Renal and vascular actions of urotensin II
2006; Elsevier BV; Volume: 70; Issue: 4 Linguagem: Inglês
10.1038/sj.ki.5001621
ISSN1523-1755
Autores Tópico(s)Hormonal Regulation and Hypertension
ResumoThe peptide hormone urotensin II (UII) has been highly conserved through the vertebrates from fish to humans. As it was shown to be the endogenous ligand for the mammalian orphan G-protein-coupled receptor GPR14, now renamed the UT receptor, interest in UII physiology has grown. Initial observations of a potent vasoconstrictor effect have been tempered with the subsequent revelation of an endothelium-dependent vasodilator action. These complex and contrasting vascular actions are both species- and vascular bed-specific. UII also plays a role in body fluid regulation in lower vertebrates, and it now appears that this extends to mammals. The kidney is a major source of both circulating and urinary UII. UII is found in both the proximal tubules and collecting ducts; the UT receptor is localized primarily to the renal medulla, with greatest expression in the inner medullary collecting ducts. Infusion in rats produced conflicting results: exogenous UII has been shown to increase glomerular filtration rate (GFR) and excretion of water and sodium, but also to reduce the same variables. Inhibition of UT receptor activity with the antagonist urantide resulted in an increase in GFR, diuresis, and natriuresis, suggesting that endogenous UII exerts a tonic influence on basal renal function. UII may also play a role in renal disease, being elevated in the circulation or urine of patients with renal failure and in experimental models of cardiovascular disease such as the spontaneously hypertensive rat. It remains to be established whether these changes represent an underlying primary cause or a compensatory response. The peptide hormone urotensin II (UII) has been highly conserved through the vertebrates from fish to humans. As it was shown to be the endogenous ligand for the mammalian orphan G-protein-coupled receptor GPR14, now renamed the UT receptor, interest in UII physiology has grown. Initial observations of a potent vasoconstrictor effect have been tempered with the subsequent revelation of an endothelium-dependent vasodilator action. These complex and contrasting vascular actions are both species- and vascular bed-specific. UII also plays a role in body fluid regulation in lower vertebrates, and it now appears that this extends to mammals. The kidney is a major source of both circulating and urinary UII. UII is found in both the proximal tubules and collecting ducts; the UT receptor is localized primarily to the renal medulla, with greatest expression in the inner medullary collecting ducts. Infusion in rats produced conflicting results: exogenous UII has been shown to increase glomerular filtration rate (GFR) and excretion of water and sodium, but also to reduce the same variables. Inhibition of UT receptor activity with the antagonist urantide resulted in an increase in GFR, diuresis, and natriuresis, suggesting that endogenous UII exerts a tonic influence on basal renal function. UII may also play a role in renal disease, being elevated in the circulation or urine of patients with renal failure and in experimental models of cardiovascular disease such as the spontaneously hypertensive rat. It remains to be established whether these changes represent an underlying primary cause or a compensatory response. Urotensin II (UII) was originally identified as one of a number of peptide hormones secreted by the fish caudal neurosecretory system. Synthesized in Dahlgren cells of the caudal spinal cord and released from the urophysis, a neurohemal organ unique to teleost fish, UII has been shown to contract vascular smooth muscle not only in fish but also in mammalian tissues.1.Balment R.J. Song W. Ashton N. Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation.Ann NY Acad Sci. 2005; 1040: 66-73Crossref PubMed Scopus (28) Google Scholar However, it was not until the discovery by Coulouarn et al.2.Coulouarn Y. Lihrmann I. Jegou S. et al.Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord.Proc Natl Acad Sci USA. 1998; 95: 15803-15808Crossref PubMed Scopus (377) Google Scholar that prepro-UII is expressed in human spinal cord, and peripheral tissues including the kidney, that a role for this peptide hormone was suspected in humans. Shortly after this report, Ames et al.3.Ames R.S. Sarau H.M. Chambers J.K. et al.Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature. 1999; 401: 282-286Crossref PubMed Scopus (789) Google Scholar published their landmark paper in the field, which demonstrated that goby UII binds to the human orphan G-protein-coupled receptor GPR14, now designated the UT receptor. Identification of the human form of UII (hUII)2.Coulouarn Y. Lihrmann I. Jegou S. et al.Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord.Proc Natl Acad Sci USA. 1998; 95: 15803-15808Crossref PubMed Scopus (377) Google Scholar revealed that it shares the cyclic hexapeptide sequence, Cys-Phe-Trp-Lys-Tyr-Cys, that is conserved across all species1.Balment R.J. Song W. Ashton N. Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation.Ann NY Acad Sci. 2005; 1040: 66-73Crossref PubMed Scopus (28) Google Scholar (Figure 1) and confers biological activity upon the molecule.4.McMaster D. Kobayashi Y. Rivier J. et al.Characterization of the biologically and antigenically important regions of urotensin II.Proc West Pharmacol Soc. 1986; 29: 205-208PubMed Google Scholar Initial attention focused on the vascular actions of UII, not least because of its extremely potent action in non-human primates. In vitro, hUII evoked contraction of a wide range of non-human primate arterial vessels; however venous vessels were unresponsive. However, Ames et al.3.Ames R.S. Sarau H.M. Chambers J.K. et al.Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature. 1999; 401: 282-286Crossref PubMed Scopus (789) Google Scholar observed less profound responses in rats, with only the thoracic aorta responding to hUII in vitro. In vivo, bolus injection of hUII led to myocardial depression, circulatory collapse, and death in the cynomolgus monkey.3.Ames R.S. Sarau H.M. Chambers J.K. et al.Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature. 1999; 401: 282-286Crossref PubMed Scopus (789) Google Scholar Subsequent studies have shown that the vasoactive properties of UII are more complex, with differences both between species and between vascular beds of the same species (reviewed by Douglas et al.;5.Douglas S.A. Dhanak D. Johns D.G. From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Table 1). Over the past few years, UII has emerged as an in vitro spasmogen, up to 100-fold more potent than endothelin I in arteries isolated from rats, humans, and a number of other mammalian species. Its pseudo-irreversible binding properties to the UT receptor have led to the suggestion that UII may function as a chronic regulator of basal vascular tone, rather than a short-term regulator of vascular resistance.5.Douglas S.A. Dhanak D. Johns D.G. From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar UII has also been shown to act as vasodilator: this action was endothelium-dependent, suggesting that vasodilatation is mediated via UT receptors on the endothelium whereas vasoconstriction is mediated via UT receptors on smooth muscle cells.5.Douglas S.A. Dhanak D. Johns D.G. From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar These contrasting effects suggest that UII plays a more complex role in the regulation of vascular tone than initial reports suggested, with UII now emerging as both a paracrine and an endocrine factor.Table 1Diverse vascular responses of mammalian species to UIIVesselSpeciesResponseIn vitro Thoracic aortaRat, rabbit, pig, marmosetConstrict Carotid arteryRatConstrict Renal arteryCynomolgus monkeyConstrict Mesenteric arteryCynomolgus monkeyConstrict Mesenteric arteryRatRelax Femoral arteryCynomolgus monkeyConstrict Basilar arteryCynomolgus monkeyConstrict Basilar arteryRatRelax Coronary arteryRat, pigRelax Coronary arteryCynomolgus monkey, dogConstrict Pulmonary arteryHumanRelax Pulmonary arteryHuman, rat, rabbit, cynomolgus monkeyConstrict Abdominal adipose tissue arteryHumanRelax Saphenous veinHumanConstrict Umbilical veinHumanConstrict Jugular veinRabbitConstrictIn vivo Mesenteric arteryRatRelax Hindquarter vascular bedRatRelax Mesenteric arteryCynomolgus monkeyConstrict Carotid arteryCynomolgus monkeyConstrictIt is notable that vascular beds from the same species show different responses. Furthermore, the same vascular beds in different species differ in their response to UII. This is most striking when comparing the effects of UII in vivo: in the cynomolgus monkey, UII causes profound vasoconstriction, yet in the rat it causes vasodilatation and a reduction systemic blood pressure. Data from Douglas et al.,5.Douglas S.A. Dhanak D. Johns D.G. From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Maguire and Davenport,31.Maguire J.J. Davenport A.P. Is urotensin-II the new endothelin?.Br J Pharmacol. 2002; 137: 579-588Crossref PubMed Scopus (131) Google Scholar Camarda et al.,32.Camarda V. Rizzi A. Calo G. et al.Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents.Naunyn Schmiedebergs Arch Pharmacol. 2002; 365: 141-149Crossref PubMed Scopus (98) Google Scholar and Douglas et al.33.Douglas S.A. Sulpizio A.C. Piercy V. et al.Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.Br J Pharmacol. 2000; 131: 1262-1274Crossref PubMed Scopus (215) Google Scholar Open table in a new tab It is notable that vascular beds from the same species show different responses. Furthermore, the same vascular beds in different species differ in their response to UII. This is most striking when comparing the effects of UII in vivo: in the cynomolgus monkey, UII causes profound vasoconstriction, yet in the rat it causes vasodilatation and a reduction systemic blood pressure. Data from Douglas et al.,5.Douglas S.A. Dhanak D. Johns D.G. From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Maguire and Davenport,31.Maguire J.J. Davenport A.P. Is urotensin-II the new endothelin?.Br J Pharmacol. 2002; 137: 579-588Crossref PubMed Scopus (131) Google Scholar Camarda et al.,32.Camarda V. Rizzi A. Calo G. et al.Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents.Naunyn Schmiedebergs Arch Pharmacol. 2002; 365: 141-149Crossref PubMed Scopus (98) Google Scholar and Douglas et al.33.Douglas S.A. Sulpizio A.C. Piercy V. et al.Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.Br J Pharmacol. 2000; 131: 1262-1274Crossref PubMed Scopus (215) Google Scholar Despite the growing interest in mammalian UII physiology, one aspect that has received little attention to date is its potential influence on renal function. Evidence that such a role might exist comes from studies in teleost fish, which show that UII contributes to their osmoregulatory physiology. A number of reports have implicated UII in the conservation of water,6.Bond H. Winter M.J. Warne J.M. et al.Plasma concentrations of arginine vasotocin and urotensin II are reduced following transfer of the euryhaline flounder (Platichthys flesus) from seawater to fresh water.Gen Comp Endocrinol. 2002; 125: 113-120Crossref PubMed Scopus (54) Google Scholar sodium, and chloride7.Loretz C.A. Species specificity and cellular mechanism of action of urotensin II in osmoregulation.in: Kobayashi H. Bern H.A. Urano A. Neurosecretion and the Biology of Neuropeptides. Springer-Verlag, Berlin1985: 479-485Google Scholar in fish species. The euryhaline flounder, Platichthys flesus, is able to osmoregulate and survive in both seawater and fresh water. When subjected to the hypo-osmotic challenge of a transfer from seawater to fresh water, plasma UII concentration fell rapidly, only returning to pre-transfer levels once the fish had adapted to the new osmotic environment over 72 h later.6.Bond H. Winter M.J. Warne J.M. et al.Plasma concentrations of arginine vasotocin and urotensin II are reduced following transfer of the euryhaline flounder (Platichthys flesus) from seawater to fresh water.Gen Comp Endocrinol. 2002; 125: 113-120Crossref PubMed Scopus (54) Google Scholar This is consistent with the notion that UII supports survival in hypertonic media by promoting water retention.1.Balment R.J. Song W. Ashton N. Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation.Ann NY Acad Sci. 2005; 1040: 66-73Crossref PubMed Scopus (28) Google Scholar UII has also been shown to regulate epithelial sodium transport. Thus, in absorptive tissues of teleost fish, such as urinary bladder and intestine, UII stimulated active sodium and chloride uptake from luminal fluid. Whereas in secretory tissues, such as opercular skin, UII inhibited active sodium and chloride transport.7.Loretz C.A. Species specificity and cellular mechanism of action of urotensin II in osmoregulation.in: Kobayashi H. Bern H.A. Urano A. Neurosecretion and the Biology of Neuropeptides. Springer-Verlag, Berlin1985: 479-485Google Scholar These observations demonstrate that UII can directly affect epithelial ion transport in fish and influence body fluid homeostasis, highlighting that UII may also influence renal function in mammals. The kidney appears to be a major source of UII synthesis in mammalian species. Prepro-UII mRNA expression has been identified in human,2.Coulouarn Y. Lihrmann I. Jegou S. et al.Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord.Proc Natl Acad Sci USA. 1998; 95: 15803-15808Crossref PubMed Scopus (377) Google Scholar,8.Matsushita M. Shichiri M. Imai T. et al.Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues.J Hypertens. 2001; 19: 2185-2190Crossref PubMed Scopus (234) Google Scholar primate, and mouse kidneys.9.Elshourbagy N.A. Douglas S.A. Shabon U. et al.Molecular and pharmacological characterization of genes encoding urotensin-II peptides and their cognate G-protein-coupled receptors from the mouse and monkey.Br J Pharmacol. 2002; 136: 9-22Crossref PubMed Scopus (122) Google Scholar Immunoreactive UII expression has been described in human renal blood vessels.10.Shenouda A. Douglas S.A. Ohlstein E.H. et al.Localization of urotensin-II immunoreactivity in normal human kidneys and renal carcinoma.J Histochem Cytochem. 2002; 50: 885-889Crossref PubMed Scopus (102) Google Scholar This was limited to the arterial vessels, which expressed UII in both endothelial and smooth muscle cells. In the tubule itself, the greatest level of expression was found in the distal and collecting tubules.10.Shenouda A. Douglas S.A. Ohlstein E.H. et al.Localization of urotensin-II immunoreactivity in normal human kidneys and renal carcinoma.J Histochem Cytochem. 2002; 50: 885-889Crossref PubMed Scopus (102) Google Scholar We observed a somewhat different pattern of UII expression in the rat kidney, with immunostaining present in the proximal tubules, outer, and inner medullary collecting ducts. This is consistent with the observation that UII mRNA expression was significantly higher in the medulla in comparison with the cortex.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar UII is also present in human8.Matsushita M. Shichiri M. Imai T. et al.Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues.J Hypertens. 2001; 19: 2185-2190Crossref PubMed Scopus (234) Google Scholar and rat11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar urine at concentrations greatly exceeding that in plasma. Human UII clearance equalled or exceeded that of creatinine in normal human subjects, leading to the suggestion that urinary UII is primarily derived from a renal source.8.Matsushita M. Shichiri M. Imai T. et al.Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues.J Hypertens. 2001; 19: 2185-2190Crossref PubMed Scopus (234) Google Scholar Measurement of arteriovenous concentration gradients revealed net secretion of UII into the circulation of the anesthetized sheep by the kidneys, as well as the heart and liver.12.Charles C.J. Rademaker M.T. Richards A.M. et al.Urotensin II: evidence for cardiac, hepatic and renal production.Peptides. 2005; 26: 2211-2214Crossref PubMed Scopus (49) Google Scholar Thus, renally derived UII may act not only as a local paracrine/autocrine factor in the kidney, but may also play a role as a circulating endocrine. UT mRNA is expressed in human,8.Matsushita M. Shichiri M. Imai T. et al.Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues.J Hypertens. 2001; 19: 2185-2190Crossref PubMed Scopus (234) Google Scholar monkey, and mouse kidneys.9.Elshourbagy N.A. Douglas S.A. Shabon U. et al.Molecular and pharmacological characterization of genes encoding urotensin-II peptides and their cognate G-protein-coupled receptors from the mouse and monkey.Br J Pharmacol. 2002; 136: 9-22Crossref PubMed Scopus (122) Google Scholar [125I]hUII-binding sites have also been identified in the Sprague–Dawley rat kidney by autoradiography.13.Disa J. Floyd L.E. Edwards R.M. et al.Identification and characterization of binding sites for human urotensin-II in Sprague–Dawley rat renal medulla using quantitative receptor autoradiography.Peptides. 2005; https://doi.org/10.1016/j.peptides.2005.1010.1004Crossref PubMed Google Scholar The majority of binding sites were found in the medulla, with very little cortical binding. This agrees with our observations, by immunohistochemistry, of UT expression in thin ascending limbs and inner medullary collecting ducts, with only occasional immunostaining in glomerular arterioles.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar We also reported that medullary UT mRNA expression was significantly greater than that in the cortex.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Several ligand-binding studies have concluded that UII interacts with a single class of binding site. Competition binding experiments showed that several isoforms of UII (goby, rat, mouse, and porcine A and B) displaced hUII radioligand from mouse and monkey UT receptors transfected into HEK-293 cells with comparable Ki values and Hill coefficients approaching unity.9.Elshourbagy N.A. Douglas S.A. Shabon U. et al.Molecular and pharmacological characterization of genes encoding urotensin-II peptides and their cognate G-protein-coupled receptors from the mouse and monkey.Br J Pharmacol. 2002; 136: 9-22Crossref PubMed Scopus (122) Google Scholar A single class of binding sites for hUII has been described in the rat outer medulla, with an apparent dissociation constant (Kd) of 1.9±0.9 nM and a maximum binding capacity (Bmax) of 408±47 amol mm2.13.Disa J. Floyd L.E. Edwards R.M. et al.Identification and characterization of binding sites for human urotensin-II in Sprague–Dawley rat renal medulla using quantitative receptor autoradiography.Peptides. 2005; https://doi.org/10.1016/j.peptides.2005.1010.1004Crossref PubMed Google Scholar Taken together, these data suggest that UII may possess renovascular effects, whereas any potential tubular actions are likely to be limited to the loop of Henlé and distal nephron. The UT receptor has also been shown to bind another peptide, urotensin-related peptide (URP). This octapeptide, identified in humans, mice, and rats,14.Sugo T. Murakami Y. Shimomura Y. et al.Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain.Biochem Biophys Res Commun. 2003; 310: 860-868Crossref PubMed Scopus (148) Google Scholar shares the cyclic hexapeptide sequence Cys-Phe-Trp-Lys-Tyr-Cys with UII (Figure 1). Despite the similarity of the mature peptides, the precursor proteins show little sequence homology, consistent with the disparate locations of the human UII and URP genes at 1p36 and 3q29, respectively. In competition binding studies, URP bound to both hUT and rUT receptors with higher affinity than that of hUII (IC50 in CHO cells expressing hUT receptors was 2.8 nM for URP vs 12 nM for hUII). In vivo, URP induced a hypotensive response in anesthetized rats of similar magnitude to that induced by rUII. Prepro-URP was identified in human kidney, although not in rat kidney;14.Sugo T. Murakami Y. Shimomura Y. et al.Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain.Biochem Biophys Res Commun. 2003; 310: 860-868Crossref PubMed Scopus (148) Google Scholar however, we have reported11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar that the rat kidney expresses URP mRNA at levels comparable with that of rUII mRNA. Hence, URP may also activate renal UT receptors and potentially influence renal function in mammals. There have only been a few reports of the effects of UII on renal function in mammals and these have had conflicting outcomes (Figure 2). We have shown recently11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar that bolus injections of rat UII (rUII) in the low pmol/100 g body weight range produced dose-related reductions in glomerular filtration rate (GFR), which were accompanied by reductions in both urine flow and sodium excretion rates. Preliminary studies in our laboratory show that continuous infusion of rUII over the same concentration range also induced a fall in GFR and an increase in the fractional excretion of sodium (AES Abdel-Razik, RJ Balment, and N Ashton, unpublished observations). However, Ovcharenko et al.15.Ovcharenko E. Abassi Z. Rubinstein I. et al.Renal effects of human urotensin-II in rats with experimental congestive heart failure.Nephrol Dial Transplant. 2006; 21: 1205-1211Crossref PubMed Scopus (24) Google Scholar saw only modest reductions in GFR and no change in sodium excretion in rats injected with hUII in the low nmol/kg dose range. This contrasts markedly with the observations of Zhang et al.16.Zhang A.Y. Chen Y.F. Zhang D.X. et al.Urotensin II is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney.Am J Physiol Renal Physiol. 2003; 285: F792-F798Crossref PubMed Scopus (96) Google Scholar who reported an increase in GFR and a diuresis and natriuresis following continuous intrarenal infusion of hUII in the low pmol/kg range, again in the rat. These differences could reflect dose-related responses or the effect of route of administration. However, Douglas et al.5.Douglas S.A. Dhanak D. Johns D.G. From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar propose another possibility which may account for much of the variability reported here and in the UII literature as a whole. They suggest that most UT receptors are occupied by endogenous UII and, as a result, only a few unoccupied receptors are available to bind exogenous UII. This lack of a spare receptor reserve leads to the variability and low efficacy observed across many studies. One way to overcome the lack of receptor reserve and expose the influence of endogenous UII is through the use of a selective UT receptor antagonist. The most potent UT receptor antagonist available to date is urantide, [Pen5, DTrp7, Orn8]hU-II(4–11), a derivative of hUII.17.Patacchini R. Santicioli P. Giuliani S. et al.Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta.Br J Pharmacol. 2003; 140: 1155-1158Crossref PubMed Scopus (95) Google Scholar Administration of urantide in vivo has provided evidence of a heretofore unsuspected role for UII in the regulation of renal function. Continuous infusion of urantide into the rat, at a dose shown to inhibit the vascular actions of exogenous UII, resulted in an increase in GFR, coupled with a diuresis and natriuresis.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Fractional excretion of sodium was 44% higher in the urantide-treated group; however, this difference did not reach statistical significance. Thus, it remains unclear whether the natriuresis was due entirely to changes in GFR or if endogenous UII also exerts a direct action on the tubule. Given that UII has been shown to stimulate epithelial sodium transport in fish7.Loretz C.A. Species specificity and cellular mechanism of action of urotensin II in osmoregulation.in: Kobayashi H. Bern H.A. Urano A. Neurosecretion and the Biology of Neuropeptides. Springer-Verlag, Berlin1985: 479-485Google Scholar and that the UT receptor is expressed in the distal nephron of the rat,11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar it is tempting to speculate that UII does have an effect on the tubule itself. Regardless of the site(s) of action, these data strongly suggest that endogenous UII exerts a tonic influence on renal function in the rat. Whether this is the case in humans remains to be determined. A pathophysiological role for UII has been implicated in a number of renal diseases, although it is not yet clear whether it has a causative or protective influence. Patients with renal dysfunction (primarily due to glomerulonephritis or diabetes mellitus) have been reported to have plasma UII concentrations two- to three-fold higher than those of controls.18.Totsune K. Takahashi K. Arihara Z. et al.Role of urotensin II in patients on dialysis.Lancet. 2001; 358: 810-811Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Similarly, patients with diabetic nephropathy have been shown to have elevated plasma and urinary UII concentrations.19.Totsune K. Takahashi K. Arihara Z. et al.Elevated plasma levels of immunoreactive urotensin II and its increased urinary excretion in patients with Type 2 diabetes mellitus: association with progress of diabetic nephropathy.Peptides. 2004; 25: 1809-1814Crossref PubMed Scopus (98) Google Scholar This was associated with a 64-fold increase in renal UII expression and a 2000-fold increase in UT expression.20.Langham R.G. Kelly D.J. Gow R.M. et al.Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy.Am J Kidney Dis. 2004; 44: 826-831Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Plasma UII has also been reported to be elevated in patients with end-stage renal disease.21.Mallamaci F. Cutrupi S. Pizzini P. et al.Urotensin II in end-stage renal disease: an inverse correlate of sympathetic function and cardiac natriuretic peptides.J Nephrol. 2005; 18: 727-732PubMed Google Scholar Interestingly, plasma UII concentration was inversely related to sympathetic activity and brain natriuretic peptide (a marker of left ventricular hypertrophy), implying that high plasma UII is associated with relative cardiovascular protection in end-stage renal disease. This was confirmed in a follow-up study in which plasma UII concentration was shown to be inversely related to fatal and non-fatal cardiovascular events in patients with end-stage renal disease, leading the authors to suggest that UII is vasculoprotective in this group.22.Zoccali C. Mallamaci F. Tripepi G. et al.Urotensin II is an inverse predictor of incident cardiovascular events in end-stage renal disease.Kidney Int. 2006; 69: 1253-1258Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In contrast, chronic heart failure (CHF) patients without reported concurrent renal disease had 43% higher plasma UII concentrations compared with controls.23.Gruson D. Rousseau M.F. Ahn S.A. et al.Circulating urotensin II levels in moderate to severe congestive heart failure: its relations with myocardial function and well established neurohormonal markers.Peptides. 2005; https://doi.org/10.1016/j.peptides.2005.1011.1019Crossref PubMed Google Scholar Furthermore, plasma UII was positively correlated with the severity of CHF and both brain natriuretic peptide and big endothelin 1 as markers of left ventricular hypertrophy. One possible explanation for this apparent anomaly is that the study in end-stage renal disease patients documented all cardiovascular events (including angina, myocardial infarction, arrhythmia, heart failure, ischemic events, and stroke) rather than CHF alone, so it is possible that the relationship between plasma UII and cardiovascular events is disease-specific. There is also evidence from experimental animal models that UII may have some role in cardiovascular disease. CHF is associated with impaired renal function and a reduction in GFR: UII was shown to induce a marked increase in renal blood flow and GFR in a rat model of CHF.15.Ovcharenko E. Abassi Z. Rubinstein I. et al.Renal effects of human urotensin-II in rats with experimental congestive heart failure.Nephrol Dial Transplant. 2006; 21: 1205-1211Crossref PubMed Scopus (24) Google Scholar This effect was nitric oxide-dependent, suggesting that UII can act as a vasodilator on the renal vasculature. Zhang et al.16.Zhang A.Y. Chen Y.F. Zhang D.X. et al.Urotensin II is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney.Am J Physiol Renal Physiol. 2003; 285: F792-F798Crossref PubMed Scopus (96) Google Scholar reached a similar conclusion after demonstrating that hUII induced an endothelium-dependent vasodilatation of the rat renal artery, which was inhibited by NG-nitro-L-arginine methyl ester. This was confirmed using a fluorescent NO indicator, 4,5-diaminofluorescein diacetate, which showed that hUII induced NO production in renal artery endothelium. Changes in UII expression and activity have also been reported in the spontaneously hypertensive rat (SHR). The plasma UII concentration was almost twofold higher in SHR compared with control Wistar–Kyoto (WKY) rats.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar This is consistent with elevated urinary UII concentrations observed in hypertensive patients.8.Matsushita M. Shichiri M. Imai T. et al.Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues.J Hypertens. 2001; 19: 2185-2190Crossref PubMed Scopus (234) Google Scholar We also observed greater UT mRNA expression in the medulla of SHR, with a similar tendency for UII mRNA expression.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Interestingly, URP mRNA expression was reduced by comparison with WKY rats, implying that there is an increase in the UII/URP ratio in the SHR kidney. The vascular response of SHR to UII administration is also enhanced: bolus intravenous injection of hUII produced a greater fall in blood pressure in SHR in comparison with WKY rats.24.Gendron G. Gobeil Jr, F. Belanger S. et al.Urotensin II-induced hypotensive responses in Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats.Peptides. 2005; 26: 1468-1474Crossref PubMed Scopus (26) Google Scholar These data suggest that the UII system is upregulated in SHR with established hypertension; however, whether this is cause or effect remains to be determined. These observations in the SHR raise an important point that must be taken into account when making comparisons across species and even different strains of the same species. Disa et al.13.Disa J. Floyd L.E. Edwards R.M. et al.Identification and characterization of binding sites for human urotensin-II in Sprague–Dawley rat renal medulla using quantitative receptor autoradiography.Peptides. 2005; https://doi.org/10.1016/j.peptides.2005.1010.1004Crossref PubMed Google Scholar noted that the low-affinity binding of [125I]hUII to renal membranes was much lower in both WKY and SHR when compared with Sprague–Dawley rats. We observed similar quantitative differences in UII, URP, and UT mRNA expression between Sprague–Dawley rats and that of WKY and SHR. UT mRNA expression in the cortex of WKY and SHR was eightfold lower and medullary expression was 11-fold lower than that in Sprague–Dawley rats.11.Song W. Abdel-Razik A.E.S. Lu W. et al.Urotensin II and renal function in the rat.Kidney Int. 2006; 69: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar The in vivo response to bolus intravenous UII also differs between rat strains: at 3–10 ng/kg, UII lowered blood pressure in WKY and Sprague–Dawley rats by 10–20%, whereas similar doses reduced blood pressure in Lewis rats by 50%.13.Disa J. Floyd L.E. Edwards R.M. et al.Identification and characterization of binding sites for human urotensin-II in Sprague–Dawley rat renal medulla using quantitative receptor autoradiography.Peptides. 2005; https://doi.org/10.1016/j.peptides.2005.1010.1004Crossref PubMed Google Scholar Thus, caution must be taken when comparing data from different rat strains as it appears that activity of the UII system varies considerably. Altered UII expression in disease states has prompted the development of a number of UT receptor antagonists (reviewed by Carotenuto et al.25.Carotenuto A. Grieco P. Rovero P. et al.Urotensin-II receptor antagonists.Curr Med Chem. 2006; 13: 267-275Crossref PubMed Scopus (27) Google Scholar). Several peptide antagonists have been identified which share a common cyclic region, similar to the conserved sequence of UII (Figure 1). This comprises D/LCys-X-D/LTrp-Orn/Lys-Z-Cys, where X is either Phe, [3-pyridyl]Ala, [4-aminophenyl]Ala, or Tyr and Z is either Tyr, Val, or tert-Leu. Of these compounds, urantide is the most potent peptide antagonist developed to date.17.Patacchini R. Santicioli P. Giuliani S. et al.Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta.Br J Pharmacol. 2003; 140: 1155-1158Crossref PubMed Scopus (95) Google Scholar It acts as a pure antagonist of the rat UT receptor, with a pA2 of 8.2 in the rat-isolated thoracic aorta bioassy;17.Patacchini R. Santicioli P. Giuliani S. et al.Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta.Br J Pharmacol. 2003; 140: 1155-1158Crossref PubMed Scopus (95) Google Scholar however, it has been shown to act as an agonist (pEC50 8.1) in a [Ca2+]i mobilization assay in CHO cells expressing the hUT receptor.26.Camarda V. Song W. Marzola E. et al.Urantide mimics urotensin-II induced calcium release in cells expressing recombinant UT receptors.Eur J Pharmacol. 2004; 498: 83-86Crossref PubMed Scopus (59) Google Scholar A number of non-peptide compounds have also been developed; these feature a basic amino group and at least two aromatic moieties. The most potent of these is the 4-ureido-quinoline derivative, palosuran (ACT-058362).27.Clozel M. Binkert C. Birker-Robaczewska M. et al.Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system.J Pharmacol Exp Ther. 2004; 311: 204-212Crossref PubMed Scopus (124) Google Scholar Palosuran is selective for the human UT receptor, with an IC50 of 3.6 nM for hUT compared with 1475 nM for rUT. A series of diarlsulfonamide derivatives have been described recently, which appear to be potent antagonists of several forms of the UT receptor. One example, SB-706375, was shown to inhibit [125I]hUII binding to the UT receptor in SJRH30 cells (Ki 5.4 nM) as well as rodent, feline, and primate recombinant UT receptors (Ki 4.7–20.7 nM).28.Douglas S.A. Behm D.J. Aiyar N.V. et al.Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375.Br J Pharmacol. 2005; 145: 620-635Crossref PubMed Scopus (50) Google Scholar Application of these and other compounds in a variety of disease models has shown that UT antagonism has potential therapeutic benefit. Thus, SB-611812, an arylsulfonamide UT antagonist, has been used to show that UII-induced re-stenosis can be reduced in rat carotid arteries following balloon angioplasty.29.Rakowski E. Hassan G.S. Dhanak D. et al.A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker.J Mol Cell Cardiol. 2005; 39: 785-791Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Administration of palosuran to streptozotocin-treated rats improved survival, increased insulin, and reduced the progression of renal damage.30.Clozel M. Hess P. Qiu C. et al.The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats.J Pharmacol Exp Ther. 2006; 316: 1115-1121Crossref PubMed Scopus (82) Google Scholar Similar effects were not seen in preliminary trials in patients with diabetic nephropathy, but further studies are underway to refine the dose regime in an attempt to improve the outcome. The therapeutic potential of UT receptor antagonists has yet to be fully realized, but it seems likely that they will be of clinical use in the treatment of hypertension, heart failure, and renal disease. In less than a decade since the discovery that UII is the endogenous ligand for the human orphan receptor GPR14, significant advances have been made in our understanding of the physiology of UII in mammals. UII has emerged as the most potent natural vasoconstrictor peptide, yet it also evokes endothelium-dependent vasodilatation. These effects are both species- and vascular bed-specific, suggesting that although some of the actions of UII have been conserved through evolution, there is also divergence. Rather less is known about UII's actions on the kidney, but recent studies from our lab and others have shown that UII influences GFR and the excretion of water and sodium. A direct effect on the tubular handling of sodium has yet to be demonstrated unequivocally, but circumstantial evidence points to the distal nephron as a potential site of action. The kidney has emerged as one of the main sources of UII in both humans and the rat, where it acts both as a paracrine and a circulating endocrine factor. Many of the biological effects of UII may also be induced by URP, which shares the conserved amino-acid sequence that conveys biological activity. The endogenous stimuli for UII and URP secretion in mammals remain unknown, so it is not clear whether the two peptides are released under similar circumstances. Altered UII and UT expression in renal failure and cardiovascular disease models suggests that UII may play a role in the diseased kidney; whether this role is protective or causal remains to be determined.
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