The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions

Abstract

Urotensin‐II is a polypeptide ligand with neurohormone‐like activity. It mediates downstream signaling pathways through G‐protein‐coupled receptor 14 (GPR14) also known as urotensin receptor (UTR). Urotensin‐II is the most potent endogenous vasoconstrictor in mammals, promoting cardiovascular remodelling, cardiac fibrosis, and cardiomyocyte hypertrophy. It is also involved in other physiological and pathological activities, including neurosecretory effects, insulin resistance, atherosclerosis, kidney disease, and carcinogenic effects. Moreover, it is a notable player in the process of inflammatory injury, which leads to the development of inflammatory diseases. Urotensin‐II/UTR expression stimulates the accumulation of monocytes and macrophages, which promote the adhesion molecules expression, chemokines activation and release of inflammatory cytokines at inflammatory injury sites. Therefore, urotensin‐II turns out to be an important therapeutic target for the treatment options and management of associated diseases. The main downstream signaling pathways mediated through this urotensin‐II /UTR system are RhoA/ROCK, MAPKs and PI3K/AKT. Due to the importance of urotensin‐II systems in biomedicine, we consolidated a network map of urotensin‐II /UTR signaling. The described signaling map comprises 33 activation/inhibition events, 31 catalysis events, 15 molecular associations, 40 gene regulation events, 60 types of protein expression, and 11 protein translocation events. The urotensin‐II signaling pathway map is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway:WP5158). The availability of comprehensive urotensin‐II signaling in the public resource will help understand the regulation and function of this pathway in normal and pathological conditions. We believe this resource will provide a platform to the scientific community in facilitating the identification of novel therapeutic drug targets for diseases associated with urotensin‐II signaling.

Urotensin II system in chronic kidney disease

“…Lipopolysaccharide stimulated the UII system to activate migration and increase cytokine gene levels in frog leukocytes ( Tomiyama et al, 2015 ). Other studies have reported the proinflammatory action of the UII system in cells and circulation ( Clavier et al, 2020 ; Liu et al, 2015 ; Rex et al, 2022 ; Sun and Liu, 2019 ). UII also stimulates fibrosis in various tissues, including the heart, liver, and kidney ( Kemp et al, 2009 ; Liang et al, 2021 ; Liu et al, 2009 ; Tian et al, 2008a ; Zhang et al, 2007 ).…”

Urotensin II Enhances Advanced Aortic Atherosclerosis Formation and Delays Plaque Regression in Hyperlipidemic Rabbits

“…Atherosclerosis is the most important pathological bases of cardiovascular and cerebrovascular diseases, including myocardial infarctions, strokes, and disabling peripheral artery disease [ 3 ]. Urotensin II (UII), a cyclic peptide of 11 amino acids that was first discovered in teleost fish, is also linked to the pathophysiology and physiology of the heart [ 4 , 5 ]. Previous studies identified a G-protein-coupled orphan receptor 14 (GPR14) as the UII receptor (UTR) [ 6 , 7 ].…”