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


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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Neuroscience and Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
Ling-Ling
LL
Qi
San-Hua
SH
Fang
Wen-Zhen
WZ
Shi
Xue-Qin
XQ
Huang
Xia-Yan
XY
Zhang
Yun-Bi
YB
Lu
Wei-Ping
WP
Zhang
Er-Qing
EQ
Wei
D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis / Q000502:physiology*; D001253:Astrocytes / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051401:Aquaporin 4; C071435:BAY u9773; D018077:Receptors, Leukotriene; D013189:SRS-A; C412375:cysteinyl leukotriene receptor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases