BackgroundOxidative 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.ResultsAfter 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.ConclusionsBased 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.

Progranulin ( PGRN ) is a growth factor implicated in several neurodegenerative diseases, such as frontotemporal lobar degeneration. Despite its important role in the central nervous system ( CNS ), the mechanisms controlling PGRN expression in the CNS are largely unknown. Recent evidence, however, suggested that several stressors, such as hypoxia, acidosis, or oxidative stress, induce PGRN expression. The present study was mainly aimed at determining whether and, if so, how glucose deprivation affects PGRN expression in PC 12 cells. Initially, it was found that glucose deprivation gradually induced PGRN gene expression in PC 12 cells. To elucidate the underlying molecular mechanisms, several intracellular signalings that were modified in response to glucose deprivation were examined. Both adenosine monophosphate kinase ( AMPK ) activation and changes in osmotic pressure, which are modified by extracellular glucose concentration, had no effect on PGRN gene expression; on the other hand, p38 activation in response to glucose deprivation played an important role in inducing PGRN gene expression. It was also found that expression of sortilin, a PGRN receptor implicated in PGRN endocytosis, was dramatically reduced by glucose deprivation. In contrast to glucose‐dependent regulation of PGRN gene expression, AMPK activation played a central role in reducing sortilin expression. Overall, the present study suggests that the PGRN –sortilin axis is modulated by glucose deprivation via two distinct mechanisms. As PGRN is neuroprotective, this system may represent a new neuroprotective mechanism activated by glucose deprivation in the CNS .