Inhibition of KDM6A Decreased the Reactive Astrocytes Proliferation Induced by Hypoxic and Ischemic

Abstract HIBD (hypoxic-ischemic brain damage) is a common clinical problem, which is often accompanied by serious sequelae. This disease affects the life quality of patients and increases the economic burden on sufferers’ families. Many precipitating factors of HIBD have been studied, but its specific pathogenesis has not been thoroughly explored. Reactive astrogliosis is ubiquitous in HIBD and performs a variety of pathological and physiological functions. KDM6A (lysine-specific demethylase 6A) is a member of the α-ketoglutarate dioxygenase superfamily, and prolyl hydroxylase (PHD) of HIF (hypoxia-inducible factor) also belongs to this family. In this study, we focused on the role of KDM6A in the proliferation of reactive astrocytes. Astrocytes proliferated with KDM6A increased were found in the ischemic lateral brain of HIBD rats. After OGD/R (oxygen-glucose deprivation/ reoxygenation), KDM6A was significantly up-regulated, which accompanies astrocytes proliferation mediated by the imbalance of cell cycle regulation. While knockdown of KDM6A restored astrocytes proliferation and reversed pathological damage in the brain of HIBD-model rats. Transcriptome and qRT-PCR datum showed that KDM6A might contribute to post-transcriptional levels of the cell cycle pathway through the proteasome pathway (KO03050). Inhibitors of the proteasome pathway, MG-132, and Bortezomib (PS-341), could significantly up-regulate the expression of cyclin proteins after KDM6A knock-down. To sum up, this study suggested that KDM6A accelerates ischemia-hypoxia-induced astrocyte proliferation by regulating proteolysis of the cell cycle pathway. This study provides a new idea on dealing with reactive astrogliosis and novel possible evidence for the prevention and treatment of HIBD.