Urotensin-II: More Than a Mediator for Kidney

Balat, Ayşe; Büyükçelik, Mithat

doi:10.1155/2012/249790

Cited by 12 publications

(10 citation statements)

References 55 publications

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“…UII is recently shown to play a role in the immune mechanisms of tissue injury [32], [33]. In ALF, marked upregulation of UII and its receptor UTR have been demonstrated in patients [11].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of UII/UTR System Relieves Acute Inflammation of Liver through Preventing Activation of NF-κB Pathway in ALF Mice

Dong

Liu

et al. 2013

PLoS ONE

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Urotensin II (UII) is implicated in immune inflammatory diseases through its specific high-affinity UT receptor (UTR). Enhanced expression of UII/UTR was recently demonstrated in the liver with acute liver failure (ALF). Here, we analysed the relationship between UII/UTR expression and ALF in lipopolysaccharide (LPS)/D-galactosamine (GalN)-challenged mice. Thereafter, we investigated the effects produced by the inhibition of UII/UTR system using urantide, a special antagonist of UTR, and the potential molecular mechanisms involved in ALF. Urantide was administered to mice treated with LPS/GalN. Expression of UII/UTR, releases of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interferon-γ (IFN-γ), and activation of nuclear factor κB (NF-κB) signaling pathway were assessed in the lethal ALF with or without urantide pretreatment. We found that LPS/GalN-challenged mice showed high mortality and marked hepatic inflammatory infiltration and cell apoptosis as well as a significant increase of UII/UTR expression. Urantide pretreatment protected against the injury in liver following downregulation of UII/UTR expression. A close relationship between the acutely flamed hepatic injury and UII/UTR expression was observed. In addition, urantide prevented the increases of proinflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and activation of NF-κB signaling pathway induced by LPS/GalN in mice. Thus, we conclude that UII/UTR system plays a role in LPS/GalN-induced ALF. Urantide has a protective effect on the acutely inflamed injury of liver in part through preventing releases of proinflammatory cytokines and activation of NF-κB pathway.

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“…UII is recently shown to play a role in the immune mechanisms of tissue injury [32], [33]. In ALF, marked upregulation of UII and its receptor UTR have been demonstrated in patients [11].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of UII/UTR System Relieves Acute Inflammation of Liver through Preventing Activation of NF-κB Pathway in ALF Mice

Dong

Liu

et al. 2013

PLoS ONE

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“…Interestingly, angiotensin II increased UII and UT expression in tubular cells and UII interacts in synergy with angiotensin II. UII gene polymorphism has been also associated with some renal diseases and could be considered to streamline more relevant CKD patient populations for UT blockade (Balat and Buyukcelik, 2012).…”

Section: Discussionmentioning

confidence: 99%

Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities

Ozoux¹,

Briand²,

Pelat³

et al. 2020

J Pharmacol Exp Ther

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Chronic kidney disease (CKD) remains a common disorder leading to growing health and economic burden without curative treatment. In diabetic patients, CKD may result from a combination of metabolic and non-metabolic-related factors with mortality mainly driven by cardiovascular events. The marked overactivity of the urotensinergic system in diabetic patients implicates this vasoactive peptide as a possible contributor to the pathogenesis of renal as well as heart failure. Previous preclinical studies with urotensin II (UII) antagonists in chronic kidney disease were based on simple endpoints that did not reflect the complex etiology of the disease. Given this, our studies revisited the therapeutic value of UII antagonism in CKD and extensively characterize 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino) cyclohexanecarboxylic acid hydrochloride (SAR101099), a potent, selective and orally long-acting UT competitive antagonist inhibiting not only UII but also urotensin related peptide activities. SR101099 treatment more than halved proteinurea and albumin/creatinine ratio in spontaneously-hypertensive stroke-prone-(SHR-SP) rats fed with salt/fat diet and Dahl-salt-sensitive rats, respectively, and halved albuminuria in streptozotocin-induced diabetes rats. Importantly, these effects were accompanied by a decrease in mortality by 50% in SHR-SP and by 35% in the Dahl salt-sensitive rats. SAR101099 was also active on CKD-related cardiovascular pathologies, and partly preserved contractile reserve in models of heart failure induced by myocardial infarction or ischemia/reperfusion in rats and pigs, respectively. SAR101099 exhibited a good safety/tolerability profile at all tested doses in clinical phase-I studies. Together, these data suggest that CKD patient selection considering comorbidities together with new stratification modalities should unveil the urotensin antagonists' therapeutic potential.

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“…Recent studies showed that UT‐II plays a role in the immune mechanism of tissue damage . Changed expression of UT‐II and UTR, expression of endothelial and Kupffer cells and the correlation of these changes with specific cytokines have been shown in acute liver failure .…”

Section: Discussionmentioning

confidence: 99%

The Role of Urotensin Receptors in the Paracetamol‐Induced Hepatotoxicity Model in Mice: Ameliorative Potential of Urotensin II Antagonist

Palabıyık

Karakuş

Akpınar

et al. 2015

Basic Clin Pharma Tox

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We aimed to evaluate the possible protective effect of a UTR antagonist and to determine the effect of the antagonist on ALT and AST levels in serum, the mRNA expression level of UTR, tumour necrosis factor-alpha (TNF-a) and IL-1b and SOD activity, GSH and MDA levels in liver tissues, which are important mediators or markers for the hepatotoxicity animal model in mice. Animals fasted overnight and were divided into seven equal groups (n = 12). The first group was the healthy group (administered 0.1% DMSO intraperitoneally). Group 2 received only paracetamol (PARA) (administered orally at a dosage of 300 mg/kg). Groups 3 and 4 were treated with only AGO (AC7954, UTR agonist) 15 and 30 mg/kg intraperitoneally, respectively. Groups 5 and 6 were treated with only ANTA (SB657510, UTR antagonist) 30 and 60 mg/kg intraperitoneally, respectively. Group 7 was treated with AGO 30 mg/kg and ANTA 60 mg/kg intraperitoneally. One hour after the pre-treatment drugs were administered, groups 3 through 7 were given PARA. After the experimental period, the mice were killed 6 and 24 hr after PARA was administered. Antagonist administration significantly decreased the ALT and AST levels, while agonist administration did not. In addition, SOD activity and GSH levels increased, and the MDA level decreased with the pre-treatment of two antagonist doses. The increased UTR gene expression through PARA was significantly lower in both doses of the antagonist groups at 24 hr when compared with the agonist and PARA groups. This study showed that UTR antagonists have hepatoprotective and anti-inflammatory effects on high-dose PARA-induced hepatotoxicity in mice.

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Urotensin-II: More Than a Mediator for Kidney

Cited by 12 publications

References 55 publications

Inhibition of UII/UTR System Relieves Acute Inflammation of Liver through Preventing Activation of NF-κB Pathway in ALF Mice

Inhibition of UII/UTR System Relieves Acute Inflammation of Liver through Preventing Activation of NF-κB Pathway in ALF Mice

Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities

The Role of Urotensin Receptors in the Paracetamol‐Induced Hepatotoxicity Model in Mice: Ameliorative Potential of Urotensin II Antagonist

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