Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts.
Chronic cholestatic liver diseases are characterized by impaired balance between proliferation and death of cholangiocytes, as well as vanishing of bile ducts and liver failure. Ursodeoxycholic acid (UDCA) is a bile acid widely used for the therapy of cholangiopathies. However, little is known of the cytoprotective effects of UDCA on cholangiocytes. Therefore, UDCA and its taurine conjugate tauroursodeoxycholic acid (TUDCA) were administered in vivo to rats simultaneously subjected to bile duct ligation and vagotomy, a model that induces cholestasis and loss of bile ducts by apoptosis of cholangiocytes. Because these two bile acids act through Ca2+ signaling, animals were also treated with BAPTA/AM (an intracellular Ca2+ chelator) or Gö6976 (a Ca2+-dependent protein kinase C-alpha inhibitor). The administration of UDCA or TUDCA prevented the induction of apoptosis and the loss of proliferative and functional responses observed in the bile duct ligation-vagotomized rats. These effects were neutralized by the simultaneous administration of BAPTA/AM or Gö6976. UDCA and TUDCA enhanced intracellular Ca2+ and IP3 levels, together with increased phosphorylation of protein kinase C-alpha. Parallel changes were observed regarding the activation of the MAPK and PI3K pathways, changes that were abolished by addition of BAPTA/AM or Gö6976. These studies provide information that may improve the response of cholangiopathies to medical therapy.
Marzioni
Marco
M
Department of Gastroenterology, Universitá Politecnica delle Marche, Italy.
Francis
Heather
H
Benedetti
Antonio
A
Ueno
Yoshiyuki
Y
Fava
Giammarco
G
Venter
Juliet
J
Reichenbach
Ramona
R
Mancino
Maria Grazia
MG
Summers
Ryun
R
Alpini
Gianfranco
G
Glaser
Shannon
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001652:Bile Ducts / Q000187:drug effects* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002779:Cholestasis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D008026:Ligation; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage*; D014628:Vagotomy
D002118:Calcium; D004533:Egtazic Acid; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D051571:Protein Kinase C-alpha; D013655:Taurochenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; C031655:ursodoxicoltaurine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid