Corticotropin-releasing hormone receptors mediate opposing effects in cholestasis-induced liver cell apoptosis.
CRH receptors are expressed in human and rat liver. The current study investigated the biological role of the CRH system in the hepatocellular apoptotic process and aimed to reveal the responsible molecular mechanisms. Using a rat experimental model of common bile duct surgical ligation leading to obstructive jaundice and cholestasis, liver apoptosis was induced in the hepatic parenchyma as confirmed by the elevated expression of the early apoptotic neoepitope M30. This effect was reversed by administration of the nonselective CRH antagonist astressin but not by the selective CRH(2) antagonist astressin2B, suggesting that antagonism of the endogenous CRH(1) blocked the cholestasis-induced apoptotic mechanism. No effect was observed in the noncholestasis controls. In our experimental model, early and late apoptosis-preventing markers were induced in parallel to apoptosis; elevated gene transcript levels of the anti-apoptotic bcl-2 were found by real-time PCR in the first postoperative day and increased serum hepatocyte growth factor levels were measured by ELISA in the third postoperative day. Selective CRH(2) antagonism reversed the elevated expression of bcl-2 and hepatocyte growth factor, suggesting that this receptor type mediated antiapoptotic actions of the endogenous CRH system, opposing the preapoptotic ones mediated by CRH(1). In conclusion, the present study indicated that the CRH neuroendocrine system regulates cholestasis-induced apoptosis in the hepatic parenchyma via receptor-specific pathways. These data may contribute to better understanding of the CRH biology and its pathophysiological significance in the periphery.
Paschos
Konstantinos A
KA
Department of Pharmacology, Democritus University of Thrace, Dragana, 68100 Alexandroupolis, Thrace, Greece.
Charsou
Chara
C
Constantinidis
Theodoros C
TC
Anagnostoulis
Stavros
S
Lambropoulou
Maria
M
Papachristou
Fotini
F
Simopoulos
Konstantinos
K
Chatzaki
Ekaterini
E
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002779:Cholestasis / Q000378:metabolism / Q000473:pathology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D017228:Hepatocyte Growth Factor / Q000097:blood; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; C104416:astressin; D017228:Hepatocyte Growth Factor; D003346:Corticotropin-Releasing Hormone