p38 and ERK1/2-Dependent Activation of c-Jun Is Required for the Downregulation of Oxidative Stress-Induced ER[alpha] 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 naturally aging C57BL/6J female mice. We employed an oxidative stress cell model receiving 2-hydroxyestradiol (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 promoter regions. Administration of the antioxidants Rg1 and astaxanthin 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. Keywords: Estrogen receptor [alpha], Oxidative stress, Astrocyte, Hypothalamus, C-Jun