Interactions of connexin 43 and aquaporin-4 in the formation of glioma-induced brain edema.

Connexin 43 (Cx43) and aquaporin-4 (AQP4) have important roles in the formation of glioma-induced brain edema; however, the association between these two factors in the development of edema has remained to be elucidated. In the present study, immunofluorescence and western blot analysis revealed that in a rat model of intracranial C6 glioma, Cx43 expression levels were low to undetectable and AQP4 expression levels were low in glioma cells. Significantly higher Cx43 and AQP4 levels were detected in the tissue surrounding the glioma. To further investigate the potential interaction between Cx43 and AQP4, normal glial cells and C6 glioma cells were cultured in hypotonic medium. Reverse transcription quantitative polymerase chain reaction indicated that AQP4 and Cx43 mRNA expression levels increased as a function of time in normal glial cells and C6 glioma cells in a hypotonic environment. However, the increase observed in normal glial cells was significantly lower than that observed in C6 glioma cells. Furthermore, AQP4 expression levels changed prior to alterations in Cx43 expression. Following AQP4 silencing in C6 cells, the increase in Cx43 expression was significantly attenuated (P<0.05). In normal cells, Cx43 silencing did not influence AQP4 expression (P>0.05). Therefore, it was hypothesized that AQP4 and Cx43 had two distinct mechanisms underlying brain edema formation within and surrounding the glioma. Cx43 may be a downstream effector of AQP4. The elucidation of this pathway may aid in the development of drugs targeting the interaction between AQP4 and Cx43, providing novel therapeutic possibilities for glioma-induced brain edema.