p38 and ERK1/2-dependent activation of c-Jun is required for the downregulation of oxidative stress-induced ERα in hypothalamic astrocytes

Introduction: Gonadotropin-releasing hormone (GnRH) is a hypothalamic neuropeptide that plays important roles in the female fertility. Accumulating evidence suggests that ER alpha present in the astrocytes of the hypothalamus region is essential for production of GnRH. The astrocytes display age-related senescence associated to oxidative stress induced by the estrogen metabolites. However, it is still unclear whether and how ER alpha expression changes during astrocyte aging. Methods: Immunofluorescence was performed to analyze the ER alpha gene levels in hypothalamic astrocytes of natural aging C57BL/6J female mice. We employed an oxidative stress cell model receiving 2OH-E2 intervention to confirm the downregulation of ER alpha expression in primary astrocytes. Western blot analysis was used to explore which oxidative stress signaling pathways induced loss of the ER alpha gene. Finally, ChIP-qPCR was employed to evaluate whether the c-Jun protein is able to regulate ER alpha gene expression. Results: Compared to young mice, we found that the ER alpha expression of mid-aged mice was significantly decreased. In hypothalamic astrocytes, 2OH-E2 treatment significantly reduced the expression of the ER alpha gene. Moreover, we observed that transcription factor c-Jun could directly inhibit transcriptional ER alpha gene expression and might also reduce it by decreasing H3K27 acetylation at promotor regions. Administration of the antioxidants Rg1 and AST significantly attenuated the decrease in ER alpha gene expression induced by oxidative stress. Conclusions: The current data demonstrate that oxidative stress leads to loss of ER alpha involving the activation of the p38 and ERK1/2 pathways and the induction of the c-Jun protein in hypothalamic astrocytes. C-Jun protein regulates ER alpha gene expression via direct transcriptional repression or involving histone acetylation modifications at ER alpha gene promoter sites.