Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae

Vasogenic edema is one of the most serious clinical problems in brain tumors and tightly connected to water shifts between the different fluid compartments in the brain. Aquaporin water channels have been recognized to have an important impact on the development of edematous swelling in the brain. Astrocytes, which are believed to induce or at least maintain the blood-brain barrier in the brain capillary endothelial cells, express the aquaporin isoform AQP4. Normally, AQP4 is highly concentrated in the glial membrane where astrocytes contact mesenchymal space, such as perivascular or brain superficial regions. Parenchymal membranes do not show any immunocytochemical AQP4-specific signal. We investigated the AQP4 expression in human glioblastoma and correlated it with the expression pattern of the extracellular heparan sulfate proteoglycan agrin and members of the dystrophin-dystroglycan complex. We found that AQP4 completely covered the surface of the glioma cells. alpha-Dystroglycan was absent from glial membranes but retained in endothelial membranes. Utrophin and dystrophin remained restricted to the endfoot membrane in those cells in which AQP4 had been redistributed, whereas alpha-syntrophin redistributed together with AQP4 across the entire cell surface. Since alpha-dystroglycan operates as a binding protein for agrin, these observations support the suggestions that (1) AQP4 is tightly associated with the dystrophin-dystroglycan complex, and (2) agrin is necessary for the polarized distribution of AQP4 in the astrocyte. The results are discussed in connection with the fact that normally AQP4 is assembled in the so-called orthogonal arrays of particles (OAPs).The restriction of AQP4/OAPs to the endfoot membrane may be dependent on the presence of agrin, and this might be essentially connected to the ability of astrocytes to maintain the integrity of the blood-brain barrier.