Disease relevance of UTS2

• These results strongly suggest that subjects with S89N in the UTS2 gene are more insulin-resistant and thus more susceptible to type 2 diabetes mellitus development [1].
• Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates [2].
• Urinary hUII concentrations from patients with essential hypertension and those with renal tubular abnormality, but not with glomerular diseases, were significantly greater than those from normal individuals [3].
• U-II is proposed to contribute to human diseases including atherosclerosis, cardiac hypertrophy, pulmonary hypertension and tumour growth [4].
• In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia [5].

Psychiatry related information on UTS2

• Following ICV administration, hU-II (3-10 micrograms ICV) increased rearing and grooming, and increased motor activity in a familiar environment [6].
• Recently, physiological data have provided further evidence that UII is indeed a modulator of REM sleep [7].

High impact information on UTS2

• Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization [2].
• The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far [2].
• Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man [2].
• Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities [2].
• In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction [2].

Chemical compound and disease context of UTS2

• Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in hypertension and atherosclerosis [8].
• These findings suggest that hU-II may play a novel role in pulmonary hypertension by promoting remodeling processes via activation of NADPH oxidases [9].
• Among these inhibitors, sulfaphenazole and phalloidin were able to reduce hU-II-induced hypotension [10].
• In contrast, 1 hour after intravenous urotensin II (40 nmol/kg bolus; n=6), a sustained tachycardia (+25+/-8 bpm) ensued, but cardiac output, cardiac contractility, total peripheral conductance, and plasma glucose levels did not change significantly [11].
• The role of more recently delineated vasoactive pathways such as urotensin-II/GPR 14 and anandamide/CB1 receptor in portal hypertension must be examined [12].

Biological context of UTS2

• The aim of this study is to investigate a possible contribution of SNPs in the UTS2 gene to the development of Type 2 diabetes [13].
• For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function [14].
• The allele frequency of 89N was significantly higher in type 2 diabetic patients than in both elderly normal subjects (P = 0.0018) and subjects with normal glucose tolerance (P = 0.0011), whereas the allele frequency of T21M and -605G>A in the UTS2 gene and those of two SNPs in the GPR14 gene were essentially identical in these three groups [1].
• The few structure-activity relationship studies reported to date attributed a critical role to this portion, with the Trp-Lys-Tyr motif appearing as the key determinant of U-II bioactivity [15].
• On the basis of its spectrum of activities, hU-II has been suggested to modulate cardiovascular homeostasis and possibly to be involved in certain cardiovascular pathologies [16].

Anatomical context of UTS2

• The resulting fractional excretion of hUII, exceeding the glomerular filtration rate, suggests a renal origin of urinary UII-LI. hUII mRNAs were abundantly expressed in the kidney and the right atrium, but far less so in the vasculature, whereas GPR14 mRNAs were equally and abundantly expressed in both cardiovascular and renal tissues [3].
• Using immunohistochemistry we demonstrated U-II immunoreactivity in endothelial, smooth muscle and inflammatory cells of both carotid and aortic plaques, with a clear propensity for intimal staining [17].
• In contrast, in humans U-II has emerged as a ubiquitious constrictor of both arteries and veins in vitro and elicits a reduction in blood flow in the forearm and skin microcirculation in vivo [4].
• We found that lymphocytes were by far the largest producers of U-II mRNA [17].
• We also extended our PCR analysis to include leukocyte expression of U-II and GPR14 [17].

Associations of UTS2 with chemical compounds

• Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 [2].
• Additionally, the effects of pre-treatment with the nitric oxide (NO) synthase blocker, nitro-l-arginine methyl ester (l-NAME), and the cyclooxygenase inhibitor, indomethacin, on the renal haemodynamic response to hU-II were studied in CHF rats [18].
• The effect of U-II on the vascular system is variable, depending on species, vascular bed and calibre of the vessel [19].
• Immunohistochemical studies showed intense UII peptide staining in diabetic tissue localized predominantly to tubular epithelial cells, and fluorescein-labeled ligand binding studies showed a similar tubular pattern of distribution [20].
• [Bz-Phe(6)]U-II bound the receptor expressed in COS-7 cells with high affinity (IC(50) 0.7 nM) and was as potent as U-II in the agonist-induced production of inositol phosphate [21].

Physical interactions of UTS2

• In the present study, a number of interesting structural features pertaining to the N-terminus of urotensin II have been evaluated for binding to cloned human and rat urotensin II receptors and functional effects on rat upper thoracic aorta smooth muscle preparations [22].

Regulatory relationships of UTS2

• Radioligand binding analysis showed high affinity binding of UII to membrane preparations isolated from HEK293 cells stably expressing rat GPR14 [23].
• 2. Although the somatostatin (SST) antagonist SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide) is purported to block U-II-induced contractions in rat isolated aorta, little is known about its specific pharmacological properties [24].
• In TE-671 cells, U-II stimulated extracellular signal regulated kinase phosphorylation and increased c-fos mRNA expression [25].
• Somatostatin receptor antagonists dose-dependently inhibited human urotensin II-induced Ca2+ transients in rat thoracic aorta rings [26].
• URP was found to bind and activate the human or rat UII receptors (GPR14) and showed a hypotensive effect when administered to anesthetized rats [27].

Other interactions of UTS2

• Urotensin-II is a neuropeptide "somatostatin-like" cyclic peptide, which was originally isolated from fish spinal cords, and which has recently been cloned from human [28].
• Is urotensin-II the new endothelin [4]?
• Accordingly, the present study sought to examine the expression and localization of UII and its receptor in kidney tissue from patients with diabetic nephropathy [20].
• These data suggest that hUII is an autocrine/paracrine growth factor for renal epithelial cells via activation of both protein kinase C and ERK1/2 pathways as well as Ca(2+) influx via voltage-dependent Ca(2+) channels [29].
• The synthesized compounds seem to be selective for the UII receptor as no activities were observed at the closely related SSTR3 and 5 receptors [30].

Analytical, diagnostic and therapeutic context of UTS2

• RESULTS: Gel filtration and reverse-phase high performance liquid chromatography of human urine extracts revealed a single major peak of hUII-LI co-eluting with known hUII [3].
• Using quantitative real-time RT-PCR we observed both increased U-II and GPR14 mRNA expression in tissue extracts from abdominal aortic aneurysms [17].
• Non-vascular, peripheral actions of U-II include potent inotropy and airway smooth muscle constriction and U-II and its receptor are present throughout rat brain implying a possible neurotransmitter or neuromodulatory role in the central nervous system [4].
• RESULTS: In human diabetic tissue, gene expression of UII and UT were increased 45- and almost 2,000-fold in comparison to control nephrectomy tissue, respectively (P < 0.0001) [20].
• A total of 41 analogs focusing on these characteristics were developed and evaluated using a binding assay on membranes from a stable HEK-293 cell line containing the human or rat U-II receptor, a functional assay for Ca2+ mobilization on transiently transfected CHO-K1 cells with the human or rat U-II receptor, and a rat thoracic aorta bioassay [31].

References