Urotensin II Research Articles

Expressions of irisin and urotensin II and their relationships with blood pressure in patients with preeclampsia

ABSTRACTThe aims of this study are to observe irisin and urotensin II (UII) levels in serum and placenta in normal pregnant and preeclamptic women and investigate the relationship between expressions irisin and UII, and their association with blood pressure. A total of 67 pregnant subjects were recruited, including 31 healthy and 36 preeclamptic pregnant women. Serum irisin and UII concentrations were measured. Expressions of fibronectin type III domain-containing protein 5 (FNDC5) (irisin precursor) and UII in placenta specimens were performed. There was no significant difference of serum irisin levels between severe preeclamptic (SPE)) patients, mild preeclamptic (MPE) patients and normal controls, while serum UII was significantly higher in preeclamptic women than normal pregnancy. There was no relationship between serum UII and irisin levels. In patients with preeclampsia, serum irisin was negatively associated with systolic and diastolic blood pressure(r = −0.350, P = 0.004, r = −0.307, P = 0.011), while serum UII was positively associated with systolic blood pressure (r = 0.291, P = 0.031). Serum irisin, UII, urinary protein level, BMI and serum creatinine were the independent determinants of blood pressure in preeclampsia by multiple regression analysis. Protein expression of FNDC5 and UII was upregulated in placenta of patients with SPE and positively correlated with systolic blood pressure and urinary protein level. We firstly verify that serum irisin and placental irisin precursor expressions have differently correlated with blood pressure. Expressions of irisin and urotensin II have relationships with blood pressure in patients with preeclampsia

Urotensin II enhances transforming growth factor‑β1 expression and secretion in the kidney during aristolochic acid nephropathy.

Aristolochic acid is a component of many types of Chinese medicine, which are commonly used to treat almost all human diseases. However, aristolochic acid may cause nephropathy. Urotensin II (UII) and transforming growth factor (TGF)‑β1 are important signaling factors, which are expressed at elevated levels during the development of nephropathy. However, the association between UII and TGF‑β1 expression remains unclear. In the current study, the regulatory association between UII and TGF‑β1 expression was investigated using a rat aristolochic acid nephropathy model and the NRK‑52E cell line. The expression levels of UII and TGF‑β1 were identified to be constantly increased in the rat aristolochic acid nephropathy model, even 10days after administration of Aristolochiaemanshuriensis decoction was terminated. Notably, increases in the TGF‑β1 expression levels occurred later than those of UII. Furthermore, UII enhanced TGF‑β1 expression in, and secretion from, NRK‑52E cells. These data indicate that UII and TGF‑β1 are important in the development of aristolochic acid nephropathy, and UII enhances TGF‑β1 expression levels and secretion during aristolochic acid nephropathy. However, the underlying mechanisms for the precise roles of UII and TGF‑β1 as well as the method by which UII regulates the expression TGF‑β1 in aristolochic acid nephropathy remain to be elucidated in future studies.

The G Protein-Coupled Receptor UT of the Neuropeptide Urotensin II Displays Structural and Functional Chemokine Features.

The urotensinergic system was previously considered as being linked to numerous physiopathological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions. Thus, it turns out that the actions of the urotensin II (UII)/G protein-coupled receptor UT system in animal models are currently not predictive enough in regard to their effects in human clinical trials and that UII analogs, established to target UT, were not as beneficial as expected in pathological situations. Thus, many questions remain regarding the overall signaling profiles of UT leading to complex involvement in cardiovascular and inflammatory responses as well as cancer. We address the potential UT chemotactic structural and functional definition under an evolutionary angle, by the existence of a common conserved structural feature among chemokine receptorsopioïdergic receptors and UT, i.e., a specific proline position in the transmembrane domain-2 TM2 (P2.58) likely responsible for a kink helical structure that would play a key role in chemokine functions. Even if the last decade was devoted to the elucidation of the cardiovascular control by the urotensinergic system, we also attempt here to discuss the role of UII on inflammation and migration, likely providing a peptide chemokine status for UII. Indeed, our recent work established that activation of UT by a gradient concentration of UII recruits Gαi/o and Gα13 couplings in a spatiotemporal way, controlling key signaling events leading to chemotaxis. We think that this new vision of the urotensinergic system should help considering UT as a chemotactic therapeutic target in pathological situations involving cell chemoattraction.

Plasma Urotensin II levels in children and adolescents with chronic kidney disease: a single-centre study

BackgroundIncreased plasma Urotensin II (UII) levels have been found in adults with renal diseases. Studies in children are scarce. The objective of the study is to estimate plasma UII levels in subjects with chronic kidney disease (CKD) stages 3 to 5 and renal transplant recipients (RTR). In addition, the correlation of UII with anthropometric features and biochemical parameters was assessed.MethodsFifty-four subjects, aged 3 to 20 years old, 23 with CKD, 13 with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) and 18 RTR were enrolled. A detailed clinical evaluation was performed. Biochemical parameters of renal and liver function were measured. Plasma UII levels were measured in all patients and in 117 healthy controls, using a high sensitive enzyme immunoassay (EIA) kit. All data were analyzed using STATA™ (Version 10.1).ResultsMedian UII and mean log-transformed UII levels were significantly higher in CKD and RTR patients compared to healthy subjects (p < 0.001). HD patients had higher but not statistically significant UII and log-UII levels than controls. UII levels increased significantly at the end of the HD session and were higher than controls and in line to those of other patients. The geometric scores of UII in HD (before dialysis), CKD and RTR patients increased respectively by 42, 136 and 164% in comparison with controls. Metabolic acidosis was associated with statistical significant change in log-UII levels (p = 0.001). Patients with metabolic acidosis had an increase in UII concentration by 76% compared to those without acidosis.ConclusionsChildren and adolescents with CKD, particularly those who are not on HD and RTR, have significantly higher levels of UII than healthy subjects. UII levels increase significantly at the end of the HD session. The presence of metabolic acidosis affects significantly plasma UII levels.

A novel urotensin II receptor antagonist, KR-36676, prevents ABCA1 repression via ERK/IL-1β pathway

Urotensin II (U-II), the most potent vasoconstrictor peptide known to date, is expressed at a high level in vascular smooth muscle cells (VSMC) and endothelial cells, whereas its receptor, urotensin (UT) receptor, is abundant in monocytes and macrophages of atherosclerotic lesions. U-II is highly present in the coronary arteries of the atherosclerotic patients compared to normal subjects. Recently, U-II was shown to down-regulate ATP binding cassette transporter-A1 (ABCA1) expression, which is responsible for reverse cholesterol transport in macrophages of atherosclerotic lesions. However, the mechanism of this observation was not clearly elucidated. Previous studies also revealed that the proinflammatory cytokine interleukin-1β (IL-1β) repressed ABCA1 expression. To clarify the signaling pathway involved with respect to U-II-induced ABCA1 down-regulation, we investigated whether IL-1ß was involved. Our results provided that U-II repressed ABCA1 through an ERK/ IL-1ß pathway. We further demonstrated that U-II receptor antagonist KR-36676 decreased IL-1ß production and significantly led to a recovery of ABCA1 expression at both mRNA and protein levels. In previous investigations, U-II receptor antagonists have been shown to protect atherosclerosis in cell and animal models. Our results imply that U-II receptor antagonist KR-36676 might be a potent candidate for treating atherosclerosis, and leading to a recovery of ABCA1 expression, affected by the ERK/IL-1ß pathway.

Central and Peripheral Effects of Urotensin II and Urotensin II-Related Peptides on Cardiac Baroreflex Sensitivity in Trout.

The baroreflex response is an essential component of the cardiovascular regulation that buffers abrupt changes in blood pressure to maintain homeostasis. Urotensin II (UII) and its receptor UT are present in the brain and in peripheral cardiovascular tissues of fish and mammals. Intracerebroventricular (ICV) injection of UII in these vertebrates provokes hypertension and tachycardia, suggesting that the cardio-inhibitory baroreflex response is impaired. Since nothing is known about the effect of UII on the cardiac baroreflex sensitivity (BRS), we decided to clarify the changes in spontaneous BRS using a cross spectral analysis technique of systolic blood pressure (SBP) and R–R interval variabilities after ICV and intra-arterial (IA) injections of trout UII in the unanesthetized trout. We contrasted the effects of UII with those observed for the UII-related peptides (URP), URP1 and URP2. Compared with vehicle-injected trout, ICV injection of UII (5–500 pmol) produced a gradual increase in SBP, a decrease in the R–R interval (reflecting a tachycardia) associated with a dose-dependent reduction of the BRS. The threshold dose for a significant effect on these parameters was 50 pmol (BRS; −55%; 1450 ± 165 ms/kPa vs. 3240 ± 300 ms/kPa; P < 0.05). Only the 500-pmol dose of URP2 caused a significant increase in SBP without changing significantly the R–R interval but reduced the BRS. IA injection of UII (5–500 pmol) caused a dose-dependent elevation of SBP. Contrasting with the ICV effects of UII, the R–R interval increased (reflecting a bradycardia) up to the 50-pmol dose while the BRS remained unchanged (50 pmol; 2530 ± 270 ms/kPa vs. 2600 ± 180 ms/kPa; P < 0.05). Nonetheless, the highest dose of UII reduced the BRS as did the highest dose of URP1. In conclusion, the contrasting effect of low picomolar doses of UII after central and peripheral injection on the BRS suggests that only the central urotensinergic system is involved in the attenuation of the BRS. The limited and quite divergent effects of URP1 and URP2 on the BRS, indicate that the action of UII is specific for this peptide. Further studies are required to elucidate the site(s) and mechanisms of action of UII on the baroreflex pathways. Whether such effects of central UII on the BRS exist in mammals including humans warrants further investigations.

A Novel Urotensin II Receptor Antagonist, KR-36996 Inhibits Smooth Muscle Proliferation through ERK/ROS Pathway.

Urotensin II (UII) is a mitogenic and hypertrophic agent that can induce the proliferation of vascular cells. UII inhibition has been considered as beneficial strategy for atherosclerosis and restenosis. However, currently there is no therapeutics clinically available for atherosclerosis or restenosis. In this study, we evaluated the effects of a newly synthesized UII receptor (UT) antagonist, KR-36996, on the proliferation of SMCs in vitro and neointima formation in vivo in comparison with GSK-1440115, a known potent UT antagonist. In primary human aortic SMCs (HASMCs), UII (50 nM) induced proliferation was significantly inhibited by KR-36996 at 1, 10, and 100 nM which showed greater potency (IC50: 3.5 nM) than GSK-1440115 (IC50: 82.3 nM). UII-induced proliferation of HASMC cells was inhibited by U0126, an ERK1/2 inhibitor, but not by SP600125 (inhibitor of JNK) or SB202190 (inhibitor of p38 MAPK). UII increased the phosphorylation level of ERK1/2. Such increase was significantly inhibited by KR-36996. UII-induced proliferation was also inhibited by trolox, a scavenger for reactive oxygen species (ROS). UII-induced ROS generation was also decreased by KR-36996 treatment. In a carotid artery ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with KR-36996 (30 mg/kg) which showed better efficacy than GSK-1440115. These results suggest that KR-36996 is a better candidate than GSK-1440115 in preventing vascular proliferation in the pathogenesis of atherosclerosis and restenosis.

Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution.

Conformation and dynamics of the vasoconstrictive peptides human urotensin II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring conformations, open and folded, with rapidly interchanging subtypes. The open states are characterized by turns of various types centered at K8Y9 or F6W7 predominantly with no or only sparsely populated transannular hydrogen bonds. The folded conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F6W7K8 or W7K8Y9. Some of these conformations have not been characterized previously. The equilibrium populations that are experimentally difficult to access were estimated by replica-exchange MD simulations and validated by comparison of experimental NMR data with chemical shifts calculated with density-functional theory. UII exhibits approximately 72% open:28% folded conformations in aqueous solution. URP shows very similar ring conformations as UII but differs in an open:folded equilibrium shifted further toward open conformations (86:14) possibly arising from the absence of folded N-terminal tail-ring interaction. The results suggest that the different biological effects of UII and URP are not caused by differences in ring conformations but rather by different interactions with UTR.

Urotensinergic system genes in experimental subarachnoid hemorrhage

ObjectiveCerebral vasospasm, one of the main complications of subarachnoid hemorrhage (SAH), is characterized by arterial constriction and mainly occurs from day 4 until the second week after the event. Urotensin-II (U-II) has been described as the most potent vasoconstrictor peptide in mammals. An analysis is made of the serum U-II concentrations and mRNA expression levels of U-II, urotensin related peptide (URP) and urotensin receptor (UT) genes in an experimental murine model of SAH. DesignAn experimental study was carried out. SettingExperimental operating room of the Biomedicine Institute of Seville (IBiS), Virgen del Rocío University Hospital (Seville, Spain). Participants96 Wistar rats: 74 SAH and 22 sham intervention animals. InterventionsDay 1: blood sampling, followed by the percutaneous injection of 100μl saline (sham) or blood (SAH) into the subarachnoid space. Day 5: blood sampling, followed by sacrifice of the animals. Main variables of interestWeight, early mortality, serum U-II levels, mRNA values for U-II, URP and UT. ResultsSerum U-II levels increased in the SAH group from day 1 (0.62pg/mL [IQR 0.36–1.08]) to day 5 (0.74pg/mL [IQR 0.39–1.43]) (p<0.05), though not in the sham group (0.56pg/mL [IQR 0.06–0.83] day 1; 0.37pg/mL [IQR 0.23–0.62] day 5; p=0.959). Between-group differences were found on day 5 (p<0.05). The ROC analysis showed that the day 5 serum U-II levels (AUC=0.691), URP mRNA (AUC=0.706) and UT mRNA (AUC=0.713) could discriminate between sham and SAH rats. The normal serum U-II concentration range in rats was 0.56pg/mL (IQR 0.06–0.83). ConclusionThe urotensinergic system is upregulated on day 5 in an experimental model of SAH.

Evaluation of serum urotensin-II levels of children with attention deficit hyperactivity disorder and autism spectrum disorder

Objective: Urotensin-II (U-II) is one of the most vasoconstrictive substrates for the mammals. Lately, this substrate is thought to be responsible for developing of the neuropsychiatric disorders, by causing an abnormal brain bloodstream situation. Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are frequently seen disorders in childhood and their etiologies are remain unclear. This study evaluated the serum urotensin-II levels of children with ASD and ADHD and compared with healthy subjects' urotensin-II levels. Methods: Total of 179 children between age of 4-12, 60 of them diagnosed with ADHD and 60 of children with ASD, according to the DSM-5 criteria and both had no treatment for at least a month and 59 of healthy subjects whom they all admitted to the Ankara Pediatric Hematology-Oncology Training and Research Hospital were included. Schedule for Affective Disorders and Schizophrenia for School-Age Children, a semi-structured interview, was applied to all subjects. Venous samples of the participants were given after a-12 hours starvation. Serum U-II levels were analyzed by the use of ELISA kits. SPSS 16.0 was used for analysis and p

The role of urotensin II and atherosclerotic risk factors in patients with slow coronary flow.

BackgroundSlow coronary flow (SCF) is an angiographic finding characterized with delayed opacification of epicardial coronary arteries without obstructive coronary disease. Urotensin II (UII) is an important vascular peptide, which has an important role in hypertension, coronary artery disease, and vascular remodeling in addition to potent vasoconstrictor effect.ObjectivesWe investigated UII levels, hypertension, and other atherosclerotic risk factors in patients with SCF, a variety of coronary artery disease.MethodsWe enrolled 14 patients with SCF and 29 subjects with normal coronary arteries without SCF. We compared the UII levels and the atherosclerotic risk factors between patients with SCF and control subjects with normal coronary flow.ResultsUII concentrations were significantly higher in patients with SCF compared to controls (711.0 ± 19.4 vs. 701.5 ± 27.2 ng/mL, p = 0.006). We detected a positive correlation between SCF and age (r = 0.476, p = 0.001), BMI (r = 0.404, p = .002), UII concentrations (r = 0.422, p = 0.006), and hypertension (r = 0.594, p = 0.001).ConclusionWe identified increased UII levels in patients with SCF. We think that UII concentrations may be informative on SCF pathogenesis due to relationship with inflammation, atherosclerosis, and vascular remodeling.

Age-Related Reduction of Contractile Responses to Urotensin II Is Seen in Aortas from Wistar Rats but Not from Type 2 Diabetic Goto-Kakizaki Rats.

Vascular dysfunction is a common finding in type 2 diabetes, although the response to urotensin II (UII), a potent vasoconstrictor peptide, remains unclear. We investigated whether a UII-induced contraction was increased in the aortas from type 2 diabetic Goto-Kakizaki (GK) rats at the chronic stage. At 36 or 37 weeks of age (older group), a UII-induced contraction was seen in GK rats and was reduced by a Rho kinase inhibitor or urotensin receptor (UT) antagonist, whereas UII failed to induce a contraction in aortas from age-matched Wistar rats. In UII-stimulated aortas, the expression of Rho kinases, Rho A, and phosphorylated myosin phosphatase target subunit 1 did not change between the two groups; however, phosphorylation of extracellular-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) was greater in GK than in Wistar rats. Compared to intact aortas, UII-induced contractions were slightly, but not significantly, increased by endothelial denudation of the aortas of Wistar rats at 24 weeks of age. At 6 weeks of age (young group), the UII-induced contractions were seen in GK and Wistar groups. The total expression and the membrane-to-cytosol ratio of the UT protein slightly decreased in Wistar aortas with aging but not in GK aortas. These results demonstrate that the UII-induced contraction gradually decreased with aging in Wistar rats and was preserved in type 2 diabetes. Although alterations of UII-induced contractions during aging and type 2 diabetes may be associated with kinase activities (MAPKs or Rho kinase) or receptor profiles, further investigations are necessary to clarify the mechanisms.

Study the Role of Urotensin Ii as a Predictor for Hepatorenal Syndrome

1.1.Bakground and Objectives; Chronicliver disease and its complications is a common health problem worldwide. Hepatorenal syndrome (HRS type 1, 2) is one of these serious complications with high mortality.The aim of this study was to evaluate the diagnostic role of urotensin II in patients with chronic liver diseases (both ascitic and non ascitic patients). 1.2.Patientsand Methods: Forty patients were selected from Gastroenterology, Hepatology and Infectious Diseases Department, Benha University Hospital, Egypt. Group (1) 20 patients with ascites (9 males and 11 females), their ages ranged from 35-65years with mean 50.95 ± 9.84. Group (2) 20 patients without ascites as a control group (8 males and 12 females) their ages ranged from 35-63 years with mean 49.25± 9.66, from the period of March 2011 to July 2011. 1.3.Results: There was no statistically significant difference as regard CBC parameters ( p>0.05) between the ascitic group (1) and non ascitic group (2), except for platelet count, there was a statistically significant decrease between the 2 groups (p 0.05). The Ultrasound findings of the kidney's were of statistically significant difference between the two groups as regard nephropathy (8 patients in ascitic group [1] while one patient in non ascitic group [2]) (p value <0.05). There was a statistically significant correlation between Urotensin II and blood urea level in group 2, but there was not with other variables. The cut-off value of Urotensin II was of sensitivity 66.7%, specificity 64.5%, PPV 35.3% and NPP 86.96% with Accuracy 59% and p value <0.42 of no statistically significant difference. Conclusion: Urotensin II was of statistically significant positive correlation with blood urea level in patients with ascites, that means the relevant clinical importance to use urotensin II in the early stages of liver disease before development of HRS. Also it can be used to diagnose subclinical hepatic encephalopathy patients , that is confirmed with other investigation.

Urotensin II inhibitor eases neuropathic pain by suppressing the JNK/NF-κB pathway.

Urotensin II (U-II), a cyclic peptide originally isolated from the caudal neurosecretory system of fishes, can produce proinflammatory effects through its specific G protein-coupled receptor, GPR14. Neuropathic pain, a devastating disease, is related to excessive inflammation in the spinal dorsal horn. However, the relationship between U-II and neuropathic pain has not been reported. This study was designed to investigate the effect of U-II antagonist on neuropathic pain and to understand the associated mechanisms. We reported that U-II and its receptor GPR14 were persistently upregulated and activated in the dorsal horn of L4-6 spinal cord segments after chronic constriction injury (CCI) in rats. Intrathecal injection of SB657510, a specific antagonist against U-II, reversed CCI-induced thermal hyperalgesia and mechanical allodynia. Furthermore, we found that SB657510 reduced the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor-κB (NF-κB) p65 as well as subsequent secretion of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). It was also showed that both the JNK inhibitor SP600125 and the NF-κB inhibitor PDTC significantly attenuated thermal hyperalgesia and mechanical allodynia in CCI rats. Our present research showed that U-II receptor antagonist alleviated neuropathic pain possibly through the suppression of the JNK/NF-κB pathway in CCI rats, which will contribute to the better understanding of function of U-II and pathogenesis of neuropathic pain.

Increased expression of urotensin II is associated with poor prognosis in hepatocellular carcinoma.

Urotensin II (UII) and the urotensin II receptor (UT) exhibit mitogenic effects on tumor growth. Our previous study demonstrated that the UII/UT system is upregulated in hepatocellular carcinoma (HCC) and may enhance the proliferation of human hepatoma cells. However, the clinical significance of UII/UT expression in HCC remains unclear. The present study assessed UII messenger RNA (mRNA) expression in 129 surgical specimens obtained from HCC patients using reverse transcription quantitative-polymerase chain reaction. The association between UII mRNA expression and clinicopathological parameters and overall survival rates was also investigated. The results revealed that UII and UT mRNA expression was significantly increased in HCC tissue compared with adjacent non-cancerous liver tissue (P<0.001). Furthermore, a significant correlation was identified between UII expression and histological differentiation (P<0.01), tumor size (P<0.01) and tumor stage (P=0.026). Kaplan-Meier survival analysis indicated that overall survival time was significantly shorter in patients with high UII expression, compared with those with low UII expression (P<0.001). Multivariate analyses indicated that UII expression was an independent predictor of overall survival (odds ratio, 1.12; P<0.001). In addition, UII mRNA was correlated with vascular endothelial growth factor mRNA expression. Therefore, UII expression is an independent biomarker for the prognosis of patients with HCC and thus, the UII/UT system may present a novel therapeutic target for the treatment of HCC.

Comparison of two competitive enzyme immunoassay kits for quantification of plasma Urotensin-II in rats

ABSTRACTChanges in Urotensin-II (U-II) concentration, a potent vasoconstrictor peptide, have been detected in various pathologies, but it has been impossible to define a normality range. We aimed to analyze the concordance and interchangeability between two enzyme immunoassay methods developed by Phoenix Pharmaceuticals, Inc. to measure U-II plasma concentration in rats: ELISA and fluorescent EIA. Assays resulted positively correlated (r = 0.850; p < 0.01). There was a significant difference between assays values (p < 0.001). The analysis of agreement (Bland and Altman plot) stated that the mean of the differences was 2.055 (SD ± 0.588). Hence, we concluded that the two U-II assays were correlated but not interchangeable.

Role of urotensinII in advanced glycation end product-induced extracellular matrix synthesis in rat proximal tubular epithelial cells.

Urotensin II(UII) was first recognized for its constrictive and natriuretic properties in fish almost 40years ago, and recent studies have suggested that it exerts pro-fibrotic effects in a number of cell lines. In this study, we aimed to evaluate the role of UII in extracellular matrix(ECM) synthesis and secretion in advanced glycation end product(AGE)-stimulated rat proximal tubular epithelial cells(NRK-52E cells). UII promoted the proliferation of the NRK-52E cells in a dose-dependent manner over a concentration range of 10-10-10-8mol/l and this effect was partly inhibited by both nimodipine and EDTA. Furthermore, AGE-BSA promoted the mRNA and protein expression of UII, fibronectin(FN) and collagenIV(ColIV) in the NRK-52E cells in a dose-and time-dependent manner. In addition, UII promoted the mRNA expression and protein secretion of transforming growth factor(TGF)-β1, FN and ColIV by the NRK-52E cells. Our results suggest that UII promotes the proliferation of NRK-52E cells, an effect which is mediated by the influx of extracellular calcium ions. In addition, our data indicate that AGEs promote UII expression in NRK-52E cells, and that TGF-β1 signaling is a candidate pathway mediating the involvement of UII in renal fibrosis. Collectively, our data suggest that the UII-TGF-β1 signaling may be an important factor in tubulointerstitial nephropathy in diabetes.

A novel role of G protein-coupled receptor kinase 5 in urotensin II-stimulated cellular hypertrophy in H9c2UT cells.

Urotensin II (UII) is a neural hormone that induces cardiac hypertrophy and may be involved in the pathogenesis of cardiac remodeling and heart failure. Hypertrophy has been linked to histone deacetylase 5 (HDAC5) phosphorylation and nuclear factor κB (NF-κB) translocation, both of which are predominantly mediated by G protein-coupled receptor kinase 5 (GRK5). In the present study, we found that UII rapidly and strongly stimulated nuclear export of HDAC5 and nuclear import of NF-κB in H9c2 cells overexpressing the urotensin II receptor (H9c2UT). Hence, we hypothesized that GRK5 and its signaling pathway may play a role in UII-mediated cellular hypertrophy. H9c2UT cells were transduced with a GRK5 small hairpin RNA interference recombinant lentivirus, resulting in the down-regulation of GRK5. Under UII stimulation, reduced levels of GRK5 in H9c2UT cells led to suppression of UII-mediated HDAC5 phosphorylation and activation of the NF-κB signaling pathway. In contrast, UII-mediated activations of ERK1/2 and GSK3α/β were not affected by down-regulation of GRK5. In a cellular hypertrophy assay, down-regulation of GRK5 significantly suppressed UII-mediated hypertrophy of H9c2UT cells. Furthermore, UII-mediated cellular hypertrophy was inhibited by amlexanox, a selective GRK5 inhibitor, in H9c2UT cells and neonatal cardiomyocytes. Our results suggest that GRK5 may be involved in a UII-mediated hypertrophic response via activation of NF-κB and HDAC5 at least in part by ERK1/2 and GSK3α/β-independent pathways.

A urotensin II receptor antagonist, KR36676, decreases vascular remodeling and inflammation in experimental pulmonary hypertension

The pathophysiological implications of binding of urotensin II (U-II) to urotensin II receptor (UT) in pulmonary arterial hypertension (PAH) have been proposed recently. Besides high expression of U-II in experimental models and patients with PAH, U-II has been shown to increase proliferation of pulmonary vascular smooth muscle cells and inflammatory responses, which were critical for PAH pathophysiology. However, the direct role of the urotensinergic system in the pathogenesis of PAH is yet to be understood. The aim of the present study was to determine whether a novel UT antagonist, KR36676, attenuates the pathophysiological progression of PAH in an animal model of PAH. PAH was induced by a single subcutaneous injection of monocrotaline (MCT, 60mg/kg) in rats. All the animals received KR36676 (30mg/kg/day) or vehicle by oral gavage. Three weeks after MCT-injection, changes in hemodynamic parameters, extent of right ventricular hypertrophy, fibrosis and pulmonary vascular remodeling, and degree of protein expression were determined. Oral administration of KR36676 effectively decreased the MCT-induced increase in right ventricular systolic pressure, hypertrophy and fibrosis. Furthermore, wall thickness of pulmonary arterioles, proliferation of pulmonary vascular cells, and inflammatory response significantly decreased in the KR36676-treated group following MCT injection compared to that in the MCT-treated vehicle group. These preventive effects of KR36676 are mediated, at least in part, by suppression of ERK1/2 and NF-κB signaling pathways. The novel UT antagonist, KR36676, effectively prevented MCT-induced PAH progression and pulmonary vascular remodeling in rat model. Our findings support the therapeutic efficacy of UT antagonist in PAH prevention and elucidate the possible underlying mechanisms of action.

UII/GPR14 is involved in NF-κB-mediated colonic inflammation in vivo and in vitro.

The present study was conducted to investigate the molecular mechanism of urotensinII (UII) and its receptor, Gprotein‑coupled receptor 14 (GPR14), in colonic inflammation. Urantide, a special antagonist of GPR14, and GPR14-siRNA were used to inhibit GPR14 signaling in dextran sulfate sodium (DSS)‑induced inflammation in mice and Caco-2 cells. The results showed that urantide alleviated rectal bleeding, histological injury and production of interleukin (IL)-17 and tumor necrosis factor‑α (TNF‑α) caused by DSS in mice. GPR14-siRNA transfection subsequent with GPR14 inhibition reduced DSS-induced interferon-γ (IFN)-γ production in Caco-2 cells. Meanwhile, both invivo and invitro data demonstrated that inhibition of UII/GPR14 alleviated nuclear factor-κB (NF-κB) activation caused by DSS. In conclusion, UII/GPR14 signaling was involved in the DSS-induced colonic inflammation and its inhibition may serve as a potential therapeutic target, which may be associated with the NF-κB signaling pathway.