentration (R = -0.22; P = 0.049) and sodium gradient (R = -0.31; P = 0.04); however, no significant UT-B correlations were observed. Regarding the cause of end-stage kidney disease, AQP3 expression positively correlated with erythropoietin dosages in the chronic glomerulonephritis (GN) subgroup (R = 0.6; P = 0.003), but negatively in the diabetic nephropathy subgroup (R = -0.59; P = 0.004). UT-B positively correlated with inter-dialytic weight gain% in the GN subgroup (R = 0.47; P = 0.03). CONCLUSION: Maintenance hemodialysis seems significantly modify AQP3 and UT-B expression but their link to clinical and biochemical parameters needs further large-scale evaluation.

Inhibition of Urea Transporter (UT)-B Modulates LPS-Induced Inflammatory Responses in BV2 Microglia and N2a Neuroblastoma Cells.

Urea is the major nitrogen-containing product of protein metabolism, and the urea cycle is intrinsically linked to nitric oxide (NO) production via the common substrate L-arginine. Urea accumulates in the brain in neurodegenerative states, including Alzheimer's and Huntington's disease. Urea transporter B (UT-B, SLC14A1) is the primary transport protein for urea in the CNS, identified most abundantly in astrocytes. Moreover, enhanced expression of the Slc14a1 gene has been reported under neurodegenerative conditions. While the role of UT-B in disease pathology remains unclear, UT-B-deficient mice display behavioural impairment coupled with urea accumulation, NO disruption and neuronal loss. Recognising the role of inflammation in neurodegenerative disease pathology, the current short study evaluates the role of UT-B in regulating inflammatory responses. Using the specific inhibitor UTBinh-14, we investigated the impact of UT-B inhibition on LPS-induced changes in BV2 microglia and N2a neuroblastoma cells. We found that UTBinh-14 significantly attenuated LPS-induced production of TNFα and IL-6 from BV2 cells, accompanied by reduced release of NO. While we observed a similar reduction in supernatant concentration of IL-6 from N2a cells, the LPS-stimulated NO release was further augmented by UTBinh-14. These changes were accompanied by a small, but significant downregulation in UT-B expression in both cell types following incubation with LPS, which was not restored by UTBinh-14. Taken together, the current evidence implicates UT-B in regulation of inflammatory responses in microglia and neuronal-like cells. Moreover, our findings offer support for the further investigation of UT-B as a novel therapeutic target for neuroinflammatory conditions.

Physiological functions of urea transporter B.

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.

Urea-modulated UT-B urea transporter internalization is clathrin- and caveolae-dependent in infantile hemangioma-derived vascular endothelial cells.

The aim of this study was to investigate the manner of urea-modulated UT-B urea transporter (UT) internalization in infantile hemangioma-derived vascular endothelial cells (HemECs). The immunohistochemistry assay was performed to identify infancy hemangioma-derived endothelial cell line (XPTS-1) cells. Cell toxicity was detected with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Quantitative real-time polymerase chain reaction and Western blot analysis were measured to analyze the expression of UT-B. UT-B internalization was observed by confocal microscopy. The clathrin inhibitor chlorpromazine (CPZ) and caveolin endocytic disrupter methyl-ß-cyclodextrin (MßCD) were used in XPTS-1 cells transfected with UT-B-GFP to repress endocytosis. Urea-promoted UT-B expression in a concentration-dependent manner in an infantile XPTS-1 cell line. CPZ and MßCD significantly inhibited UT-B protein internalization. The pretreatment of UT-B-GFP cells with adaptor protein2 (AP2)-µ2-siRNA and caveolin-siRNA significantly inhibited UT-B protein internalization. Our findings suggested that urea-mediated UT-B UT internalization is clathrin and caveolae dependent in infantile HemECs.

Urea transport B gene induces melanoma B16 cell death via activation of p53 and mitochondrial apoptosis.

Urea Transporter B (UT-B) is a membrane channel protein that mediates the rapid transmembrane transport of urea and participates in urine concentration. Urea Transporter B is expressed in skin, but we found that there is little expression in human melanoma tissue. In this study, we examined the effects of UT-B overexpression in melanoma. The results indicated that there is no UT-B mRNA expression in B16 cells, and UT-B overexpression repressed B16 cell proliferation and induced apoptosis in vitro. We show that UT-B overexpression causes increased reactive oxygen species production, which may be caused by mitochondria dysfunction. The mitochondrial membrane potential (ΨΔm) was lower in UT-B-overexpressing B16 cells. The proteins involved in complexes I, III, IV and V of the respiratory chain were clearly downregulated in UT-B-overexpressing B16 cells, which would strongly reduce the activity of the electron transport chain. We found that mitochondrial release of cytochrome C into the cytoplasm also increased, indicating that apoptosis had been activated. In addition, UT-B overexpression reduced AKT phosphorylation and MDM2 expression and increased p53 expression; p53 activation may be involved in the anticancer effects of UT-B overexpression. Urea Transporter B overexpression also inhibited tumor growth in vivo. In conclusion, we demonstrated that UT-B may be related to the occurrence of melanoma and play a role in tumor development.

UT-B Urea Transporter Localization in the Bovine Gastrointestinal Tract.

Facilitative UT-B urea transporters play an important role in the urea nitrogen salvaging process that occurs in the gastrointestinal tract of mammals, particularly ruminants. Gastrointestinal UT-B transporters have previously been reported in various ruminant species-including cow, sheep and goat. In this present study, UT-B transporter localization was investigated in tissues throughout the bovine gastrointestinal tract. RT-PCR analysis showed that UT-B2 was the predominant UT-B mRNA transcript expressed in dorsal, ventral and cranial ruminal sacs, while alternative UT-B transcripts were present in other gastrointestinal tissues. Immunoblotting analysis detected a strong, glycosylated ~50 kDa UT-B2 protein in all three ruminal sacs. Immunolocalization studies showed that UT-B2 protein was predominantly localized to the plasma membrane of cells in the stratum basale layer of all ruminal sac papillae. In contrast, other UT-B protein staining was detected in the basolateral membranes of the surface epithelial cells lining the abomasum, colon and rectum. Overall, these findings confirm that UT-B2 cellular localization is similar in all ruminal sacs and that other UT-B proteins are located in epithelial cells lining various tissues in the bovine gastrointestinal tract.

Architecture of the human renal inner medulla and functional implications.

The architecture of the inner stripe of the outer medulla of the human kidney has long been known to exhibit distinctive configurations; however, inner medullary architecture remains poorly defined. Using immunohistochemistry with segment-specific antibodies for membrane fluid and solute transporters and other proteins, we identified a number of distinctive functional features of human inner medulla. In the outer inner medulla, aquaporin-1 (AQP1)-positive long-loop descending thin limbs (DTLs) lie alongside descending and ascending vasa recta (DVR, AVR) within vascular bundles. These vascular bundles are continuations of outer medullary vascular bundles. Bundles containing DTLs and vasa recta lie at the margins of coalescing collecting duct (CD) clusters, thereby forming two regions, the vascular bundle region and the CD cluster region. Although AQP1 and urea transporter UT-B are abundantly expressed in long-loop DTLs and DVR, respectively, their expression declines with depth below the outer medulla. Transcellular water and urea fluxes likely decline in these segments at progressively deeper levels. Smooth muscle myosin heavy chain protein is also expressed in DVR of the inner stripe and the upper inner medulla, but is sparsely expressed at deeper inner medullary levels. In rodent inner medulla, fenestrated capillaries abut CDs along their entire length, paralleling ascending thin limbs (ATLs), forming distinct compartments (interstitial nodal spaces; INSs); however, in humans this architecture rarely occurs. Thus INSs are relatively infrequent in the human inner medulla, unlike in the rodent where they are abundant. UT-B is expressed within the papillary epithelium of the lower inner medulla, indicating a transcellular pathway for urea across this epithelium.

High salt-diet reduces SLC14A1 gene expression in the choroid plexus of Dahl salt sensitive rats.

Elevated Na(+) concentration ([Na(+)]) in the cerebrospinal fluid (CSF) contributes to the development of salt-sensitive hypertension. CSF is formed by the choroid plexus (CP) in cerebral ventricles, and [Na(+)] in CSF is controlled by transporters in CP. Here, we examined the effect of high salt diet on the expression of urea transporters (UTs) in the CP of Dahl S vs Dahl R rats using real time PCR. High salt intake (8%, for 2 weeks) did not alter the mRNA levels of UT-A (encoded by SLC14A2 gene) in the CP of either Dahl S or Dahl R rats. In contrast, the mRNA levels of UT-B (encoded by SLC14A1 gene) were significantly reduced in the CP of Dahl S rats on high salt diet as compared with Dahl R rats or Dahl S rats on normal salt diet. Reduced UT-B expression was associated with increased [Na(+)] in the CSF and elevated mean arterial pressure (MAP) in Dahl S rats treated with high salt diet, as measured by radiotelemetry. High salt diet-induced reduction in UT-B protein expression in the CP of Dahl S rats was confirmed by Western blot. Immunohistochemistry using UT-B specific antibodies demonstrated that UT-B protein was expressed on the epithelial cells in the CP. These data indicate that high salt diet induces elevations in CSF [Na(+)] and in MAP, both of which are associated with reduced UT-B expression in the CP of Dahl S rats, as compared with Dahl R rats. The results suggest that altered UT-B expression in the CP may contribute to an imbalance of water and electrolytes in the CSF of Dahl S rats on high salt diet, thereby leading to alterations in MAP.

Short-chain fatty acids and acidic pH upregulate UT-B, GPR41, and GPR4 in rumen epithelial cells of goats.

Currently, the mechanism(s) responsible for the regulation of urea transporter B (UT-B) expression levels in the epithelium of the rumen remain unclear. We hypothesized that rumen fermentation products affect ruminal UT-B expression. Therefore, the effects of short-chain fatty acids (SCFA), pH, ammonia, and urea on mRNA and protein levels of UT-B were assayed in primary rumen epithelial cell cultures and in rumen epithelium obtained from intact goats. In vitro, SCFA and acidic pH were found to synergetically stimulate both mRNA and protein expression of UT-B, whereas NH4Cl decreased mRNA and protein levels of UT-B at pH 6.8. Treatment with urea increased both levels at pH 7.4. When goats received a diet rich in nitrogen (N) and nonfiber carbohydrates (NFC), their rumen epithelium had higher levels of UT-B, and the rumen contained higher concentrations of SCFA and NH3-N with a lower pH. An increase in plasma urea-N concentration was also observed compared with the plasma of the goats that received a diet low in N and NFC. In a second feeding trial, goats that received a NFC-rich, but isonitrogenous, diet had higher mRNA and protein levels of UT-B, and higher levels of G protein-coupled receptor (GPR) 41 and GPR4, in their rumen epithelium. The ruminal concentrations of SCFA and NH3-N also increased, while a lower pH was detected. In contrast, the serum urea-N concentrations remained unchanged. These data indicate that ruminal SCFA and pH are key factors, via GPR4 and GPR41, in the dietary regulation of UT-B expression, and they have priority over changes in plasma urea.

Computational exploration of SLC14A1 genetic variants through structure modeling, protein-ligand docking, and molecular dynamics simulation.

The urea transporter UT-B1, encoded by the SLC14A1 gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of bladder cancer and many other diseases. Several studies reported the association of genetic alterations in the SLC14A1 (UT-B1) gene with bladder carcinogenesis, suggesting a need for thorough characterization of the UT-B1 protein's coding and non-coding variants. This study used various computational techniques to investigate the commonly occurring germ-line missense and non-coding SNPs (ncSNPs) of the SLC14A1 gene (UT-B1) for their structural, functional, and molecular implications for disease susceptibility and dysfunctionality. SLC14A1 missense variants, primarily identified from the ENSEMBL genome browser, were screened through twelve functionality prediction tools leading to two variants D280Y (predicted detrimental by maximum tools) and D280N (high global MAF) for rs1058396. Subsequently, the ConSurf and NetSurf tools revealed the D280 residue to be in a variable site and exposed on the protein surface. According to I-Mutant2.0 and MUpro, both variants are predicted to cause a significant effect on protein stability. Analysis of molecular docking anticipated these two variants to decrease the binding affinity of UT-B1 protein for the examined ligands to a significant extent. Molecular dynamics also disclosed the possible destabilization of the UT-B1 protein due to single nucleotide polymorphism compared to wild-type protein which may result in impaired protein function. Furthermore, several non-coding SNPs were estimated to affect transcription factor binding and regulation of SLC14A1 gene expression. Additionally, two ncSNPs were found to affect miRNA-based post-transcriptional regulation by creating new seed regions for miRNA binding. This comprehensive in-silico study of SLC14A1 gene variants may serve as a springboard for future large-scale investigations examining SLC14A1 polymorphisms.

Regional investigation of UT-B urea transporters in the rat brain.

Recent studies have reported increased levels of urea in the aging brain and various neurological disorders. Additionally, these diseased tissues also have increased expression of the UT-B transporter that regulates urea transport in the brain. However, little is known regarding the actual UT-B protein distribution across the brain in either normal or diseased states. This current study investigated UT-B protein abundance across three regions of the rat brain - anterior, posterior and cerebellum. Endpoint RT-PCR experiments showed that there were no regional differences in UT-B RNA expression (NS, N = 3, ANOVA), whilst Western blotting confirmed no difference in the abundance of a 35 kDa UT-B protein (NS, N = 3-4, ANOVA). In contrast, there was a significant variation in a non-UT-B 100 kDa protein (P < 0.001, N = 3-4, ANOVA), which was also detected by anti-UT-B antibodies. Using the C6 rat astrocyte cell line, Western blot analysis showed that 48-h incubation in either 5 mM or 10 mM significantly increased a 30-45 kDa UT-B protein signal (P < 0.05, N = 3, ANOVA). Furthermore, investigation of compartmentalized C6 protein samples showed the 30-45 kDa signal in the membrane fraction, whilst the 100 kDa non-UT-B signal was predominantly in the cytosolic fraction. Finally, immunolocalization studies gave surprisingly weak detection of rat UT-B, except for strong staining of red blood cells in the cerebellum. In conclusion, this study confirmed that RNA expression and protein abundance of UT-B were equal across all regions of the rat brain, suggesting that urea levels were also similar. However, it also highlighted some of the technical challenges of studying urea transporters at the protein level.

Localization of urea transporter B in the developing bovine rumen.

Urea nitrogen secreted from blood to rumen is a crucial factor shaping the symbiotic relationship between host ruminants and their microbial populations. Passage of urea across rumen epithelia is facilitated by urea transporter B (UT-B), but the long-term regulation of these proteins remains unclear. As ruminal function develops over a period of months, the developing rumen is an excellent model with which to investigate this regulation. Using rumen epithelium samples of calves from birth to 96 d of age, this study performed immunolocalization studies to localize and semi-quantify UT-B protein development. As expected, preliminary experiments confirmed that ruminal monocarboxylate transporter 1 (MCT1) short chain fatty acid transporter protein abundance increased with age (P < 0.01, n = 4). Further investigation revealed that ruminal UT-B was present in the first few weeks of life and initially detected in the basolateral membrane of stratum basale cells. Over the next 2 months, UT-B staining spread to other epithelial layers and semi-quantification indicated that UT-B abundance significantly increased with age (P < 0.01, n = 4 or 6). These changes were in line with the development of rumen function after the advent of solid feed intake and weaning, exhibiting a similar pattern to both MCT1 transporters and papillae growth. This study therefore confirmed age-dependent changes of in situ ruminal UT-B protein, adding to our understanding of the long-term regulation of ruminal urea transporters.

The role of rumen epithelial urea transport proteins in urea nitrogen salvage: A review.

The symbiotic relationship between the host and the rumen microbiome plays a crucial role in ruminant physiology. One of the most important processes enabling this relationship is urea nitrogen salvaging (UNS). This process is important for both maintaining ruminant nitrogen balance and supporting production of their major energy supply, bacterially-derived short chain fatty acids (SCFA). The key step in UNS is the trans-epithelial movement of urea across the ruminal wall and this is a highly regulated process. At the molecular level, the key transport route is via the facilitative urea transporter-B2, localized to ruminal papillae epithelial layers. Additional urea transport through aquaporins (AQP), such as AQP3, is now also viewed as important. Long-term regulation of these ruminal urea transport proteins appears to mainly involve dietary fermentable carbohydrates; whereas, transepithelial urea transport is finely regulated by local conditions, such as CO2 levels, pH and SCFA concentration. Although the key principles of ruminal urea transport physiology are now understood, there remains much that is unknown regarding the regulatory pathways. One reason for this is the limited number of techniques currently used in many studies in the field. Therefore, future research in this area that combines a greater range of techniques could facilitate improvements to livestock efficiency, and potentially, reductions in the levels of waste nitrogen entering the environment.

Sex-Related Differences in UT-B Urea Transporter Abundance in Fallow Deer Rumen.

Rumen studies have focused almost exclusively on livestock species under strictly regimented diets. This means that the ruminal condition of free-living and free-feeding wildlife remains practically unstudied. Urea nitrogen salvaging, a process by which urea is passed into the rumen, to both provide a valuable source of nitrogen for bacterial growth and to buffer the potentially harmful acidic effects of bacterial short chain fatty acids, has remained unexplored in wild ruminants, such as deer. UT-B2 transporters are the key proteins reported to facilitate the transepithelial ruminal urea transport. In this study, we investigate the expression, abundance and localisation of urea transporters in the rumen of a semi-wild fallow deer (Dama dama) population. Physical measurements confirmed that males had larger rumen than females, while adults had longer papillae than juveniles. Initial RT-PCR experiments confirmed the expression of UT-B2, while immunolocalisation studies revealed that strong UT-B staining was present in the stratum basale of deer rumen. Western blotting analysis demonstrated that a 50 kDa UT-B2 protein was significantly more abundant in adult females compared to adult males. This study confirms the presence of UT-B2 urea transporters in deer rumen and suggests that sex-related differences occur, bringing new insight into our understanding of rumen physiology.

Osmotic regulation of UT-B urea transporters in the RT4 human urothelial cell line.

Facilitative UT-B urea transporters play important physiological roles in numerous tissues, including the urino-genital tract. Previous studies have shown that urothelial UT-B transporters are crucial to bladder function in a variety of mammalian species. Using the RT4 bladder urothelial cell line, this study investigated the potential osmotic regulation of human UT-B transporters. Initial end-point PCR experiments confirmed expression of both UT-B1 and UT-B2 transcripts in RT4 cells. Western blotting analysis revealed glycosylated UT-B protein to be highly abundant and immunolocalization experiments showed it was predominantly located on the plasma membrane. Further PCR experiments suggested that a 48 hr, NaCl-induced raise in external osmolality increased expression of UT-B transcripts. Importantly, these NaCl-induced changes also significantly increased UT-B protein abundance (p < .01, n = 7, ANOVA), whereas mannitol-induced changes in external osmolality had no effect (NS, n = 4, ANOVA). Finally, similar increases in both UT-B RNA expression and protein abundance were observed with urea-induced changes to external osmolality (p < .05, n = 4, ANOVA). In conclusion, these findings strongly suggest that increases in external osmolality, via either NaCl or urea, can regulate human urothelial UT-B transporters.

Investigation of facilitative urea transporters in the human gastrointestinal tract.

The symbiotic relationship between humans and their intestinal microbiome is supported by urea nitrogen salvaging. Previous studies have shown that colonic UT-B urea transporters play a significant role in this important physiological process. This current study investigated UT-A and UT-B urea transporter expression along the human gastrointestinal tract. Initial end-point PCR experiments determined that UT-A RNA was predominantly expressed in the small intestine, while UT-B RNA was expressed in stomach, small intestine, and colon. Using western blotting experiments, a strong 40-60 kDa UT-B signal was found to be abundant in both ileum and colon. Importantly, this signal was deglycosylated by PNGaseF enzyme treatment to a core protein of 30 kDa in both tissues. Further immunolocalization studies revealed UT-B transporter proteins were present at the apical membrane of the villi in the ileum, but predominantly at the basolateral membrane of the colonic surface epithelial cells. Finally, a blind scoring immunolocalization study suggested that there was no significant difference in UT-B abundance throughout the colon (NS, ANOVA, N = 5-21). In conclusion, this current study suggested UT-B to be the main human intestinal urea transporter. Intriguingly, these data suggested that the same UT-B isoform was present in all intestinal epithelial cells, but that the precise cellular location varied.

The knockout of urea transporter-B improves the hemorheological properties of erythrocyte.

OBJECTIVE: Urea transporter-B (UT-B), highly expressed in erythrocyte, confers specific permeability to urea, urea analogues and water. The purpose of this study was to determine the hemorheological properties of UT-B null erythrocyte using a series of biophysical techniques. METHODS AND RESULTS: The blood was taken from UT-B knockout and wild-type mice and the hemorheological parameters were measured. The UT-B inhibitor, PU-14, was used to treat the erythrocyte of wild-type mice in vitro and the deformability of the treated erythrocyte was analyzed. The results showed that UT-B knockout improves the hemorheological properties of erythrocyte, including increased erythrocyte deformation index, small deformation index, orientation index, low osmotic fragility and high electrophoretic rate. The UT-B inhibitor PU-14 had the similar effect as UT-B knockout on the deformation indices. The whole blood viscosity in UT-B knockout mice showed reduction trend as compared to wild-type mice. CONCLUSIONS: The data indicate that UT-B is involved in the regulation of hemorheology, which suggests that UT-B may be a potential therapeutic target for improving the hemorheology in some metabolic and hereditary diseases.