Basic Research
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Feb 21, 2006; 12(7): 1049-1055
Published online Feb 21, 2006. doi: 10.3748/wjg.v12.i7.1049
PI 3-kinase pathway is responsible for antiapoptotic effects of atrial natriuretic peptide in rat liver transplantation
Uwe Grutzner, Melanie Keller, Michael Bach, Alexandra K Kiemer, Herbert Meissner, Manfred Bilzer, Stefan Zahler, Alexander L Gerbes, Angelika M Vollmar
Uwe Grutzner, Michael Bach, Institute for Surgical Research, Klinikum Großhadern, University of Munich, D-81377 Munich, Germany
Melanie Keller, Stefan Zahler, Angelika M. Vollmar, Department of Pharmacy, University of Munich, D-81377 Munich, Germany
Alexandra K Kiemer, Department of Pharmaceutical Biology, University of Saarland, D-66123 Saarbrücken, Germany
Herbert Meissner, Institute of Pathology, University of Munich, D-81377 Munich, Germany
Manfred Bilzer, Alexander L Gerbes, Department of Medicine II, Klinikum Großhadern, University of Munich, Munich, D-81377 Germany
Co-first-author: Uwe Grützner and Melanie Keller
Supported by the DFG (FOR 440/1) and the Alexander von Humboldt Foundation (A.K.K).
Correspondence to: Angelika M Vollmar, Department of Pharmacy, Butenandtstr. 5-13,D-81377 Munich, Germany.
Telephone: +49-89-2180-77172 Fax: +49-89-2180-77170
Received: June 30, 2005
Revised: July 2, 2005
Accepted: August 26, 2005
Published online: February 21, 2006

AIM: To investigate the in vivo effect of atrial natriuretic peptide (ANP) and its signaling pathway during orthotopic rat liver transplantation.

METHODS: Rats were infused with NaCl, ANP (5 µg/kg), wortmannin (WM, 16 µg/kg), or a combination of both for 20 min. Livers were stored in UW solution (4 °C) for 24 h, transplanted and reperfused. Apoptosis was examined by caspase-3 activity and TUNEL staining. Phosphorylation of Akt and Bad was visualized by Western blotting and phospho-Akt-localization by confocal microscopy.

RESULTS: ANP-pretreatment decreased caspase-3 activity and TUNEL-positive cells after cold ischemia, indicating antiapoptotic effects of ANP in vivo. The antiapoptotic signaling of ANP was most likely caused by phosphorylation of Akt and Bad, since pretreatment with PI 3-kinase inhibitor WM abrogated the ANP-induced reduction of caspase-3 activity. Interestingly, analysis of liver tissue by confocal microscopy showed translocation of phosphorylated Akt to the plasma membrane of hepatocytes evoked by ANP.

CONCLUSION: ANP activates the PI-3-kinase pathway in the liver in vivo leading to phosphorylation of Bad, an event triggering antiapoptotic signaling cascade in ischemic liver.

Keywords: Bad, Apoptosis, Hormonal preconditioning, Ischemia reperfusion injury