Apoptosis induced by 5-(N,N-hexamethylene)-amiloride in regenerating liver after partial hepatectomy.
The effects of a specific inhibitor of the Na+/H+ exchanger, 5-(N,N-hexamethylene)-amiloride (HMA), on liver regeneration after partial hepatectomy were investigated. A single injection of HMA inhibited DNA synthesis and caused apoptosis in regenerating liver. Characteristic DNA fragmentation was observed at 4 h after partial hepatectomy with HMA-injection. The activity of Jun N-terminal kinase (JNK) increased to a maximal level at 15 min after partial hepatectomy in HMA-injected rats, while it was not detected until 30 min in the control. Western blot analysis revealed that the injection of HMA markedly increased c-Jun and phosphorylated c-Jun protein levels at 30 min after partial hepatectomy. An increase in p53 was also observed at 30 min after the HMA-injection and was followed by the upregulation of p21WAF1/CIP1 protein expression at 1 h after partial hepatectomy. These results suggested that HMA induced apoptosis accompanied by the activation of JNK and the upregulation of c-Jun, p53 and p21WAF1/CIP1 expression at an early stage of liver regeneration.
Suzuki
Tomoko
T
Department of Food Science and Nutrition, Nara Women's University, Nara 630 Japan.
Tsukamoto
Ikuyo
I
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000096:biosynthesis; D053938:DNA Fragmentation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D016158:Genes, p53 / Q000187:drug effects; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013937:Thymidine Kinase / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D000970:Antineoplastic Agents; C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016755:Proto-Oncogene Proteins c-jun; D017923:Sodium-Hydrogen Exchangers; C057360:5-(N,N-hexamethylene)amiloride; D012313:RNA; D000584:Amiloride; D004247:DNA; D013937:Thymidine Kinase; D048031:JNK Mitogen-Activated Protein Kinases