Abstract
BackgroundRetinal degeneration in transgenic rats that express a mutant cilia gene polycystin-2 (CMV-PKD2(1/703)HA) is characterized by initial photoreceptor degeneration and glial activation, followed by vasoregression and neuronal degeneration (Feng et al., 2009, PLoS One 4: e7328). It is unknown whether glial activation contributes to neurovascular degeneration after photoreceptor degeneration. We characterized the reactivity of Müller glial cells in retinas of rats that express defective polycystin-2.MethodsAge-matched Sprague-Dawley rats served as control. Retinal slices were immunostained for intermediate filaments, the potassium channel Kir4.1, and aquaporins 1 and 4. The potassium conductance of isolated Müller cells was recorded by whole-cell patch clamping. The osmotic swelling characteristics of Müller cells were determined by superfusion of retinal slices with a hypoosmotic solution.FindingsMüller cells in retinas of transgenic rats displayed upregulation of GFAP and nestin which was not observed in control cells. Whereas aquaporin-1 labeling of photoreceptor cells disappeared along with the degeneration of the cells, aquaporin-1 emerged in glial cells in the inner retina of transgenic rats. Aquaporin-4 was upregulated around degenerating photoreceptor cells. There was an age-dependent redistribution of Kir4.1 in retinas of transgenic rats, with a more even distribution along glial membranes and a downregulation of perivascular Kir4.1. Müller cells of transgenic rats displayed a slight decrease in their Kir conductance as compared to control. Müller cells in retinal tissues from transgenic rats swelled immediately under hypoosmotic stress; this was not observed in control cells. Osmotic swelling was induced by oxidative-nitrosative stress, mitochondrial dysfunction, and inflammatory lipid mediators.InterpretationCellular swelling suggests that the rapid water transport through Müller cells in response to osmotic stress is altered as compared to control. The dislocation of Kir4.1 will disturb the retinal potassium and water homeostasis, and osmotic generation of free radicals and inflammatory lipids may contribute to neurovascular injury.
Highlights
Degeneration of the outer retina caused by photoreceptor cell death is a characteristic of blinding diseases including retinitis pigmentosa, age-related macular degeneration, and retinal light injury
As previously described [13,15], retinal tissues of transgenic rats that express defective polycystin-2 displayed an age-dependent decrease in the tickness of the outer and inner retinal layers (Figs. 1 and 2A)
We found that Muller cells in retinas of rats with defective polycystin-2 displayed an upregulation of intermediate filaments (Figs. 1, 2, 4), a moderate decrease in the Kir channel-mediated potassium conductance (Fig. 7A, 7C), an altered distribution of Kir4.1 protein (Figs. 1 and 6), upregulation of AQP1 (Figs. 1 and 3), and an increased expression of AQP4 around the degenerating photoreceptor cells (Figs. 1 and 5)
Summary
Degeneration of the outer retina caused by photoreceptor cell death is a characteristic of blinding diseases including retinitis pigmentosa, age-related macular degeneration, and retinal light injury. Retinal diseases caused by primary photoreceptor cell death are often characterized by secondary damage to the inner retina. It has been suggested that reactive retinal glial (Muller) cells play a role in the propagation of the initial photoreceptor degeneration to the neuronal damage in the inner retina [5]. Retinal degeneration in transgenic rats that express a mutant cilia gene polycystin-2 (CMV-PKD2(1/703)HA) is characterized by initial photoreceptor degeneration and glial activation, followed by vasoregression and neuronal degeneration (Feng et al, 2009, PLoS One 4: e7328). It is unknown whether glial activation contributes to neurovascular degeneration after photoreceptor degeneration. We characterized the reactivity of Muller glial cells in retinas of rats that express defective polycystin-2
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