Enhanced renal sensitivity of the spontaneously hypertensive rat to urotensin II

Abstract

Abdel-Razik AE, Balment RJ, Ashton N. Enhanced renal sensitivity of the spontaneously hypertensive rat to urotensin II. Am J Physiol Renal Physiol 295: F1239 -F1247, 2008. First published August 13, 2008 doi:10.1152/ajprenal.90374.2008.-Urotensin II (UII) has been implicated widely in cardiovascular disease. The mechanism(s) through which it contributes to elevated blood pressure is unknown, but its emerging role as a regulator of mammalian renal function suggests that the kidney might be involved. The aim of this study was to determine the effect of UII on renal function in the spontaneously hypertensive rat (SHR). UII infusion (6 pmol ⅐ min Ϫ1 ⅐ 100 g body wt Ϫ1 ) in anesthetized SHR and control Wistar-Kyoto (WKY) rats produced marked reductions in glomerular filtration rate (⌬GFR WKY, n ϭ 7, Ϫ0.3 Ϯ 0.1 vs. SHR, n ϭ 7, Ϫ0.6 Ϯ 0.1 ml ⅐ min Ϫ1 ⅐ 100 g body wt Ϫ1 , P ϭ 0.03), urine flow, and sodium excretion rates, which were greater in SHR by comparison with WKY rats. WKY rats also showed an increase in fractional excretion of sodium (⌬FENa; ϩ0.6 Ϯ 0.1%, P ϭ 0.02) in contrast to SHR in which no such change was observed (⌬FENa Ϫ0.6 Ϯ 0.2%). Blockade of the UII receptor (UT), and thus endogenous UII activity, with urantide evoked an increase in GFR which was greater in SHR (ϩ0.3 Ϯ 0.1) compared with WKY rats (ϩ0.1 Ϯ 0.1 ml ⅐ min Ϫ1 ⅐ 100 g body wt Ϫ1 , P ϭ 0.04) and was accompanied by a diuresis and natriuresis. UII and UT mRNA expression were greater in the renal medulla than the cortex of both strains; however, expression levels were up to threefold higher in SHR tissue. SHR are more sensitive than WKY to UII, which acts primarily to lower GFR thus favoring salt retention in this model of hypertension.UT receptor; kidney; glomerular filtration rate; sodium THE NOVEL PEPTIDE hormone urotensin II (UII), originally identified in a neurohemal organ unique to fish (3), is now known to be expressed in many mammalian species, including humans (9) and rats (8). UII binds to a single specific G protein-coupled receptor (2, 18), designated the UT receptor (11), which is expressed abundantly in the nervous (13) and cardiorenal systems (20,30). The potent vasoconstrictor actions of UII (2) appear to be mediated by Ca 2ϩ mobilization through activation of a number of signaling pathways, including Ca 2ϩ channels, tyrosine kinase, p38MAPK, and ERK1/2 (26). UII also has a vasodepressor action, particularly in the rat, which is endothelium and nitric oxide dependent (26).UII has been implicated widely in cardiovascular disease. Plasma (7) and cerebrospinal fluid (31) UII concentrations have been positively correlated with blood pressure in hypertensive patients and single nucleotide polymorphisms of the UII gene have been associated with the development of essential hypertension (35). Elevated plasma or urinary UII concentrations have also been reported in patients with portal hypertension (15), congestive heart failure (22, 27), and renal failure (21, 32). These observations led to the suggestion that UII plays a role in card...

Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of the Urotensin-II Receptor Antagonist Palosuran in Healthy Male Subjects

“…However, in this study, after multiple-dose treatment with palosuran, we were not able to detect an effect on plasma U-II levels and urinary excretion parameters. Several reports in animals suggest that U-II has an important role in the occurrence of renal fibrosis and dysfunction [40,41], which is substantiated by the fact that U-II is produced in the kidney [42]. As the (patho)physiological pathway of U-II has not been fully characterized in patients or healthy subjects, differences in physiology could explain the absence of effect in healthy subjects in this study.…”

Pressor and renal regional hemodynamic effects of urotensin II in neonatal pigs

“…However, the physiological role of UII in the kidney remains controversial with studies reporting attenuation and elevation of important renal parameters, including total renal blood flow (RBF), glomerular filtration rate (GFR), urine flow rate (UV), and urinary sodium (U Na V) and potassium (U K V) excretion (Zhang et al 2003, Ovcharenko et al 2006, Song et al 2006, Abdel-Razik et al 2008a,b, Shi et al 2008.…”

Urotensin‐II receptor antagonism does not improve renal haemodynamics or function in rats with endotoxin‐induced acute kidney injury

“…18,19 These experiments showed that urantide increased GFR, urine output and urinary sodium excretion in both strains. 18,19 In addition, these investigators found that infusion of rat U-II reduced RBF, GFR, urine output and urinary sodium excretion, and that these effects were blocked by urantide. 18,19 Taken together, these results show that endogenous U-II exerts a tonic vasoconstrictor influence on the renal vasculature in rats.…”

“…17 In the rat kidney, U-II has been shown to cause both renal vasoconstriction and vasodilation. 10,14,[18][19][20] The effects of endogenous U-II on renal function has been examined with the selective UT receptor antagonist, urantide, both in normotensive rat strains (Sprague-Dawley) and in spontaneously hypertensive rats (SHR). 18,19 These experiments showed that urantide increased GFR, urine output and urinary sodium excretion in both strains.…”

“…10,14,[18][19][20] The effects of endogenous U-II on renal function has been examined with the selective UT receptor antagonist, urantide, both in normotensive rat strains (Sprague-Dawley) and in spontaneously hypertensive rats (SHR). 18,19 These experiments showed that urantide increased GFR, urine output and urinary sodium excretion in both strains. 18,19 In addition, these investigators found that infusion of rat U-II reduced RBF, GFR, urine output and urinary sodium excretion, and that these effects were blocked by urantide.…”