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Regulation of H 2 O 2 -induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes
Recent studies have suggested that, in certain cases, necrosis, like apoptosis, may be programmed, involving the activation and inhibition of many signaling pathways. In this study, we examined whether necrosis induced by H 2 O 2 is regulated by signaling pathways in primary hepatocytes. A detailed...
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| Published in: | American Journal of Physiology: Cell Physiology 2008-07, Vol.295 (1), p.C50-C63 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
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| Summary: | Recent studies have suggested that, in certain cases, necrosis, like apoptosis, may be programmed, involving the activation and inhibition of many signaling pathways. In this study, we examined whether necrosis induced by H
2
O
2
is regulated by signaling pathways in primary hepatocytes. A detailed time course revealed that H
2
O
2
treated to hepatocytes is consumed within minutes, but hepatocytes undergo necrosis several hours later. Thus, H
2
O
2
treatment induces a “lag phase” where signaling changes occur, including PKC activation, Akt (PKB) downregulation, activation of JNK, and downregulation of AMP-activated kinase (AMPK). Investigation of various inhibitors demonstrated that PKC inhibitors were effective in reducing necrosis caused by H
2
O
2
(∼80%). PKC inhibitor treatment decreased PKC activity but, surprisingly, also upregulated Akt and AMPK, suggesting that various PKC isoforms negatively regulate Akt and AMPK. Akt did not appear to play a significant role in H
2
O
2
-induced necrosis, since PKC inhibitor treatment protected hepatocytes from H
2
O
2
even when Akt was inhibited. On the other hand, compound C, a selective AMPK inhibitor, abrogated the protective effect of PKC inhibitors against necrosis induced by H
2
O
2
. Furthermore, AMPK activators protected against H
2
O
2
-induced necrosis, suggesting that much of the protective effect of PKC inhibition was mediated through the upregulation of AMPK. Work with PKC inhibitors suggested that atypical PKC downregulates AMPK in response to H
2
O
2
. Knockdown of PKC-α using antisense oligonucleotides also slightly protected (∼22%) against H
2
O
2
. Taken together, our data demonstrate that the modulation of signaling pathways involving PKC and AMPK can alter H
2
O
2
-induced necrosis, suggesting that a signaling “program” is important in mediating H
2
O
2
-induced necrosis in primary hepatocytes. |
|---|---|
| ISSN: | 0363-6143 1522-1563 |
| DOI: | 10.1152/ajpcell.90654.2007 |