A potassium channel-linked mechanism of glial cell swelling in the postischemic retina
Introduction
The development of brain edema is a major cause of morbidity and death in a variety of common neurological disorders. In addition to the disruption of the blood–brain barrier which favors plasma protein and water influx into the brain parenchyma, the swelling of glial cell endfeet around blood vessels constitutes a hallmark of edema development as it indicates a breakdown of homeostatic mechanisms which contributes to neuronal degeneration. The molecular mechanisms and the pathophysiology of the disturbed cerebral water balance during edema are poorly understood. However, in the last years, it became obvious that aquaporins, water-transporting channels mainly expressed by glial cells, play a crucial role in mediating fast water fluxes at the blood/cerebrospinal fluid–brain interfaces (Verkman, 2002). Normally, there is a substantial continuous water efflux out of the neural tissue since the high rate of neuronal ATP synthesis generates a huge amount of water, and since the uptake of metabolic substrates such as glucose is coupled to an influx of water which must be cleared out of the cells (Amiry-Moghaddam et al., 2003). The normal route for the constitutive water efflux from neurons is via uptake by glial cells and release into the blood or into the cerebrospinal fluid (in brain)/the vitreous body (in retina). This water release from glial cells occurs through their perivascular, subpial, and/or vitreous-facing endfeet. Aquaporin-4 (AQP4) water channels have been crucially implicated in mediating these water fluxes Amiry-Moghaddam et al., 2003, Nagelhus et al., 1999; it has been shown that AQP4 is associated with the orthogonal arrays of particles Verbavatz et al., 1997, Wolburg, 1995 and abundantly expressed in the membranes of glial cell endfeet lining the pial surface and surrounding the blood vessels Frigeri et al., 1995, Nielsen et al., 1997. AQP4 mislocation has been suggested to be crucially implicated in the development of postischemic brain edema Amiry-Moghaddam et al., 2003, Manley et al., 2000.
The retinal equivalent of brain edema is the macular edema which is an important complication of various different retinal diseases, as it contributes to photoreceptor degeneration and neuronal cell death (Tso, 1982). In patients with uveitis or diabetes mellitus, macular edema is the major cause of blindness. Macular edema may cause a thickening of the whole macula and/or the formation of large cysts in two retinal layers, the inner nuclear and Henle fiber layers Loeffler et al., 1992, Wolter, 1981. Both an increased extracellular fluid volume (Gass et al., 1985) and a swelling of retinal glial (Müller) cells (Yanoff et al., 1984) may contribute to the development of macular edema; the swelling of Müller cells in the macula was described to precede extracellular edema formation and it was suggested that the cysts are formed by swollen and dying Müller cells Fine and Brucker, 1981, Yanoff et al., 1984. However, the pathogenesis of retinal glial cell swelling is not yet resolved. Since ischemia–reperfusion is apparently one major factor in retinal edema development Marmor, 1999, Tso, 1982, Yanoff et al., 1984, we studied osmotic responses of rat retinal glial cells before and after experimental transient ischemia.
The observation that in glial cells of the retina, a certain type of K+ channels (the Kir4.1 subunit) and the AQP4 protein are co-enriched in perivascular and vitreous-facing membrane domains, has led to the suggestion that retinal water transport is coupled to transglial K+ currents (Nagelhus et al., 1999). Thus, we investigated whether an altered K+ channel expression might be involved in the formation of cytotoxic edema, that is, in glial cell swelling. Indeed, we found that the ischemia-evoked facilitation of cell swelling was accompanied by a mislocation of glial K+ channels, and that blockade of K+ channels facilitates swelling of normal cells under hypotonic stress (a situation resembling hypoxia-induced cytotoxic edema in the brain). The data prompted us to suggest a novel pathomechanism of postischemic glial cell swelling, based upon dramatic changes in K+ channel expression.
Section snippets
Ischemia-induced glial cell swelling
To investigate whether ischemia modifies the swelling characteristics of retinal glial cells, we induced retinal ischemia in rat eyes by raising the intraocular pressure above the systolic pressure for 60 min. Three days after reperfusion, we recorded the cross-sectional area of vital dye-labeled glial (Müller) cell somata in acutely isolated retinal slices (Fig. 1A). The somata swelled strongly (approximately 30% increase in cross-sectional area; P < 0.05) when the slices were superfused with
Discussion
Ischemic–hypoxic conditions are crucially implicated in the development of edema in brain (Xiao, 2002) and retina Marmor, 1999, Tso, 1982, Yanoff et al., 1984. This includes swelling of perivascular astrocytic cell endfeet in brain and of retinal glial cells in the macula (Yanoff et al., 1984), underlining the importance of perivascular, subpial, and vitreous-facing glial cell endfeet for CNS water transport. In particular, water fluxes in neural tissues are mediated by glial AQP4 water
Ischemia model
Transient retinal ischemia was induced in one eye of adult Long–Evans rats, weighing 250–350 g, while the other eye remained untreated or was sham-treated, and served as control. The animals were kept without food for 12 h; then, ketamine/xylazine anesthesia was induced. The anterior chamber of the treated eye was cannulated from the pars plana with a 27-gauge infusion needle connected to a bag containing normal saline. The intraocular pressure was increased to 160 mm Hg for 60 min by elevating
Acknowledgements
This work was supported by grants from the Bundesministerium für Bildung und Forschung (Interdisciplinary Center for Clinical Research at the University of Leipzig, 01KS9504, Project C21) and from the Deutsche Forschungsgemeinschaft (Re 849/8-3).
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