Trichostatin a prevents TGF-beta1-induced apoptosis by inhibiting ERK activation in human renal tubular epithelial cells.
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 beta1 (TGF-beta1)-induced apoptosis in cultured human renal proximal tubular epithelial cells (RPTECs). TGF-beta1-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-beta1-induced apoptosis and the activation of caspase-8 and caspase-9 in RPTECs but did not inhibit the TGF-beta1-induced phosphorylation of Smad3 and p38 mitogen-activated protein kinase (MAPK). However, TSA inhibited the TGF-beta1-induced phosphorylation of extracellular signal regulated kinase (ERK), and the MAPK/ERK kinase inhibitor U0126, which specifically inhibits ERK, also prevented TGF-beta1-induced apoptosis. Our results show, for the first time, that TSA inhibits TGF-beta1-induced ERK activation and overrides pro-apoptotic signals like Smad3 and p38 in human RPTECs.
Yoshikawa
Masahiro
M
Department of Internal Medicine, Division of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.
Hishikawa
Keiichi
K
Idei
Mana
M
Fujita
Toshiro
T
D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007684:Kidney Tubules / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D006877:Hydroxamic Acids; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C012589:trichostatin A; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; D053453:Caspase 9