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    • In astrocytes mitogen activated protein kinases MAPKs are ac

    2021-06-10

    In astrocytes, mitogen-activated protein kinases (MAPKs) are activated after OGD-induced ischemic injury (Yung and Tolkovsky, 2003, Niu et al., 2009) and they regulate induction of AQP expression (Arima et al., 2003, McCoy and Sontheimer, 2010). It is well known that MAPKs, including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK) and p38 enzymes, are activated by extracellular factors and function in various cellular roles (Pearson et al., 2001, Kumar et al., 2003, Ji et al., 2009). However, it is unknown whether activation of MAPKs is the mechanism of CysLT2 receptor-mediated ischemic astrocyte injury and AQP4 expression after exposure to OGD. In the present study, we examined CysLT2 receptor-mediated ischemic injury and its relation to AQP4 expression, and activation of MAPKs in this process in rat astrocytes after exposure to OGD. The goal was to reveal the mechanism underlying CysLT2 receptor-mediated ischemic injury in astrocytes.
    Materials and methods
    Results
    Discussion In the present study, we found that the CysLT2 receptor mediates up-regulated expression of AQP4 after OGD/R in primary cultures of astrocytes, and up-regulated AQP4 is related to OGD/R-induced astrocyte injury. This process is regulated by activation of the ERK1/2 and p38 MAPK signaling pathways. The important finding in the present study was that the CysLT2 receptor-mediated ischemic injury in astrocytes was associated with up-regulated AQP4. In our previous study, we found the CysLT2 receptor mediates moderate (4h) OGD-induced injury while the CysLT1 receptor mediates mild (1h) OGD-induced proliferation in rat astrocytes (Huang et al., 2008); we also reported CysLT2 receptor mediated up-regulation of AQP4 expression in mouse substance p and rat astrocytes (Wang et al., 2006). However, whether the CysLT2 receptor-mediated ischemic injury in astrocytes is associated with up-regulated AQP4 remains unclear. Here we confirmed that up-regulation of AQP4 expression is involved in CysLT2 receptor-mediated ischemic injury substance p in astrocytes. This finding was verified in two ways in our experiments. First, CysLT2 receptor antagonists blocked both AQP4 up-regulation and cell injury after OGD/R. Second, knockdown of AQP4 expression by siRNA attenuated OGD/R-induced astrocyte injury. As evidenced elsewhere, inhibition of AQP4 expression by edaravone, a free radical scavenger, attenuates neurological injury and brain edema after focal cerebral ischemia in rats (Kikuchi et al., 2009), and AQP4 knockout mice show less severe lesions after cerebral ischemia (Manley et al., 2000). In rat astrocytes, the anesthetic propofol provides neuroprotective effects and down-regulates AQP4 expression after OGD/reoxygenation (Zhu et al., 2009). Why AQP4 up-regulation induces ischemic-like injury in astrocytes is unclear, but may be related to unbalanced water transport and the resultant astrocyte swelling (cytotoxic edema) (Manley et al., 2004, Manley et al., 2000). In addition, we found that LTD4 induced the up-regulation of AQP4 expression in vivo and the CysLT1 receptor antagonist failed to antagonize the effect of LTD4. Therefore, we speculate that CysLT2 receptor may mediate the up-regulation of AQP4 expression. Because CysLT2 receptor antagonists are not available for in vivo study, the speculation has not been confirmed and the role of CysLT2 receptor in ischemic brain injury is unclear. Fortunately, we can use siRNAs to down-regulate CysLT2 receptor in vitro. We expect to clarify whether CysLT2 receptor mediates up-regulation of AQP4 expression and ischemic cerebral injury in vivo in the near future. Another important finding in the present study is clarification of the signaling pathway. We found that increased phosphorylation of ERK1/2 and p38, but not JNK, mediated the up-regulation of AQP4 induced by CysLT2 receptors. CysLT2 receptor antagonists attenuated ERK1/2 and p38 phosphorylation after OGD/R, and inhibitors of ERK1/2 and p38 attenuated AQP4 up-regulation and astrocyte injury after OGD/R. The signaling pathways for the responses to activated CysLT2 receptors are associated with the early growth response-1 (EGR-1) (Uzonyi et al., 2006) and NF-κB/AP-1 transcription factors (Thompson et al., 2008), but the regulation by ERK1/2 or p38 has not been reported. ERK1/2 activation is considered to be the signaling pathway for responses to CysLT1 receptors, such as astrocyte proliferation (Ciccarelli et al., 2004) and activation of the small GTP-binding protein Ras in differentiated U937 cells (Capra et al., 2004). Since ERK1/2 activation induces EGR-1 expression (Park and Koh, 1999) and EGR-1 regulates CysLT2 receptor responses (Uzonyi et al., 2006), ERK1/2 activation might be an intermedial step in the CysLT2 receptor signaling pathway. Although ERK1/2 is generally known to be involved in cell survival, the activation of ERK1/2 also contributes to cell death under certain conditions, such as neuronal oxidative stress or ischemia-induced brain injury (Zhuang and Schnellmann, 2006). This is consistent with our finding in ischemic astrocytes.