Unexpected protection of glomerular mesangial cells from oxidant-triggered apoptosis by bioflavonoid quercetin.
Bioflavonoid quercetin is known as an anti-cancer agent that induces apoptosis of tumor cells. Currently, however, little is understood about the effect of this drug on the function of normal cells. In this report, we address an unexpected, novel action of quercetin against apoptosis. Pretreatment with quercetin protected mesangial cells from hydrogen peroxide (H2O2)-induced apoptosis. A similar effect was observed in other cell types including LLC-PK1 epithelial cells and NRK49F fibroblasts. To explore the molecular mechanisms involved, we tested the effect of quercetin on c-Jun/activator protein-1 AP-1), the crucial mediator for H2O2-initiated apoptosis. Northern blot analysis revealed that quercetin suppressed the c-jun expression by H2O2. This was correlated with blunted activation of 12-O-tetradecanoylphorbol 13-acetate response element (TRE) in response to H2O2. These results suggested that quercetin inhibited apoptosis via intervention in the c-Jun/AP-1 pathway. To further investigate the action of quercetin, its effect on tyrosine kinases was studied. Immunoblot analysis revealed that H2O2 induced tyrosine phosphorylation. Quercetin inhibited this process in a dose-dependent manner. Inactivation of tyrosine kinases was an event upstream of c-Jun/AP-1, because tyrosine kinase inhibitors suppressed both activation of c-Jun/AP-1 and induction of apoptosis by H2O2. These findings elucidated the novel action of quercetin as an apoptosis inhibitor. This cytoprotective effect was found to be via suppression of the tyrosine kinase-c-Jun/AP-1 pathway triggered by oxidant stress.
Yokoo
T
T
Department of Medicine, University College London Medical School, Rayne Institute, United Kingdom.
Kitamura
M
M
D000818:Animals; D017209:Apoptosis; D005419:Flavonoids / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D016877:Oxidants / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D005419:Flavonoids; D016877:Oxidants; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014443:Tyrosine; D011794:Quercetin; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases