title: Signaling through hepatocyte vasopressin receptor 1 protects mouse liver from ischemia-reperfusion injury.
abstract: Terlipressin has been used extensively in the management of certain complications associated with end-stage liver diseases (ESLDs). In our pilot study, terlipressin treatment showed beneficial effects on liver function in patients with decompensated cirrhosis, however whether it plays a role in liver ischemia-reperfusion injury (IRI) remains unknown. Using a mouse nonlethal hepatic IR model, we found terlipressin administration significantly ameliorated IR-induced liver apoptosis, necrosis and inflammation. Furthermore, despite its known effect on visceral vasoconstriction, hemodynamic evaluation of murine hepatic tissue after IR revealed no change of overall hepatic blood flow after terlipressin treatment. Further studies identified the upregulation of vasopressin receptor 1 (V1R) expression on hepatocytes upon IR. In isolated hepatocyte hypoxia/reoxygenation model, the active component of terlipressin, lysine vasopressin, conferred hepatocytes resistant to oxidative stress-induced apoptosis. Mechanistic studies revealed the V1R engagement activated the Wnt/β-catenin/FoxO3a/AKT pathway, which subsequently circumvented the proapoptotic events, thus ameliorated hepatocyte apoptosis. Furthermore, genetic knockdown of V1R expression in hepatocyte cell lines or blockade of this signaling pathway abrogated such protective effect.
  
  
  CONCLUSIONS
  These data highlight the functional importance of the hepatocyte V1R/Wnt/β-catenin/FoxO3a/AKT pathway in protecting liver from oxidative stress-induced injury.
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital (ZJPPH), Hangzhou, Zhejiang, PR China.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Affiliated Yiwu Hospital, Wenzhou Medical University, Yiwu, Zhejiang, PR China.
authors.forename: Gaojian
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Surgery, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital (ZJPPH), Hangzhou, Zhejiang, PR China.
authors.forename: Tonghui
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Radiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital (ZJPPH), Hangzhou, Zhejiang, PR China.
authors.forename: Liping
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, PR China.
authors.forename: Jilin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital (ZJPPH), Hangzhou, Zhejiang, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection / Q000502:physiology; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008236:Lypressin / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; D008236:Lypressin; D051057:Proto-Oncogene Proteins c-akt
keywords: Pathology Section; apoptosis; hepatocyte; hypoxia; inflammation; vasopressin receptor