act-058362 and Kidney-Diseases

Urotensin II (U-II) is a vasoactive peptide with many potent effects in the cardiorenovascular system. U-II activates a G-protein-coupled receptor termed UT. UT and U-II are highly expressed in the cardiovascular and renal system. Patients with various cardiovascular diseases show high U-II plasma levels. It was demonstrated that elevated U-II plasma levels and increased UT expression seem to play a role in heart failure, end-stage renal disease and atherosclerosis. U-II induces potent changes in vascular tone regulation. In addition, U-II stimulates vascular smooth muscle cell proliferation and cardiomyocyte hypertrophy. Currently several pharmaceutical companies are developing compounds to control the U-II/UT system. There are preclinical and some clinical studies showing potential benefits of inhibiting U-II function in renal disease, heart failure, and diabetes. This article will review both pre- and clinical data concerning cardiorenovascular effects of U-II.

Topics: Animals; Cardiovascular System; Heart Diseases; Humans; Kidney; Kidney Diseases; Myocardium; Quinolines; Receptors, G-Protein-Coupled; Tissue Distribution; Urea; Urotensins; Vasoconstriction; Vasodilation

Cyclosporine-A (CsA) is widely used for immunosuppressive therapy in renal transplantation. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA. Urotensin II (U-II), a novel peptide with a powerful influence on vascular biology, has been added to the list of potential renal vascular regulators. Upregulation of the urotensin receptors and elevation of plasma U-II levels are thought to possibly play a role in the etiology of renal failure.. The present study examines this hypothesis by evaluating renal function and histology with regard to the potential role of U-II and its antagonist, palosuran, in the pathogenesis of CsA-induced nephrotoxicity in rats.. Male Sprague-Dawley rats were treated with CsA (15 mg/kg, for 21 days, intraperitoneally) or CsA + palosuran (300 mg/kg, for 21 days). Renal function was measured and histopathology, U-II immunostaining and protein detection with western blotting of the kidneys were performed.. Cyclosporine-A administration caused a marked decline in creatinine clearance (Ccr). Fractional sodium excretion (FENa) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsA-treated rats. Cyclosporine-A treatment resulted in a marked deterioration in renal histology and an increase in the expression of U-II protein in the kidneys. Palosuran's improvement of renal function manifested as a significant decrease in serum creatinine levels and a significant increase in urine creatinine levels, resulting in a marked increase in Ccr. Palosuran produced a significant normalization of kidney histology and prevented an increase in U-II expression.. Cyclosporine-A-induced renal impairment was accompanied by an increase in U-II expression in kidneys and a contrary decrease in systemic U-II levels. Palosuran improved the condition of rats suffering from renal dysfunction by preventing the decrease in renal U-II expression without affecting the systemic levels of U-II. The protective effect of palosuran in CsA nephrotoxicity is possibly independent of its U-II receptor antagonism.

Topics: Animals; Creatinine; Cyclosporine; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Models, Animal; Quinolines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Urea; Urotensins

Urotensin-II (U-II) is a cyclic peptide now described as the most potent vasoconstrictor known. U-II binds to a specific G protein-coupled receptor, formerly the orphan receptor GPR14, now renamed urotensin receptor (UT receptor), and present in mammalian species. Palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) is a new potent and specific antagonist of the human UT receptor. ACT-058362 antagonizes the specific binding of (125)I-labeled U-II on natural and recombinant cells carrying the human UT receptor with a high affinity in the low nanomolar range and a competitive mode of antagonism, revealed only with prolonged incubation times. ACT-058362 also inhibits U-II-induced calcium mobilization and mitogen-activated protein kinase phosphorylation. The binding inhibitory potency of ACT-058362 is more than 100-fold less on the rat than on the human UT receptor, which is reflected in a pD'(2) value of 5.2 for inhibiting contraction of isolated rat aortic rings induced by U-II. In functional assays of short incubation times, ACT-058362 behaves as an apparent noncompetitive inhibitor. In vivo, intravenous ACT-058362 prevents the no-reflow phenomenon, which follows renal artery clamping in rats, without decreasing blood pressure and prevents the subsequent development of acute renal failure and the histological consequences of ischemia. In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia. As a selective renal vasodilator, ACT-058362 may be effective in other renal diseases.

Topics: Animals; Aorta, Thoracic; Disease Models, Animal; Humans; Ischemia; Kidney Diseases; Male; Quinolines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renal Insufficiency; Urea; Urotensins; Vasoconstriction