CysLT2 receptor-mediated AQP4 up-regulation is involved in ischemic-like injury through activation of ERK and p38 MAPK in rat astrocytes

Abstract Aims We previously reported that cysteinyl leukotriene receptor 2 (CysLT 2 ) mediates ischemic astrocyte injury, and leukotriene D 4 -activated CysLT 2 receptor up-regulates the water channel aquaporin 4 (AQP4). Here we investigated the mechanism underlying CysLT 2 receptor-mediated ischemic astrocyte injury induced by 4-h oxygen-glucose deprivation and 24-h recovery (OGD/R). Main methods Primary cultures of rat astrocytes were treated by OGD/R to construct the cell injury model. AQP4 expression was inhibited by small interfering RNA (siRNA). The expressions of AQP4 and CysLTs receptors, and the MAPK signaling pathway were determined. Key findings OGD/R induced astrocyte injury, and increased expression of the CysLT 2 (but not CysLT 1 ) receptor and AQP4. OGD/R-induced cell injury and AQP4 up-regulation were inhibited by a CysLT 2 receptor antagonist (Bay cysLT2) and a non-selective CysLT receptor antagonist (Bay u9773), but not by a CysLT 1 receptor antagonist (montelukast). Knockdown of AQP4 by siRNA attenuated OGD/R injury. Furthermore, OGD/R increased phosphorylation of ERK1/2 and p38, whose inhibitors relieved the cell injury and AQP4 up-regulation. Significance The CysLT 2 receptor mediates AQP4 up-regulation in astrocytes, and up-regulated AQP4 leads to OGD/R-induced injury, which results from activation of the ERK1/2 and p38 MAPK pathways.