S-adenosylmethionine and cAMP confer differential cytoprotection against bile acid-induced apoptosis in canine renal tubular cells and primary rat hepatocytes |
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| Authors: | Webster Cynthia R L Boria Pedro Usechak Paul Anwer M Sawkat |
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| Institution: | Department of Clinical Sciences, Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA. |
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| Abstract: | Cholestasis results in the accumulation of cytotoxic bile acids in the body. The cytoprotective effect of S-adenosylmethionine (SAMe) and cAMP were compared in two in vitro models of bile acid-induced apoptosis. Primary cultures of rat hepatocytes and canine renal tubular cells (Madin-Darby canine kidney MDCK] cells stably transfected with the conjugated bile salt transporter, sodium Na+]/taurocholate cotransporting polypeptide Ntcp]) were treated with conjugated bile acids and monitored for apoptosis. Glycine-conjugated bile acids caused similar amounts of apoptosis, whereas taurine-conjugated bile acids were five to 10 times more toxic in MDCK-Ntcp cells than in hepatocytes. Treatment with the 1,4-butanedisulfonate salt of SAMe (500 microM) or the stable chlorophenylthio-cAMP analogue (100 microM) inhibited bile acid-induced apoptosis in hepatocytes by 70% and 40%, respectively. In MDCK-Ntcp cells, SAMe inhibited apoptosis by 20%, but cAMP was without effect. Immunoblotting for activation of putative survival kinases in cAMP-treated cells (phosphorylated protein kinase B Akt] or mitogen-activated protein kinase MAPK]) was done using phosphospecific antibodies. cAMP increased Akt phosphorylation threefold in hepatocytes but not in MDCK-Ntcp cells. Activation of p42/p44 MAPK was inhibited by cAMP in both cells. SAMe protects against bile acid-induced apoptosis in hepatocytes and MDCK-Ntcp cells. The cytoprotective effect of cAMP is seen only in hepatocytes and may reflect tissue-specific activation of Akt. |
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