Involvement of mitogen-activated protein kinase pathways in ferrous iron-induced aquaporin-4 expression in cultured astrocytes

Abstract

Iron is an essential element for multiple metabolic reactions, but excessive iron accumulation in the brain can lead to astrocyte swelling and death and cause cerebral edema. Aquaporin-4 (AQP4) is the important water channel expressed in the astrocytes, and maintains the water homeostasis of the brain. Previous study has shown that iron deposition could increase AQP4 expression, however, the mechanism of AQP4 expression upregulation after iron overload is still unclear. In this study, we investigated the effect of ferrous iron overload on AQP4 expression in cultured mouse astrocytes. Primary cultures of astrocytes were exposed to ferrous iron, and the expression of AQP4 as well as the swelling of astrocyte were determined. AQP4 expression was inhibited by small interfering RNA (siRNA). The role of oxidative stress and mitogen-activated protein kinases (MAPKs) signaling pathway in ferrous iron-induced AQP4 expression upregulation were further studied. Ferrous iron exposure induced astrocyte death as well as cell swelling, and increased AQP4 expression. AQP4 gene silencing after siRNA transfection attenuated ferrous iron-induced astrocyte death. After treatment with antioxidants, the increased AQP4 expression was diminished. MAPKs were activated after ferrous iron treatment, and inhibitors of ERK and p38-MAPK relieved AQP4 expression upregulation as well as astrocyte death. These results suggest that ferrous iron has distinctive toxic effects on cultured astrocytes and induces AQP4 expression upregulation. MAPKs activation may play important roles in ferrous iron-induced astrocyte death through upregulation of AQP4 expression.