Urotensin II receptor deficiency ameliorates ligation-induced carotid intimal hyperplasia partially through the RhoA-YAP1 pathway.

Intimal hyperplasia (IH) is a common pathological feature of vascular proliferative diseases, such as atherosclerosis and restenosis after angioplasty. Urotensin II (UII) and its receptor (UTR) are widely expressed in cardiovascular tissues. However, it remains unclear whether the UII/UTR system is involved in IH. Right unilateral common carotid artery ligation was performed and maintained for 21 days to induce IH in UTR knockout (UTR-/-) and wild-type (WT) mice. Histological analysis revealed that compared with WT mice, UTR-deficient mice exhibited a decreased neointimal area, angiostenosis and intima-media ratio. Immunostaining revealed fewer smooth muscle cells (SMCs), endothelial cells and macrophages in the lesions of UTR-/- mice than in those of WT mice. Protein interaction analysis suggested that the UTR may affect cell proliferation by regulating YAP and its downstream target genes. In vitro experiments revealed that UII can promote the proliferation and migration of SMCs, and western blotting also revealed that UII increased the protein expression of RhoA, CTGF, Cyclin D1 and PCNA and downregulated p-YAP protein expression, while these effects could be partly reversed by urantide. To evaluate the translational value of UTRs in IH management, WT mice were also treated with two doses of urantide, a UTR antagonist, to confirm the benefit of UTR blockade in IH progression. A high dose of urantide (600 µg/kg/day), rather than a low dose (60 µg/kg/day), successfully improved ligation-induced IH compared with that in mice receiving vehicle. The results of the present study suggested that the UII/UTR system may regulate IH partly through the RhoA-YAP signaling pathway.

Impact of Classic Adrenal Secretagogues on mRNA Levels of Urotensin II and Its Receptor in Adrenal Gland of Rats.

Urotensin 2 (Uts2) is a biologically active peptide involved in the regulation of a variety of physiological and pathophysiological processes. In both the human and rat adrenal gland, the expressions of the Uts2 gene and its receptor (Uts2r) have been described. This paper focuses on the description of the hormonal control of the mRNA levels of urotensin II and its receptor in the adrenal gland of the rat, both in vitro and in vivo. The initial in vitro experiments were carried out on freshly isolated rat adrenocortical cells and their primary culture. The obtained results indicated a stimulating PKA-independent effect of ACTH on the Uts2 mRNA level in the tested cells, with no changes in the Uts2r transcript. Subsequent in vivo experiments showed that ACTH-induced adrenal growth was accompanied by an elevated level of the Uts2 mRNA, with unchanged expression of Uts2r. In the other types of in vivo gland growth studied, enucleation-induced adrenal regeneration and compensatory growth of the gland, the mRNA levels of the studied genes showed no significant differences. The only exception was hemiadrenalectomy, which led to a significant increase in Uts2 mRNA expression level 24 h after surgery. In 12-week-old rats of both sexes, gonadectomy led to a significant increase in the level of Uts2 mRNA in the adrenal gland, an effect that was prevented by sex hormones' replacement. No changes in Uts2r transcript levels were observed under these conditions. Thus, this study suggests that the regulation of Uts2 and Uts2r mRNA levels differs significantly in the rat adrenal gland. While Uts2 transcript levels appear to be mainly dependent on ACTH action, Uts2r mRNA levels are not under the control of this hormone.

Dynamic changes of urotensin II and its receptor during ovarian development of olive flounder Paralichthys olivaceus.

Urotensin II (UII) is a kind of fish somatostatins cyclic peptide, which was originally extracted from the caudal neurosecretory system (CNSS). The system of UII and UII receptor (UIIR) has been reported to have multiple physiological regulatory functions, such as cardiovascular control, osmoregulation, and lipid metabolism. However, the effect of UII and UIIR on the ovarian development has not been covered. This study investigated the expression pattern of UII and UIIR in the ovarian follicles and explored their impact on ovarian development in olive flounder Paralichthys olivaceus. The results showed that the highest UII and UIIR mRNA levels were observed at stage II and stage III follicles during ovarian development, respectively. In situ hybridization revealed that a strong signal of UII was expressed in the oocyte nuclei of stage II follicles, however, UIIR was found in the follicle cells and oocyte cytoplasm of stage II and stage III follicles. Similarly, immunohistochemistry found positive signal of UII was detected in the oocyte nuclei of stage II follicles. The results from in vitro culture of olive flounder follicles suggested the expression of UII and UIIR mRNA levels significantly increased by 10 IU/ml human chorionic gonadotropin (hCG) for 9 h. Furthermore, the transcriptional expression of UII and UIIR was not statistically significantly changed by 17α, 20ß-dihydroxy-4-pregnen-3-one (DHP). These results firstly suggested that UII and UII receptor may play vital roles in regulating ovarian growth in olive flounder.

Urotensin II-related peptides, Urp1 and Urp2, control zebrafish spine morphology.

The spine provides structure and support to the body, yet how it develops its characteristic morphology as the organism grows is little understood. This is underscored by the commonality of conditions in which the spine curves abnormally such as scoliosis, kyphosis, and lordosis. Understanding the origin of these spinal curves has been challenging in part due to the lack of appropriate animal models. Recently, zebrafish have emerged as promising tools with which to understand the origin of spinal curves. Using zebrafish, we demonstrate that the urotensin II-related peptides (URPs), Urp1 and Urp2, are essential for maintaining spine morphology. Urp1 and Urp2 are 10-amino acid cyclic peptides expressed by neurons lining the central canal of the spinal cord. Upon combined genetic loss of Urp1 and Urp2, adolescent-onset planar curves manifested in the caudal region of the spine. Highly similar curves were caused by mutation of Uts2r3, an URP receptor. Quantitative comparisons revealed that urotensin-associated curves were distinct from other zebrafish spinal curve mutants in curve position and direction. Last, we found that the Reissner fiber, a proteinaceous thread that sits in the central canal and has been implicated in the control of spine morphology, breaks down prior to curve formation in mutants with perturbed cilia motility but was unaffected by loss of Uts2r3. This suggests a Reissner fiber-independent mechanism of curvature in urotensin-deficient mutants. Overall, our results show that Urp1 and Urp2 control zebrafish spine morphology and establish new animal models of spine deformity.

The backbone, or spine, is an integral part of the human body, providing support to our torsos so that we can sit, stand, bend and twist. If this structure does not form correctly, it can lead to pain, neurologic problems, and mobility issues. The spine normally has curves, but these can become deformed for many reasons, including genetic and muscular factors. There are also cases in which the cause of a spine distortion is unknown, such as in scoliosis (where the spine twists to the side), lordosis (where the lower part of the spine curves excessively), and kyphosis (where the upper part of the spine shows extreme curvature). The structure of the spine is laid out during embryonic development and maintained throughout life. Experiments in zebrafish have shown that a crucial element in preserving the shape of the spine is the flow of cerebrospinal fluid or CSF. Propelled by the movement of little 'hairs' at the surface of specialized cells, this liquid runs through our central nervous system along a cavity lined with neurons. These nerve cells produce Urp1 and Urp2, two short molecules (or peptides) built from the same components as proteins. In zebrafish embryos, lowering the levels of these peptides had previously been shown to cause early body deformities. But what role, if any, do Urp1 and Urp2 play in maintaining the shape of the spine in adult zebrafish? Bearce et al. set out to answer this question. First, they generated mutant zebrafish which did not carry either Urp1, Urp2 or both peptides. Contrary to previous findings, all three of these mutants developed normally as embryos. Once they were adults, zebrafish lacking Urp1 exhibited normal spines, while those lacking Urp2 had slightly deformed curves. However, zebrafish lacking both peptides had prominent curves in the tail-region of their spines, somewhat akin to lordosis in humans. This indicates that both peptides are necessary for adult spine structure, but work in a semi-redundant manner. Interestingly, the defects observed first appeared in adolescent fish and gradually worsened as they grew; many forms of human spinal abnormalities follow a similar trajectory. Bearce et al. also tested the role of the protein Uts2r3, a receptor for peptides which belong to the urotensin family (such as Urp1 and Urp2). Fish lacking this protein showed normal spine structure as embryos, but distorted spinal curves as adults, suggesting that Urp1 and Urp2 might control spine morphology by signaling via the Uts2r3 receptor. Together, Bearce et al.'s observations show that disturbing urotensin signaling leads to a lordosis-like condition in adult zebrafish, with evident deformities in the tail-region of the spine. Considering the broad similarities in structures between the zebrafish and the human spine, these results point to a possible involvement of urotensin signaling in spine distortion in humans. More studies using zebrafish will likely provide further insights into the principles that control the shape of the spine and what goes wrong when it breaks down.

Role of miR-146a rs2910164 and UTS2 rs228648 Genetic Variants in Behçet's Disease.

BACKGROUND: Behçet's disease (BD) is a chronic autoimmune inflammatory disease. Clinical studies revealed that both microRNAs and urotensin II (UTS2) play a significant role in the development of autoinflammatory diseases. PURPOSE: The study aimed to determine the association between miR-146a rs2910164 and UTS2 rs228648 genetic variants and BD susceptibility. In addition, the relationship between these gene variants and clinical and laboratory outcomes among Egyptian patients was investigated. METHODS: The distributions of miR-146a rs2910164 and UTS2 rs228648 (p.Thr21Met) variants were analyzed in 94 patients with BD and 115 healthy control subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Taqman Real-time PCR techniques. RESULTS: Frequencies of the G/G genotype and G allele of miR-146a rs2910164 variant were significantly higher in patients with BD compared with normal controls (p = .042, OR = 2.31; p = .022, OR = 1.58, respectively). The frequencies of the Thr/Thr genotype and the Thr allele of UTS2 rs228648 variant were significantly higher in subjects with BD compared with normal controls (p = .028, OR = 3.35; p = .032, OR = 1.60, respectively). CONCLUSION: Our results suggest that miR-146a rs2910164 and UTS2 rs228648 variants have significant roles in both the development and clinical modulation of BD in Egyptian patients.

Sterculia tragacantha Lindl Aqueous Leaf Extract Ameliorate Cardiomyopathy in Streptozotocin-induced Diabetic Rats via Urotensin II and FABP3 Expressions.

Sterculia tragacantha (ST) Lindl leaf is commonly used locally in the management of diabetes mellitus (DM) and its complications. This study was aimed at assessing the valuable effects of ST leaf on streptozotocin-diabetic cardiomyopathy (DCM). Streptozotocin was administered intraperitoneally to the experimental animals to induce DM, and hence, placed on different doses of ST for 14 days. Thereafter, on the 15th day of the experiment, the animals were euthanized, and a number of cardiomyopathy indices were investigated. The diabetic rats exhibited a momentous increase in hyperlipidemia, lipid peroxidation as well as a significant (p < 0.05) decline in antioxidant enzyme activities. The serum creatine kinase MB (CK-MB), C-reactive protein (CRP), cardiac troponin I, tumour necrosis factor-alpha (TNF-α) and urotensin II expression revealed a significant (p < 0.05) upsurge in diabetic rats. Also, the expression of GLUT4 and fatty acid-binding protein 3 (FABP3) were significantly (p < 0.05) reduced in diabetic rats. However, at the conclusion of the experimental trial ST significantly (p < 0.05) attenuated hyperlipidemia, oxidative stress biomarkers by augmenting the antioxidant enzyme activities and decrease in lipid peroxidation, ameliorated CK-MB, CRP, cardiac troponin I, TNF-α, and urotensin-II levels, and improved GLUT4 and FABP3 expressions. Similarly, the administration of ST prevented histological alterations in the heart of diabetic animals. Therefore, the obtained results suggest that ST could mitigate DCM in streptozotocin-induced diabetic rats.

Dynamic Changes in Plasma Urotensin II and Its Correlation With Plaque Stability.

ABSTRACT: Urotensin II (UII) is involved in the formation of atherosclerosis, but its role in the stability of atherosclerotic plaques is unknown. The purpose of this study was to observe the dynamic changes in plasma UII and analyze its relationship to the stability of atherosclerotic plaques. One hundred thirty-five consecutive patients with acute coronary syndrome (ACS) were enrolled. The plasma UII levels were measured immediately after admission and during three-month follow-up. A vulnerable plaque model was established using local transfection of a recombinant P53 adenovirus into plaques in rabbits fed with a high-cholesterol diet and subjected to balloon arterial injury. The levels of plasma UII were measured weekly. The changes in plasma UII during the formation of atherosclerotic plaques and before and after plaque transfection were observed. The morphology of the plaques and the expression, distribution, and quantitative expression of UII in the plaques also were observed. Our results showed that the levels of plasma UII in patients with ACS at admission were lower than levels observed at the three-month follow-up. UII dynamic changes and its correlation with plaque stabilities were further verified in rabbits with atherosclerotic vulnerable plaques. The UII levels in rabbits were significantly decreased immediately after the P53 gene transfection, which led to plaque instability and rupture. These results suggested that UII expression was down-regulated in ACS, which may be related to its ability to modulate mechanisms involved in plaque stability and instability.

Diel rhythm of urotensin I mRNA expression and its involvement in the locomotor activity and appetite regulation in olive flounder Paralichthys olivaceus.

Urotensin I (UI), a member of the corticotropin-releasing hormone family of peptides, regulates a diverse array of physiological functions, including appetite regulation, defensive behavior and stress response. In this study, firstly, the tissue-specific distribution of UI mRNA in olive flounder (Paralichthys olivaceus) was characterized and we found that UI mRNA was highly expressed in caudal neurosecretory system (CNSS) tissue. Secondly, alignment analysis found that a conserved cAMP response binding (CREB) site and a TATA element were located in the proximal promoter of UI gene. In addition, treatment of forskolin activatated cAMP-CREB pathway and induced the up-regulation of UI mRNA in cultured CNSS, suggesting the role of CREB in regulating the UI mRNA expression. Furthermore, plasma UI concentration and UI mRNA in CNSS showed obvious daily rhythm, with higher values in the daytime while lower values in the nighttime. Thirdly, using bold personality (BP) and shy personality (SP) flounder as an animal model, we found that flounder exhibited significantly higher locomotor activity in the nighttime than in the daytime (P < 0.001), and BP flounder showed significantly higher locomotor activity (P < 0.001) compared with SP flounder both in the daytime and nighttime. Analysis of feeding behavior revealed that BP flounder showed a shorter latency to feed and more attacks to prey. Furthermore, the qPCR and immunohistochemistry results showed that BP flounder expressed significantly lower level of UI mRNA and protein in CNSS tissue. Collectively, our study suggested that the UI plays an important role in locomotor activity and appetite regulation, which provides a basis for understanding the mechanism of defensive behavior and animal personality in flounder.

Adolescent Idiopathic Scoliosis: Fishy Tales of Crooked Spines.

Adolescent idiopathic scoliosis (AIS) is a common skeletal disorder, characterized by abnormal spine curvatures. In zebrafish, cilia-driven cerebrospinal fluid flow and urotensin II pathway activity are required for proper spine morphogenesis. Genetic studies with AIS patients now establish a conservation of the zebrafish findings in the etiology of the disease.

Expression of urotensin II is positively correlated with pyroptosis-related molecules in patients with severe preeclampsia.

Purpose: We studied the expression of urotensin II (UII) and its relationships with markers of pyroptosis in preeclampsia. Methods: 48 pregnant subjects were recruited consisting of 28 severe preeclampsia pregnancies (SPE) and 20 healthy pregnancies. We detected expressions of UII and markers of pyroptosis such as NLR-family pyrin domain (PYD)-containing 3 (NLRP-3), caspase-1/4/5, interleukin-1ß (IL-1ß), and gasdermin D (GSDMD) in placentas of patients with SPE and healthy pregnancies. Results: SPE group have higher expression of UII and NLRP-3, caspase-1, interleukin-1ß (IL-1ß), and GSDMD than that normal controls by IHC, real-time PCR, and western blot. IHC analysis manifests that the expressions of UII and pyroptosis-related molecules are mainly located in the placental cytotrophoblasts. Expressions of UII mRNA and protein are significantly positively correlated with pyroptosis marker such as NLRP3, caspase-1, GSDMD mRNA and protein by Pearson correlation analysis. Moreover, UII, NLRP-3, caspase-1, interleukin-1ß (IL-1ß), and GSDMD are positively related with systolic blood pressure, meanwhile caspase-1 and GSDMD are positively correlated with urine protein in SPE patients. We firstly verify that UII has a positive correlation with pyroptosis markers in placentas of preeclampsia patients; besides, pyroptosis-related proteins are positively correlated with systolic blood pressure and urine protein in patients with severe preeclampsia.

Characterization of four urotensin II receptors (UTS2Rs) in chickens.

Urotensin II receptor (UTS2R) is suggested to mediate the actions of urotensin II (UTS2) and UTS2-related peptide (URP, also called UTS2B) in mammals. However, the information regarding the gene structure, functionality and tissue expression of UTS2/URP receptor remains largely unknown in non-mammalian vertebrates including birds. In this study, using RACE-PCR, we cloned the full-length cDNAs of four chicken UTS2/URP receptors and designated them as cUTS2R1, cUTS2R2, cUTS2R3 and cUTS2R5 respectively, according to their evolutionary origin. The cloned cUTS2R1, cUTS2R2, cUTS2R3 and cUTS2R5 are predicted to encode 7-transmembrane receptors of 382, 343, 331 and 363 amino acids respectively, which show 50-66 % amino acid sequence identity with human UTS2R. Using cell-based luciferase reporter assays and Western blot, we demonstrated that chicken UTS2Rs expressed in HEK293 cells could be effectively activated by synthetic chicken UTS2-12, UTS2-17 and URP peptides, and their activation can elevate intracellular calcium concentration and activate MAPK/ERK signaling cascade, indicating that the four UTS2Rs are functional and capable of mediating UTS2/URP actions in chickens. Quantitative real-time PCR revealed that the four receptors are widely, but differentially, expressed in adult chicken tissues, while cUTS2 and cURP are highly expressed in the hindbrain and spinal cord, and moderately/weakly expressed in other tissues examined including the spleen and gonads. Taken together, our data provide first piece of evidence that all four UTS2Rs are functional in an avian species and help to reveal the conserved roles of UTS2R signaling across vertebrates.

On being the right shape: Roles for motile cilia and cerebrospinal fluid flow in body and spine morphology.

How developing and growing organisms attain their proper shape is a central problem of developmental biology. In this review, we investigate this question with respect to how the body axis and spine form in their characteristic linear head-to-tail fashion in vertebrates. Recent work in the zebrafish has implicated motile cilia and cerebrospinal fluid flow in axial morphogenesis and spinal straightness. We begin by introducing motile cilia, the fluid flows they generate and their roles in zebrafish development and growth. We then describe how cilia control body and spine shape through sensory cells in the spinal canal, a thread-like extracellular structure called the Reissner fiber, and expression of neuropeptide signals. Last, we discuss zebrafish mutants in which spinal straightness breaks down and three-dimensional curves form. These curves resemble the common but little-understood human disease Idiopathic Scoliosis. Zebrafish research is therefore poised to make progress in our understanding of this condition and, more generally, how body and spine shape is acquired and maintained through development and growth.

Association of resistin (rs3745367) and urotensin II (rs228648 and rs2890565) gene polymorphisms with risk of type 2 diabetes mellitus in Indian population.

Insulin resistance may become the most powerful predictor of future development of type 2 diabetes mellitus (T2DM) and a therapeutic target for the treatment of the same. Both Resistin, an adipose derived peptide hormone and Urotensin II a potent vasoconstrictor, are reported to be involved in the development of insulin resistance and T2DM but the results remain contradictory. Therefore, investigations were carried out to study the association of T2DM and single nucleotide polymorphism (SNP) in Resistin (RETN) gene at rs3745367 (+ 299 G > A) and Urotensin II (UTS2) gene at rs228648 (+ 143 G > A) and rs2890565 (+ 3836 C > T) in a North Indian population. Method: The present case-control study, conducted from August 2017 to July 2020, involved 168 T2DM patients and 102 healthy controls. SNPs rs3745367, rs228648 and rs2890565 were amplified from genomic DNA in the studied samples by polymerase chain reaction (PCR) using specific primers. The amplified products were genotyped by restriction fragment length polymorphism (RFLP) using particular restriction endonucleases. Clinical parameters viz. glycosylated haemoglobin (HbA1c), fasting blood glucose (FBG), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (CHL) and fasting insulin were determined by enzymatic methods. Result and conclusion: A statistically significant association between T2DM and RETN gene at SNP rs3745367 (p = 0.001) and UTS2 gene at SNP rs2890565 (p = 0.001) was observed. In RETN gene SNP rs3745367, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were found to be higher in GA + AA combined genotype than in GG genotype for T2DM subjects. Regression analysis revealed that SNP rs2890565 and HOMA-IR were independently associated with the risk of development of T2DM when three SNPs were taken as independent variable adjusted for clinical variables. Among four haplotypes, A/T was found associated with increased risk of T2DM as determined for rs228648 and rs2890565 of UTS2 gene. It can be concluded from these results that polymorphism at rs3745367 of RETN gene and at rs2890565 of UTS2 gene are associated with risk of T2DM in North Indian population.

Reissner fibre-induced urotensin signalling from cerebrospinal fluid-contacting neurons prevents scoliosis of the vertebrate spine.

Reissner fibre (RF), discovered by the 19th-century German anatomist Ernst Reissner, is a filamentous structure present in cerebrospinal fluid (CSF). RF forms by aggregation of a glycoprotein called SCO-spondin (Sspo), but its function has remained enigmatic. Recent studies have shown that zebrafish sspo mutants develop a curved embryonic body axis. Zebrafish embryos with impaired cilia motility also develop curved bodies, which arises from failure of expression of urotensin related peptide (urp) genes in CSF-contacting neurons (CSF-cNs), impairing downstream signalling in trunk muscles. Here, we show that sspo mutants can survive into adulthood, but display severe curvatures of the vertebral column, resembling the common human spine disorder idiopathic scoliosis (IS). sspo mutants also exhibit significant reduction of urp gene expression from CSF-cNs. Consistent with epinephrine in CSF being bound by RF and required for urp expression, treating sspo mutants with this catecholamine rescued expression of the urp genes and axial defects. More strikingly, providing Urp2, specifically in the CSF-cNs, rescued body curvature of sspo homozygotes during larval stages as well as in the adult. These findings bridge existing gaps in our knowledge between cilia motility, RF, Urp signalling and spine deformities, and suggest that targeting the Urotensin pathway could provide novel therapeutic avenues for IS.

Urotensin receptor antagonist urantide improves atherosclerosis-related kidney injury by inhibiting JAK2/STAT3 signaling pathway in rats.

OBJECTIVE: To investigate the role of urantide in the prevention and treatment of atherosclerotic nephropathy by antagonizing the urotensin II/urotensin receptor (UII/UT) system and regulating JAK2/STAT3 signaling pathway. METHODS: Atherosclerosis (AS) rats were treated with urantide at a concentration of 30 µg/kg for 3, 7, 14 days. RESULTS: An excessive expression of UII and its receptor G protein-coupled receptor 14 (GPR14) was seen in AS rat kidneys and the expression was significantly reduced after urantide administration. Either body weight, renal functions of urea nitrogen, urine proteins and anion gaps or expression of kidney injury-related genes Agtr1α, Nox4, Cyba and Ncf1 were improved after AS rats were treated with urantide. After antagonizing the UII/GPR14 system by using urantide, the expression of genes and proteins in the JAK2/STAT3 and ERK pathways was decreased, and the nuclear protein p-STAT3 and p-ERK were obviously decreased. p-JAK2 and p-STAT3 were decreased in the urantide group in a time-dependent manner. The UII/GPR14 system and JAK2/STAT3 signals were localized in tubules and then glomeruli to affect renal reabsorption and filtration. CONCLUSION: Urantide can effectively block the UII/GPR14 system by regulating the JAK2/STAT3 signaling pathway to prevent and treat atherosclerosis-related kidney injury. At this stage, effective inhibition of inflammatory signaling pathways is of great significance in the treatment of atherosclerosis.

The peptide compound urantide regulates collagen metabolism in atherosclerotic rat hearts and inhibits the JAK2/STAT3 pathway.

The aim of the present study was to investigate the effect of urantide on collagen metabolism in the hearts of rats with atherosclerosis (AS) by evaluating the expression of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway constituents. Urantide was delivered to rats with AS via tail vein injection for 3, 7 and 14 days. Serological indicators were identified by an automated biochemical analyzer. Histomorphological changes in the cardiac tissue of rats were observed by pathological staining techniques. The expression of genes and proteins was assessed using reverse transcription­quantitative PCR and western blot analysis, respectively. Localization of proteins was detected by immunofluorescence. Overexpression of urotensin II (UII) and its receptor, G protein­coupled receptor 14 (GPR14), was observed in the hearts of rats with AS and the expression of both proteins significantly declined after urantide administration. Triglyceride, total cholesterol, low­density lipoprotein, high­density lipoprotein and calcium levels were improved in rats with AS following treatment with urantide. Notably, urantide was able to antagonize the UII/GPR14 system. Urantide treatment resulted in markedly decreased expression levels of matrix metalloproteinase 2 (MMP­2), collagen type I/III, and genes and proteins in the JAK2/STAT3 pathway. By contrast, TIMP metallopeptidase inhibitor 2 (TIMP­2) levels were increased. In addition, the MMP­2/TIMP­2 protein ratio was significantly decreased in rats treated with urantide compared with AS rats with no urantide treatment. Constituents of the JAK2/STAT3 pathway and collagen type I/III were found to be localized in the diseased tissue and blood vessels of the hearts of rats with AS. In conclusion, urantide was able to effectively block the UII/GPR14 system by regulating the JAK2/STAT3 pathway and collagen metabolism. Inhibition of the UII/GPR14 system may prevent and potentially treat atherosclerotic myocardial fibrosis. Based on the current results, it was hypothesized that collagen metabolism may be associated with the JAK2/STAT3 pathway.

Urotensin-related gene transcripts mark developmental emergence of the male forebrain vocal control system in songbirds.

Songbirds communicate through learned vocalizations, using a forebrain circuit with convergent similarity to vocal-control circuitry in humans. This circuit is incomplete in female zebra finches, hence only males sing. We show that the UTS2B gene, encoding Urotensin-Related Peptide (URP), is uniquely expressed in a key pre-motor vocal nucleus (HVC), and specifically marks the neurons that form a male-specific projection that encodes timing features of learned song. UTS2B-expressing cells appear early in males, prior to projection formation, but are not observed in the female nucleus. We find no expression evidence for canonical receptors within the vocal circuit, suggesting either signalling to other brain regions via diffusion or transduction through other receptor systems. Urotensins have not previously been implicated in vocal control, but we find an annotation in Allen Human Brain Atlas of increased UTS2B expression within portions of human inferior frontal cortex implicated in human speech and singing. Thus UTS2B (URP) is a novel neural marker that may have conserved functions for vocal communication.

Gene expression and hormone secretion profile of urotensin I associated with osmotic challenge in caudal neurosecretory system of the euryhaline flounder, Platichthys flesus.

The caudal neurosecretory system (CNSS) is a part of stress response system, a neuroendocrine structure unique to fish. To gain a better understanding of the physiological roles of CNSS in fluid homeostasis, we characterized the tissue distribution of urotensin I (UI) expression in European flounder (Platichthys flesus), analyzed the effect chronic exposure to seawater (SW) or freshwater (FW), transfer from SW to FW, and reverse transfer on mRNA levels of UI, L-type Ca2+ channels and Ca-activated K+ channels transcripts in CNSS. The tissue distribution demonstrated that the CNSS is dominant sites of UI expression, and UI mRNA level in fore brain appeared greater than other non-CNSS tissues. There were no consistent differences in CNSS UI expression or urophysis UI content between SW- and FW-adapted fish in July and September. After transfer from SW to FW, at 8 h CNSS UI expression was significantly increased, but urophysis UI content was no significantly changes. At 24 h transfer from SW to FW, expression of CNSS UI was no apparent change and urophysis UI content was reduced. At 8 h and 24 h after transfer from FW to SW UI expression and urophysis UI content was no significantly effect. The expression of bursting dependent L-type Ca2+ channels and Ca-activated K+ channels in SW-adapted fish significantly decreased compared to those in FW-adapted. However, there were no differences in transfer from SW to FW or from FW to SW at 8 h and 24 h. Thus, these results suggest CNSS UI acts as a modulator in response to osmotic stress and plays important roles in the body fluid homeostasis.

Cilia-driven cerebrospinal fluid flow directs expression of urotensin neuropeptides to straighten the vertebrate body axis.

Straightening of the body axis is a major morphogenetic event that produces the typical head-to-tail shape of the vertebrate embryo. Defects in axial straightening can lead to debilitating disorders such as idiopathic scoliosis, characterized by three-dimensional curvatures of the spine1. Although abnormal cerebrospinal fluid (CSF) flow has been implicated in the development of idiopathic scoliosis2, the molecular mechanisms operating downstream of CSF flow remain obscure. Here we show that, in zebrafish embryos, cilia-driven CSF flow transports adrenergic signals that induce urotensin neuropeptides in CSF-contacting neurons along the spinal cord. Urotensins activate their receptor on slow-twitch muscle fibers of the dorsal somite; the contraction of these fibers likely results in straightening of the body axis. Consistent with this, mutation of the urotensin receptor resulted in severe scoliosis in adult zebrafish, closely mimicking the human disorder. These findings suggest that disruption of urotensin signaling by impaired CSF flow could be a critical etiological factor underlying the pathology of idiopathic scoliosis.

Urotensin-II gene rs228648 polymorphism associated with the risk of diabetes mellitus.

Background: Urotensin-II (UII) rs228648 polymorphism has been reported to be associated with the risk of diabetes mellitus (DM) with inconsistent results. The present study sought to reassess the relationship between this polymorphism and susceptibility to DM by meta-analysis.Methods: Relevant eligible studies and whole genome association study (GWAS) data electronically searched were pooled to evaluate the strength of the association with odds ratios (ORs) and 95% confidence intervals (CIs).Results: Seven case-control studies involving 894 cases and 1186 controls were finally included in the meta-analysis. Overall analyses indicated that UII gene rs228648 variant was significantly associated with reduced risk of DM (allele, A vs. G: OR = 0.68, 95%CI = 0.56-0.82; dominant, AA+GA vs. GG: OR = 0.70, 95%CI = 0.53-0.91; homozygote, AA vs. GG: OR = 0.41, 95%CI = 0.28-0.61; recessive, AA vs. GA+GG: OR = 0.36, 95%CI = 0.19-0.71). In subgroup analyses based on ethnicity, the results showed a significant association of rs228648 polymorphism with decreased risk of DM in Chinese population under all five genetic models as well as in non-Chinese population under heterozygote and recessive models. Stratified analyses by specific type of DM also presented a significant association for common diabetes mellitus (CDM) under allele and homozygote as well as gestational diabetes mellitus (GDM) under all genetic models except for homozygote model. However, the synthetic analysis with GWAS data suggested an increased risk of DM with rs228648 effect allele in European population (OR = 1.01, 95%CI = 1.00-1.02).Conclusion: The present meta-analysis preliminarily suggested a potentially opposite role of rs228648 polymorphism associated with DM risk in the Chinese and European population. Further studies are in great request to verify the results.