Increased expression of urotensin II, urotensin II-related peptide and urotensin II receptor mRNAs in the cardiovascular organs of hypertensive rats: Comparison with endothelin-1

Abstract

Urotensin II (UII) and urotensin II-related peptide (URP) are novel vasoactive peptides that share urotensin II receptor (UT). We have recently reported that expressions of URP and UT were up-regulated in kidneys of rats with renal failure or hypertension. To clarify possible changes of the UII system expression in cardiovascular organs with hypertension, we examined the gene expression of UII, URP and UT in hearts and aortae of hypertensive rats. Furthermore, the expression was compared with that of endothelin-1 (ET-1). Quantitative reverse transcription polymerase chain reaction analysis showed that expression levels of UII mRNA and UT mRNA were significantly elevated in the atrium of 11–12-week-old spontaneously hypertensive rats (SHR) compared with age-matched Wistar–Kyoto rats (WKY). Moreover, UT mRNA expression was elevated in the ventricle of 11–12-week-old SHR. In the aorta, expression levels of URP mRNA and UT mRNA were significantly elevated in 11–12-week-old SHR compared with age-matched WKY, similarly to those in the kidney. In contrast, expression levels of ET-1 were significantly decreased in both the heart and the kidney of 11–12-week-old SHR compared with age-matched WKY. Immunohistochemistry showed that URP and UT were immunostained in cardiomyocytes, with weaker immunostaining in vascular endothelial and smooth muscle cells, in both SHR and WKY. These findings indicate that the gene expression of the UII system components (UII, URP and UT) and ET-1 is differently regulated in hypertension, and that the UII system in the heart and aortae may have certain pathophysiological roles in hypertension.

Introduction

Urotensin II (UII) is initially isolated from the caudal neurosecretory system of teleost fish [22]. The cDNA encoding human UII precursor was cloned [6], and UII was identified as an endogenous ligand for the orphan G-protein-coupled receptor GPR14 (urotensin II receptor, UT) [1]. UII is a more potent vasoconstrictor peptide than endothelin-1 (ET-1) [1], whereas it has also vasodilator effects on some vessels via the release of vasodilator substances such as nitric oxide from endothelial cells [3], [28]. Furthermore, UII has various biological actions, such as stimulation of cell proliferation [26], [30], [37] and positive inotropic action [25]. Plasma concentrations of UII are elevated in patients with hypertension [5], congestive heart failure [21], [24], chronic renal failure [34] and diabetes mellitus [32], [33].

Urotensin II-related peptide (URP), another ligand for UT, was discovered from rat brain, and identified in human and mice [16], [29]. URP has approximately the same binding affinity to UT, but less potency than UII in contracting rat aortic strips in vitro [4]. URP dilated rat coronary arteries, with 10-fold less potency compared with rat UII [23]. UII and URP mRNAs were similarly expressed in human and rat tissues, with high expression levels found in the spinal cord and testis.

We have recently reported that expressions of URP and UT were up-regulated in kidneys of rats with renal failure or hypertension [17]. However, changes of URP and UT expression in the cardiovascular organs have not been studied in hypertension. To clarify possible changes of the UII system expression in hypertension, we examined the gene expression of UII, URP and UT in the heart and aorta of hypertensive rats. Furthermore, UII and URP have similar biological actions to ET-1, such as vasoconstriction, cell proliferation and cardiac hypertrophy. The expression of UII, URP and UT in the heart, aorta and kidney was therefore compared with that of ET-1.