Tempol inhibits growth of As4.1 juxtaglomerular cells via cell cycle             arrest and apoptosis.
A stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-osyl (Tempol)             is widely used as an antioxidant in vitro and in vivo. In this study, we investigated             the effects of Tempol on the growth of As4.1 juxtaglomerular cells in relation             to cell cycle and cell death. Tempol dose-dependently decreased the growth of             As4.1 cells with an IC50 of ~1 mM at 48 h. DNA flow cytometry analysis and BrdU             staining indicated that Tempol induced S phase arrest, which is accompanied by             a downregulation of cyclin A. Tempol also induced apoptotic cell death, which             was accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψm), an             activation of caspase-3 and cleavage of poly(ADP-ribose)polymerase-1 (PARP-1).             Furthermore, Tempol increased reactive oxygen species (ROS) levels, and the phosphorylation             of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK).             MEK and JNK inhibitors significantly attenuated a growth inhibition in Tempol-treated             As4.1 cells. In conclusion, Tempol inhibited the growth of As4.1 cells via cell             cycle arrest and apoptosis. Tempol also activated ERK and JNK signaling, which             was responsible for cell growth inhibition. Our present data provide useful information             for the toxicological effects of Tempol in juxtaglomerular cells in relation to             cell growth inhibition and cell death.
Department of Physiology, Research Institute for Endocrine Sciences,                     Chonbuk National University Medical School, Jeonju 561-180, Republic of                     Korea.
Yong Hwan
YH
Han
Woo Hyun
WH
Park
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D019925:Cyclin A / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013113:Spin Labels
D003497:Cyclic N-Oxides; D019925:Cyclin A; D017382:Reactive Oxygen Species; D013113:Spin Labels; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005978:Glutathione; C001803:tempol