TUDCA prevents cholestasis and canalicular damage induced by ischemia-reperfusion injury in the rat, modulating PKCalpha-ezrin pathway

Transpl Int. 2008 Aug;21(8):792-800. doi: 10.1111/j.1432-2277.2008.00682.x. Epub 2008 Apr 23.

Abstract

Cholestasis, induced by liver ischemia-reperfusion injury (IRI), is characterized by dilatation of bile canaliculi and loss of microvilli. Tauroursodeoxycholic acid (TUDCA) is an anti-cholestatic agent, modulating protein kinase C (PKC) alpha pathway. PKC reduces ischemic damage in several organs, its isoform alpha modulates ezrin, a key protein in the maintenance of cell lamellipoidal extensions. We evaluated the effects of TUDCA on cholestasis, canalicular changes and PKCalpha-ezrin expression in a rat model of liver IRI. Livers flushed and stored with Belzer solution or Belzer + 10 mm TUDCA (4 degrees C for 6 h) were reperfused (37 degrees C with O(2)) with Krebs-Ringer bicarbonate + 2.5 micromol/min of Taurocholate or TUDCA. Bile was harvested for bile flow assessment. Liver tissue was employed for Electron Microscopy (EM) and for PKCalpha and ezrin immunoblot and immunofluorescence. The same experiments were conducted with the PKCalpha inhibitor Go-6976. TUDCA-treated livers showed increased bile flow (0.25+/-0.17 vs. 0.042+/-0.02 microl/min/g liver, P<0.05) and better preservation of microvilli and bile canalicular area at EM. These effects were associated with increased PKCalpha and ezrin expression (P=0.03 and P=0.04 vs. control respectively), as also confirmed by immunofluorescence data. PKCalpha inhibition abolished these TUDCA effects. TUDCA administration during IRI reduces cholestasis and canalicular damage in the liver modulating PKCalpha-ezrin pathway.

MeSH terms

  • Animals
  • Bile
  • Bile Canaliculi / pathology*
  • Bile Canaliculi / ultrastructure
  • Carbazoles / pharmacology
  • Cholagogues and Choleretics / therapeutic use*
  • Cholestasis / etiology
  • Cholestasis / pathology
  • Cholestasis / physiopathology
  • Cholestasis / prevention & control*
  • Cytoskeletal Proteins / drug effects
  • Cytoskeletal Proteins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • L-Lactate Dehydrogenase / metabolism
  • Liver / blood supply*
  • Liver / metabolism
  • Male
  • Microscopy, Electron, Scanning
  • Protein Kinase C-alpha / antagonists & inhibitors
  • Protein Kinase C-alpha / drug effects
  • Protein Kinase C-alpha / metabolism*
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / complications
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Taurochenodeoxycholic Acid / pharmacology
  • Taurochenodeoxycholic Acid / therapeutic use*

Substances

  • Carbazoles
  • Cholagogues and Choleretics
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • ezrin
  • Go 6976
  • Taurochenodeoxycholic Acid
  • tauroursodeoxycholic acid
  • L-Lactate Dehydrogenase
  • Protein Kinase C-alpha