The urotensinergic system was previously considered as being linked to numerous pathophysiological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions. Based on this expectation, validation of urotensin II (UII) receptor (UT) antagonism in cell lines expressing rat or human UT, observations in animal models, and even clinical results were not as beneficial as expected, probably because of the complex effects of the urotensinergic system depending on the vascular bed, the studied animal species, and/or the administration route. Thus, it turns out that the actions of the UII/UT system in animal models are currently not predictive enough in regard to their effects in human clinical trials, thus many questions remain regarding the overall signaling profiles of UT leading to complex involvement in cardiovascular, inflammatory responses, and cancer. We, here, propose that UII may rather play chemokine functions leading to long-term tissue remodeling and tumorigenesis, at least in part due to the pleiotropic functions of UT oriented toward chemoattractant activities.
At the end of the 1960s, Drs. Bern and Lederis attributed the name “urotensins” to a series of biologically active peptides isolated from the urophysis neurosecretory system of the teleost fish Gillichthys mirabilis. Among those, UII was characterized through its ability to stimulate smooth muscle cells (1). Then, the amino acid sequence of UII was subsequently identified in a number of other fish species, and the presence of the UII peptide was discovered in the brain of a tetrapod, the frog Rana ridibunda (2, 3) two decades later (Table 1). Based on these observations, the gene encoding UII has been the subject of more research and was successfully identified in various mammalian species including in monkey and human (Table 1) (4, 5). The neuropeptide UII is composed of 11 amino acids in primates (including Homo sapiens) to 17 amino acids in the mouse and shows remarkable conservation of the C-terminal CFWKYC hexapeptide portion formed by the covalent disulfide bridge (Table 1) during evolution, suggesting a crucial importance of the cycle in biological activity. To date, UII has been characterized in a single species of invertebrates, the Aplysia californica (6), in a form composed of 20 amino acids and whose cyclic hexapeptide differs from vertebrates by only two residues (F→L and Y→V) (7).
Table 1. Comparison of the sequences of urotensin II (UII) and urotensin II-related peptide (URP) in different species of tetrapods.
All the amino acid sequences of UII identified so far are mostly deduced from cDNAs and correspond to the C-terminal part of its precursor. In human, the deduced sequence of prepro-UII, cloned from colon tumor or placental library, evolved from alternative splicing of the human UTS2 gene, yielding a 124 (isoform b, NP_006777) and 139 (isoform a, NP_068835.1) amino acid variants. The two encoded isoforms are identical for the last 97 amino acids but differ at their N-terminal end exhibiting the signal peptide. The mature peptide UII results from the proteolysis of preproprotein UII at the tribasic site KKR by a specific urotensin converting enzyme (UCE), which is not still identified (4, 5). Study on the conversion of a 25 amino acid C-terminal fragment of preproprotein to mature peptide revealed that the endoprotease Furin and the serine protease trypsin, may act, respectively, as intracellular and extracellular UCE (12). This enzymatic cleavage appears necessary to confer biological activity (13).
In comparison with primate prepro-UII, precursors of rat and mouse UII markedly diverge by the amino acid composition of the N-flanking domain of the cyclic hexapeptide and by the absence of a typical cleavage site (KKR) for pro-hormone converting enzymes in the upstream region of UII sequence (10). These observations led Sugo and collaborators to characterize UII immunoreactivity detected in the brain of the two rodent species and to isolate, in 2003, a peptide similar to UII, the urotensin II-related peptide (URP) (9). Later on, the cloning of the prepro-URP cDNAs, in human, mouse, and rat revealed 54% homology between human and rat vs 47% homology between human and mouse (14). However, the URP sequence is identical in all mammals and corresponds to human Ala 1–UII 4–11. Finally, although URP was initially thought to exist only in tetrapods, its gene has been identified in the genome of several teleost fishes (15, 16). Together, the sequences of UII, URP, and somastostatin display high homology in particular at the level of the cyclic hexapeptide sequence and it was established that URP is a peptide paralog of UII (17).
Urotensin II and URP are widely distributed in the cardiovascular, renal, and endocrine systems. In humans, high expression levels of UII are found in the myocardium (18), the atria, and the ventricles (19–21). UII has also been detected in the heart of rats (4, 9, 20) and mice (11, 22). At the vascular level, the presence of mRNA for prepro-UII has been demonstrated in the arterial network, primarily in the thoracic aorta, pulmonary arteries, and arterioles. In contrast, it is almost absent in the venous network, with the exception of the saphenous and umbilical veins (19–21).
Several studies show that kidney is a major site of production of circulating UII in humans (9, 20, 21, 23, 24). The peptide is particularly abundant in glomerular epithelial cells, convoluted tubules, and collecting ducts (20, 25). Surprisingly, the level of expression of UII in the kidney of monkey and mice is weak (11), stressing some important differences between species. UII is also expressed in endocrine glands, such as pancreas or adrenal gland, in humans and rats (5, 23, 26). Nevertheless, the mRNA for UII is undetectable in these tissues in monkey and mice (11, 22), again raising the question of the occurrence of a conserved cardiovascular and/or endocrine role of UII among the different species.
Even though the identification of URP has been done more than 10 years ago, data concerning this peptide are considerably much more incomplete. Nevertheless, it is worth noting that the expression of prepro-URP is predominant in the gonads and placenta of humans and in the testis of rats (9). URP and its mRNA are also expressed in kidney (8, 9) and in the ventricles and myocardium of the rat heart (27, 28). The expression of the two peptides extends to the spleen, thymus, liver, stomach, and intestines (5, 9, 11, 20, 22, 23, 29, 30).
Within the central nervous system (CNS), UII immunoreactivity is mainly associated with motoneurons of the hypoglossal nucleus of the brainstem and the ventral horn of the spinal cord. This neuronal subpopulation also strongly expresses UII in the nuclei of the abducens, facial, trigeminal, and hypoglossal cranial nerves in rats (10, 31) and those of the caudal part of the spinal cord in mice (10, 32), rats (10, 31), and humans (4, 5). Surprisingly, UII is apparently absent from the brainstem of monkey (4, 11). URP mRNAs are localized in the spinal cord of humans and rats, at expression levels considerably lower than those of UII (9). In mice, URP mRNA is found in the brainstem and in motoneurons of the anterior horn of the spinal cord (22). Finally, URP is present in neuronal cell bodies of the preoptic region and in fibers of the median eminence and the organum vasculosum of the lamina terminalis, which is involved in thermoregulation (33).
Thus, UII and URP are
