Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 642, Issue 1-3, Pages 28-36Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2010.05.055
Keywords
TGF-beta 1; Tubular epithelial cell; Apoptosis; TSA; ERK
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Funding
- Mochida Pharmaceutical Co., Ltd.
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Histone deacetylase (HDAC) inhibitors have recently been reported to have possible reno-protective effects in the last few years. In this study, we found that tricostatin A (TSA), an HDAC inhibitor, prevented transforming growth factor beta 1 (TGF-beta 1)-induced apoptosis in cultured human renal proximal tubular epithelial cells (RFTECs). TGF-beta 1-induced apoptosis via the activation of both caspase-8 and caspase-9 but did not activate the Fas receptor and did not alter Bcl-2 or Bax protein expression. TSA prevented TGF-beta 1-induced apoptosis and the activation of caspase-8 and caspase-9 in RPTECs but did not inhibit the TGF-beta 1-induced phosphorylation of Smad3 and p38 mitogen-activated protein kinase (MAPK). However, TSA inhibited the TGF-beta 1-induced phosphorylation of extracellular signal regulated kinase (ERK), and the MAPK/ERK kinase inhibitor U0126, which specifically inhibits ERK, also prevented TGF-beta 1-induced apoptosis. Our results show, for the first time, that TSA inhibits TGF-beta 1-induced ERK activation and overrides pro-apoptotic signals like Smad3 and p38 in human RPTECs. (C) 2010 Elsevier B.V. All rights reserved.
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