The main water channel of the brain, aquaporin-4 (AQP4), is one of the classical water-specific aquaporins. It is expressed in many epithelial tissues in the basolateral membrane domain. It is present in the membranes of supporting cells in most sensory organs in a specifically adapted pattern: in the supporting cells of the olfactory mucosa, AQP4 occurs along the basolateral aspects, in mammalian retinal Müller cells it is highly polarized. In the cochlear epithelium of the inner ear, it is expressed basolaterally in some cells but strictly basally in others. Within the central nervous system, aquaporin-4 (AQP4) is expressed by cells of the astroglial family, more specifically, by astrocytes and ependymal cells. In the mammalian brain, AQP4 is located in high density in the membranes of astrocytic endfeet facing the pial surface and surrounding blood vessels. At these locations, AQP4 plays a role in the maintenance of ionic homeostasis and volume regulation. This highly polarized expression has not been observed in the brain of fish where astroglial cells have long processes and occur mostly as radial glial cells. In the brain of the zebrafish, AQP4 immunoreactivity is found along the radial extent of astroglial cells. This suggests that the polarized expression of AQP4 was not present at all stages of evolution. Thus, a polarized expression of AQP4 as part of a control mechanism for a stable ionic environment and water balanced occurred at several locations in supporting and glial cells during evolution. This initially basolateral membrane localization of AQP4 is shifted to highly polarized expression in astrocytic endfeet in the mammalian brain and serves as a part of the neurovascular unit to efficiently maintain homeostasis.

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Proliferation of astrocytes plays an essential role during ontogeny and in the adult brain, where it occurs following trauma and in inflammation and neurodegenerative diseases as well as in normal, healthy mammals. The cellular mechanisms underlying glial proliferation remain poorly understood. As dopamine is known to modulate proliferation in different cell populations, we investigated the effects of dopamine on the proliferation of striatal astrocytes in vitro. We found that dopamine reduced proliferation. As proliferation involves, among other things, a change in cell volume, which normally comes with water movement across the membrane, water channels might represent a molecular target of the dopamine effect. Therefore we studied the effect of dopamine on aquaporin 4 (AQP4) expression, the main aquaporin subtype expressed in glial cells, and observed a down-regulation of the AQP4-M23 isoform. This down-regulation was the cause of the dopamine-induced decrease in proliferation as knockdown of AQP4 using siRNA techniques mimicked the effects of dopamine on proliferation. Furthermore, stimulation of glial proliferation by basic fibroblast growth factor was also abolished by knocking down AQP4. In addition, blocking of AQP4 with 10 mum tetraethylammonium inhibited osmotically induced cell swelling and stimulation of glial cell proliferation by basic fibroblast growth factor. These results demonstrate a clear-cut involvement of AQP4 in the regulation of proliferation and implicate that modulation of AQP4 could be used therapeutically in the treatment of neurodegenerative diseases as well as in the regulation of reactive astrogliosis by preventing or reducing the glia scar formation, thus improving regeneration following ischemia or other trauma.

Sensory transduction in the cochlea depends on perilymphatic-endolymphatic potassium (K(+)) recycling. It has been suggested that the epithelial supporting cells (SCs) of the cochlear duct may form the intracellular K(+) recycling pathway. Thus, they must be endowed with molecular mechanisms that facilitate K(+) uptake and release, along with concomitant osmotically driven water movements. As yet, no molecules have been described that would allow for volume-equilibrated transepithelial K(+) fluxes across the SCs. This study describes the subcellular co-localisation of the K(ir)4.1 K(+) channel (K(ir)4.1) and the aquaporin-4 water channel (AQP4) in SCs, on the basis of immunohistochemical double-labelling experiments in rat and human cochleae. The results of this study reveal the expression of K(ir)4.1 in the basal or basolateral membranes of the SCs in the sensory domain of the organ of Corti that are adjacent to hair cells and in the non-sensory domains of the inner and outer sulci that abut large extracellular fluid spaces. The SCs of the inner sulcus (interdental cells, inner sulcus cells) and the outer sulcus (Hensen's cells, outer sulcus cells) display the co-localisation of K(ir)4.1 and AQP4 expression. However, the SCs in the sensory domain of the organ of Corti reveal a gap in the expression of AQP4. The outer pillar cell is devoid of both K(ir)4.1 and AQP4. The subcellular co-localisation of K(ir)4.1 and AQP4 in the SCs of the cochlea described in this study resembles that of the astroglia of the central nervous system and the glial Mueller cells in the retina.

Based on the results of this investigation, a safer location for the application of volumizing material is the subcutaneous plane in the paramedian location of both the upper lip and the lower lip. Care has to be taken when aiming to inject in the midline, as the artery can be identified more frequently in superficial positions.