RESUMO
BACKGROUND: Oxidative stress is one of the mechanisms underlying pathogenesis in neurodegenerative diseases such as Alzheimer's disease. Generally, oxidative stress represents cell toxicity; however, we recently found that oxidative stress promotes the expression of growth factor progranulin (PGRN) in HT22 murine hippocampus cells, thereby protecting the HT22 cells. In this study, we attempted to clarify whether a similar system exists in the other neuronal cell model, rat pheochromocytoma (PC12) cells. RESULTS: After confirming that high concentrations of hydrogen peroxide (H2O2; 100-250 µM) initiate PC12 cell death, we analyzed growth factor expressional changes after H2O2 treatment. We found, intriguingly, that gene expression of brain-derived neurotrophic factor (BDNF), but not PGRN was significantly induced by H2O2. Although little expression of the high affinity BDNF receptor tropomyosin-related kinase TrkB was observed in PC12 cells, expression of low affinity neurotrophin receptor, p75NTR, was clearly observed. This BDNF signaling appeared to contribute to PC12 cell protection, since PC12 cell death was significantly attenuated by BDNF treatment. CONCLUSIONS: Based on our results, we conclude that the induction of BDNF by subtoxic levels of H2O2 and its signaling may have roles in PC12 cell protection.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Regulação da Expressão Gênica , Peróxido de Hidrogênio/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/agonistas , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso , Estresse Oxidativo , Células PC12 , Progranulinas , Ratos , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de SinaisRESUMO
Nutrient availability is one of the most important signals regulating cellular fates including cell growth, differentiation, and death. Recent evidence suggests that the NAD(+)-dependent histone deacetylase sirtuin 1 (SIRT1) plays a prominent role in linking changes in nutritional availability with cellular fate regulation. SIRT1 expression is observed in neurons, yet the expressional and functional regulation of this protein is not fully understood. In the present study, we examined whether extracellular glucose concentration affects the expression and localization of SIRT1 in PC12 cells. Further, we examined levels of forkhead box O3a (FoxO3a), which is also controlled by changes in extracellular glucose concentration. We observed the total expression levels of SIRT1 and FoxO3a in PC12 cells were reduced when glucose availability increased via gene expressional control, at least in part. Nuclear localization of SIRT1 and FoxO3a was increased by glucose deprivation. Even though the changes in extracellular glucose concentration regulated SIRT1 and FoxO3a in a similar direction, the effects of nerve growth factor on these two proteins were completely different. Finally, we found the potent SIRT1 inhibitor enhanced glucose deprivation-induced cell death. Therefore, we propose that glucose deprivation-induced SIRT1 expression potentially plays a major role in protecting PC12 cells.