Urotensin ¢ò In Spontaneously Hypertensive Rats Cardiovascular System And Kidney Expression And Its Renal Function

Urotensinâ…¡(U-â…¡),a somatostatin-like peptide,was firstly isolated from the urophysis of the teleost fish.U-â…¡has recently been cloned in several mammalian species and plays its biologic roles by binding to the orphan G-protein-coupled receptor 14(GPR₁₄),which is now designated as urotensinâ…¡receptor(UT).U-â…¡/UT system is not only localized extensively in nervous system,but also affluent in cardiovascular system and kidney.The role of U-â…¡in pathogenesis of hypertension attracted more and more attention.A stimulant effect of U-â…¡in isolated human right cardiac atrium and rat papillary muscles has been reported.At the same time,U-â…¡could promote smooth muscle cellular proliferation,myocardial hypertrophy and fibrosis.Thus,U-â…¡is probably involved in cardiac remodeling.The levels of U-â…¡in hypertensive patients' plasma were higher than health adults.In rat thoracic aorta, U-â…¡is reported to be a powerful vasoconstrictor with a potency 8-to 110-fold greater than endothelin-1 in isolated aorta of the rat.Then U-â…¡might conduce to the pathogenesis of hypertension.However,the vasoactive effects of U-â…¡are reported to be dependent on both the species and the regional vascular bed examined,and diastolic effects were reported in some resistant vessels.Bolus U-â…¡injection resulted in the depression of blood pressure,heart rate and cardial contractility according to some reports.Then doubts have been raised concerning the importance of this peptide in cardiovascular physiology and pathogenesis of hypertension.Kidney is an important organ involving in blood pressure regulation in vivo.Many studies have revealed the relationship between renal function disorder and hypertensive invasion. On the hand,a series of studies demonstrate the ability of U-â…¡to regulate transepithelial transport of ions and water across a variety of osmoregulatory surfaces in teleost fish,suggesting that U-â…¡plays a role in osmoregulation in fish.With the localization of U-â…¡/UT system in kidney,some researcher began to pay attention to the influence of U-â…¡on mammalian renal function.However,there are only a few reports,which were contradictory,about renal function of U-â…¡at present and we could not induce the direct effect of U-â…¡on renal function.To research the localization of U-â…¡/UT system in cardiovascular system and kidney and the direct effect of U-â…¡on renal function in SHR could provide some experimental evidences for the mechanism of pathogenesis of hypertension in SHR.In present study,we detected the expression of Uâ…¡/UT system in heart,thoracic aorta and kidney in SHR and two-kidney,one clip(2K1C) rats by real-time polymerase chain reaction,western blot and radioimmunoassay.The data of our study suggested that in the condition of normal and high blood pressure,or spontaneous and renal hypertension,the expressions of U-â…¡/UT system were different.The levels of U-â…¡/UT system in left ventricle,thoracic aorta and kidney of 17-week-old SHR were higher than the control WKY rat,and this was coherent with blood pressure level and organic pathological changes of SHR.While analogous characters were not found in 2K1C rats.These results suggested U-â…¡/UT system is probably involved in the pathogenesis of hypertension.Through isolated thoracic aorta organ bath study,we observed U-â…¡elicited a greater contractile response in endothelium-denuded thoracic aorta in SHR compared to WKY rats,and its vasoconstrictive effect was stronger than Angâ…¡.According to our colleague's reports,U-â…¡and Angâ…¡exerted a synergistic effect on vasoconstriction.This might accelerate the progress of hypertension.The aim of our in vivo experiments is to test the hypothesis that U-â…¡might have a direct antinatriuretic action in SHR.Blood pressure and renal blood flow were measured using a pressure transducer and ultrasonic flowmeter,respectively. Parameters of renal function were measured using standard clearance methods.U-â…¡and U-â…¡receptors(UT) levels were measured by real-time polymerase chain reaction and western blot analysis.UT distribution in the kidney was examined by immunohistochemistry.Bolus U-â…¡injection(15 nmol·kg^-1) caused a transient decrease in glomerular filtration rate(GFR),urine flow rate(UV),urinary sodium excretion(U_NaV) and potassium excretion(U_KV) in parallel with the decrease in mean arterial pressure(MAP) and renal blood flow(RBF) during the first 30 minutes in adult SHR.While during the second 30 minutes following U-â…¡administration,all the variables recovered except urinary sodium excretion which kept decreased.These U-â…¡effects were not blocked by the U-â…¡ligand urantide(1μmol/kg).To observe the hemodynamic-independent antinatriuretic action of U-â…¡in SHR,minor dosage of U-â…¡was administered in SHR.We found that continuous U-â…¡infusion(0.2 nmol·kg^-1·h^-1) following a bolus U-â…¡injection(0.3 nmol·kg^-1) caused an antinatriuretic effect without any significant change in MAP,RBF,GFR,UV and U_KV during the entire 1.5-hour perfusion period in SHR.Protein levels of UT were significantly increased in the kidney of 17-week-old SHR as compared with the age-matched WKY rats.The levels of U-â…¡and UT were significantly increased in the kidney of 17-week-old SHR as compared with the age-matched WKY rats.Increased UT was localized on the kidney tubular epithelial cells in 17-week-old SHR.U-â…¡exerts a hemodynamics-independent antinatriuretic action in the kidney of adult SHR. This effect might be ascribed to an increased UT expression in the tubular epithelial cell of the kidney.In conclusion,the expressions of U-â…¡/UT system in cardiovascular system and kidney were different in the condition of normal and high blood pressure,or spontaneous and renal hypertension.U-â…¡elicited a greater contractile response in endothelium-denuded thoracic aorta in SHR compared to WKY rats.These results revealed U-â…¡/UT system is probably involved in the pathogenesis of hypertension.In vivo study suggested U-â…¡exerts a hemodynamics-independent antinatriuretic action in the kidney of adult SHR through the tubular epithelial cell of the kidney.In the elevation of blood pressure of SHR,the direct renal function of U-â…¡might play a more important role than its regulation of peripheral resistance.This will provide more evidence for us to understand the pathogenesis and mechanism of hypertension.