{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:58:17Z","timestamp":1791917897972,"version":"4.3.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T00:00:00Z","timestamp":1719360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR202110280049 ZR2021MH263"],"award-info":[{"award-number":["ZR202110280049 ZR2021MH263"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070783 82200857"],"award-info":[{"award-number":["82070783 82200857"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>We aimed to investigate the expression and motor modulatory roles of several mechano-sensitive channels (MSCs) in human ureter. Human proximal ureters were obtained from eighty patients subjected to nephrectomy. Expression of MSCs at mRNA, protein and functional levels were examined. Contractions of longitudinal ureter strips were recorded in organ bath. A fluorescent probe Diaminofluoresceins was used to measure nitric oxide (NO). RT-PCR analyses revealed predominant expression of Piezo1 and TRPV2 mRNA in intact ureter and mucosa. Immunofluorescence assays indicate proteins of MSCs (Piezo1\/Piezo2, TRPV2 and TRPV4) were mainly distributed in the urothelium. Ca2+ imaging confirmed functional expression of TRPV2, TRPV4 and Piezo1 in cultured urothelial cells. Specific agonists of Piezo1 (Yoda1, 3\u2013300\u00a0\u03bcM) and TRPV2 (cannabidiol, 3\u2013300\u00a0\u03bcM) attenuated the frequency of ureteral contractions in a dose-dependent manner while the TRPV4 agonist GSK1016790A (100\u00a0nM\u20131\u00a0\u03bcM) exerted no effect. The inhibitory effects of Piezo1 and TRPV2 agonists were significantly blocked by the selective antagonists (Dooku 1 for Piezo1, Tranilast for TRPV2), removal of the mucosa, and pretreatment with NO synthase inhibitor L-NAME (10\u00a0\u03bcM). Yoda1 (30\u00a0\u03bcM) and cannabidiol (50\u00a0\u03bcM) increased production of NO in cultured urothelial cells. Our results suggest that activation of Piezo1 or TRPV2 evokes NO production and release from mucosa that may mediate mechanical stimulus-induced reduction of ureter contractions. Our findings support the idea that targeting Piezo1 and TRPV2 channels may be a promising pharmacological strategy for ureter stone passage or colic pain relief.<\/jats:p>","DOI":"10.3389\/fphar.2024.1410565","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T04:40:44Z","timestamp":1719376844000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Activation of Piezo1 or TRPV2 channels inhibits human ureteral contractions via NO release from the mucosa"],"prefix":"10.3389","volume":"15","author":[{"given":"Jianing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiliang","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulu","family":"Zu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiulin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieke","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1152\/physrev.00030.2012","article-title":"Urothelial signaling","volume":"93","author":"Birder","year":"2013","journal-title":"Physiol. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4503","DOI":"10.1038\/s41467-019-12501-1","article-title":"A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1","volume":"10","author":"Botello-Smith","year":"2019","journal-title":"Nat. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1159\/000100830","article-title":"Physiology and pharmacology of the human ureter: basis for current and future treatments","volume":"78","author":"Canda","year":"2007","journal-title":"Urol. Int."},{"key":"B4","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/nature10812","article-title":"Piezo proteins are pore-forming subunits of mechanically activated channels","volume":"483","author":"Coste","year":"2012","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"F303","DOI":"10.1152\/ajprenal.00214.2019","article-title":"Expression and distribution of PIEZO1 in the mouse urinary tract","volume":"317","author":"Dalghi","year":"2019","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e152984","DOI":"10.1172\/jci.insight.152984","article-title":"Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception","volume":"6","author":"Dalghi","year":"2021","journal-title":"JCI Insight"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1111\/j.1476-5381.2010.01166.x","article-title":"Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes","volume":"163","author":"De Petrocellis","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"F692","DOI":"10.1152\/ajprenal.00599.2009","article-title":"Functional characterization of transient receptor potential channels in mouse urothelial cells","volume":"298","author":"Everaerts","year":"2010","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.kint.2021.02.021","article-title":"PIEZO2, a mechanosensor in the urinary bladder","volume":"100","author":"Gailly","year":"2021","journal-title":"Kidney Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1111\/bcpt.12785","article-title":"Inhibitory effects of urothelium-related factors","volume":"121","author":"Guan","year":"2017","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1002\/(sici)1520-6777(1997)16:3<209::aid-nau10>3.0.co;2-g","article-title":"Localization of nitric oxide synthase and haemoxygenase, and functional effects of nitric oxide and carbon monoxide in the pig and human intravesical ureter","volume":"16","author":"Iselin","year":"1997","journal-title":"Neurourol. Urodyn."},{"key":"B12","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1113\/eph8702290","article-title":"Pyeloureteral motility and ureteral peristalsis: essential role of sensory nerves and endogenous prostaglandins","volume":"87","author":"Lang","year":"2002","journal-title":"Exp. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"37","DOI":"10.4196\/kjpp.2011.15.1.37","article-title":"Spontaneous contractions augmented by cholinergic and adrenergic systems in the human ureter","volume":"15","author":"Lee","year":"2011","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"118967","DOI":"10.1016\/j.lfs.2020.118967","article-title":"TRPM3 channel activation inhibits contraction of the isolated human ureter via CGRP released from sensory nerves","volume":"268","author":"Liu","year":"2021","journal-title":"Life Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/s41586-020-2830-7","article-title":"PIEZO2 in sensory neurons and urothelial cells coordinates urination","volume":"588","author":"Marshall","year":"2020","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1097\/01.ju.0000083492.80217.20","article-title":"Nitric oxide production within rat urothelial cells","volume":"170","author":"Mastrangelo","year":"2003","journal-title":"J. Urol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"16565","DOI":"10.1074\/jbc.M113.528638","article-title":"Functional role for Piezo1 in stretch-evoked Ca\u00b2\u207a influx and ATP release in urothelial cell cultures","volume":"289","author":"Miyamoto","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1159\/000282608","article-title":"Effects of prostaglandins E1, E2 and F2 alpha on contractility and cAMP and cGMP contents in lower urinary tract smooth muscle","volume":"52","author":"Morita","year":"1994","journal-title":"Urol. Int."},{"key":"B19","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/s0022-5347(17)43904-8","article-title":"Ureteral urine transport: changes in bolus volume, peristaltic frequency, intraluminal pressure and volume of flow resulting from autonomic drugs","volume":"137","author":"Morita","year":"1987","journal-title":"J. Urol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1556\/APhysiol.96.2009.4.2","article-title":"Ureteral motility","volume":"96","author":"Osman","year":"2009","journal-title":"Acta Physiol. Hung"},{"key":"B21","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.niox.2009.01.001","article-title":"Fluorescent indication that nitric oxide formation in NTS neurons is modulated by glutamate and GABA","volume":"20","author":"Pajolla","year":"2009","journal-title":"Nitric Oxide"},{"key":"B22","doi-asserted-by":"publisher","first-page":"S34","DOI":"10.1089\/end.2016.0063","article-title":"Understanding the ureter: challenges and opportunities","volume":"30","author":"Park","year":"2016","journal-title":"J. Endourol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1038\/sj.bjp.0702147","article-title":"Excitatory motor and electrical effects produced by tachykinins in the human and Guinea-pig isolated ureter and Guinea-pig renal pelvis","volume":"125","author":"Patacchini","year":"1998","journal-title":"Br. J. Pharmacol."},{"key":"B24","first-page":"683","article-title":"Myogenic and neurogenic factors in the control of pyeloureteral motility and ureteral peristalsis","volume":"50","author":"Santicioli","year":"1998","journal-title":"Pharmacol. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1007\/s00210-018-1510-8","article-title":"Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium","volume":"391","author":"Sellers","year":"2018","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"F396","DOI":"10.1152\/ajprenal.00127.2013","article-title":"Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium","volume":"305","author":"Shabir","year":"2013","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e07369","DOI":"10.7554\/eLife.07369","article-title":"Chemical activation of the mechanotransduction channel Piezo1","volume":"4","author":"Syeda","year":"2015","journal-title":"Elife"},{"key":"B28","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1124\/jpet.108.139295","article-title":"N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I","volume":"326","author":"Thorneloe","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1089\/end.2005.19.170","article-title":"Impact of a double-pigtail stent on ureteral peristalsis in the porcine model: initial studies using a novel implantable magnetic sensor","volume":"19","author":"Venkatesh","year":"2005","journal-title":"J. Endourol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1159\/000471948","article-title":"The physiology and pathophysiology of the ureter","volume":"2","author":"Vereecken","year":"1976","journal-title":"Eur. Urol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"F651","DOI":"10.1152\/ajprenal.00403.2002","article-title":"Hydrostatic pressure-regulated ion transport in bladder uroepithelium","volume":"285","author":"Wang","year":"2003","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"631022","DOI":"10.3389\/fphys.2021.631022","article-title":"Cell deformation at the air-liquid interface evokes intracellular Ca(2+) increase and ATP release in cultured rat urothelial cells","volume":"12","author":"Wen","year":"2021","journal-title":"Front. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"F1217","DOI":"10.1152\/ajprenal.00198.2018","article-title":"Reduced bladder responses to capsaicin and GSK-1016790A in retired-breeder female rats with diminished volume sensitivity","volume":"315","author":"Wen","year":"2018","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1113\/JP279776","article-title":"Emerging roles of the TRPV4 channel in bladder physiology and dysfunction","volume":"599","author":"Wu","year":"2021","journal-title":"J. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"762847","DOI":"10.3389\/fphys.2021.762847","article-title":"Functional expression of transient receptor potential and Piezo1 channels in cultured interstitial cells of human-bladder lamina propria","volume":"12","author":"Zhao","year":"2021","journal-title":"Front. Physiol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1410565\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T04:40:48Z","timestamp":1719376848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1410565\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,26]]},"references-count":35,"alternative-id":["10.3389\/fphar.2024.1410565"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1410565","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,26]]},"article-number":"1410565"}}