title: Differential regulation of vacuolar H+ -ATPase and Na+/H+ exchanger 3 in rat cholangiocytes after bile duct ligation.
abstract: The cholangiocytes lining the intrahepatic bile ducts modify the primary secretion from the hepatocytes. The cholangiocytes secrete HCO (3)(-) into bile when stimulated with secretin in many species, including man. However, in rats, secretin stimulation neither affects biliary HCO (3)(-) concentration nor bile flow, whereas following bile duct ligation (BDL) it induces hypercholeresis with significant increase of NaHCO(3) concentration. We hypothesized that BDL might affect the expression of cholangiocyte H(+) transporters and thereby choleresis, and determined the expression and localization of the 31 kDa vacuolar type H(+)-ATPase (V-ATPase) subunit and of Na(+)/H(+) exchanger NHE3 in the livers of control and BDL rats by real-time PCR, in situ hybridization, immunoblotting, and immunohistochemistry. In controls, secretin had no effect on bile flow, whereas following BDL, secretin increased bile flow approximately threefold. V-ATPase and NHE3 were expressed in control cholangiocytes showing intracellular and apical distribution, respectively. BDL significantly up-regulated V-ATPase mRNA and protein expression and was associated with redistribution to the apical pole in approximately 60% of the cholangiocytes lining the small bile ductules. In contrast, NHE3 expression was significantly down-regulated by BDL at the mRNA and protein level. The data demonstrate expression of V-ATPase in rat cholangiocytes. BDL-induced down-regulation of NHE3 may contribute to a reduction of Na(+) and HCO (3)(-) reabsorption and thus to their net secretion into bile. Apical localization of V-ATPase in cholangiocytes may indicate its involvement in pH regulation and/or HCO (3)(-) salvage to compensate for NHE3 down-regulation in BDL.
authors.affiliation: Department of Neuroanatomy, Center for Anatomy, University of Göttingen, Kreuzbergring 36, 37075, Göttingen, Germany. eroussa@gwdg.de
authors.forename: Eleni
authors.initials: E
authors.lastname: Roussa
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bertram
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
authors.forename: Knut Jørgen
authors.initials: KJ
authors.lastname: Labori
authors.forename: Frank
authors.initials: F
authors.lastname: Thévenod
authors.forename: Morten G
authors.initials: MG
authors.lastname: Raeder
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism; D008026:Ligation; D008110:Liver Extracts / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D012633:Secretin / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D008110:Liver Extracts; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D012633:Secretin; D012964:Sodium; D025262:Vacuolar Proton-Translocating ATPases