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A potassium channel-linked mechanism of glial cell swelling in the postischemic retina

A potassium channel-linked mechanism of glial cell swelling in the postischemic retina,10.1016/j.mcn.2004.04.005,Molecular and Cellular Neuroscience,T

A potassium channel-linked mechanism of glial cell swelling in the postischemic retina   (Citations: 70)
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The cellular mechanisms underlying glial cell swelling, a central cause of edema formation in the brain and retina, are not yet known. Here, we show that glial cells in the postischemic rat retina, but not in control retina, swell upon hypotonic stress. Swelling of control cells could be evoked when their K+ channels were blocked. After transient ischemia, glial cells strongly downregulated their K+ conductance and their prominent Kir4.1 protein expression at blood vessels and the vitreous body. In contrast, the expression of the aquaporin-4 (AQP4) (water channel) protein was only slightly altered after ischemia. Activation of D2 dopaminergic receptors prevents the hypotonic glial cell swelling. The present results elucidate the coupling of transmembraneous water fluxes to K+ currents in glial cells and reveal the role of altered K+ channel expression in the development of cytotoxic edema. We propose a mechanism of postischemic glial cell swelling where a downregulation of their K+ conductance prevents the emission of intracellularly accumulated K+ ions, resulting in osmotically driven water fluxes from the blood into the glial cells via aquaporins. Inhibition of these water fluxes may be beneficial to prevent ischemia-evoked glial cell swelling.
Journal: Molecular and Cellular Neuroscience - MOL CELL NEUROSCI , vol. 26, no. 4, pp. 493-502, 2004
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    • ...Swelling of glial cells is a characteristic feature of ischemic and traumatic brain injuries [19], and swelling of retinal glial (Mu ¨ller) cells occurs in models of ischemic and diabetic retinopathies [32, 33]...
    • ...It has been demonstrated that rapid osmotic swelling of cell somata is a characteristic feature of glial cells in slices of postischemic and diabetic retinas [32, 33]...
    • ...Though glial somata in control retinal tissues did not swell under hypotonic conditions, hypotonic challenge in the presence of potassium channel-blocking barium ions induced a significant (P \ 0.01) swelling of glial cell bodies (Fig. 1b), as previously described [32]...
    • ...Osmotic swelling is a characteristic feature of retinal glial cells under ischemic and diabetic conditions [32, 33], and...
    • ...In retinal glial cells from control animals, the intracellular sodium overload might be compensated by a rapid efflux of potassium through inwardly rectifying potassium (Kir) channels [32]...
    • ...It has been shown that under ischemic and diabetic conditions, Kir channels are downregulated and/or inactivated in retinal glial cells, resulting in cellular swelling under hypotonic conditions [32, 33]...
    • ...The downregulation of perivascular Kir channels under conditions of retinal ischemia and diabetes [32, 33] should disrupt the glia-mediated potassium clearance of the retina and the transglial water transport [8]...
    • ...The downregulation of glial Kir channels in postischemic retinas is associated with an induction of glial swelling under anisoosmotic conditions [32]...

    Florian Neumannet al. Sex Steroids Inhibit Osmotic Swelling of Retinal Glial Cells

    • ...VEGF receptors are present and active on all inflammatory cell subtypes including platelets. Inflammatory cells also produce and release VEGF.Vascular Permeability. VEGF is 50,000 times more potent than histamine in inducing vascular leakage. The increase in vascular permeability happens by a breakdown of the BRB initiated by different mechanisms. Those include: (1) leucocyte-mediated (recruitment, adhesion, stasis) endothelial injury and cell death, the underlying pathomechanism needing further clarification; (2) conformational changes and dissolution of tight junctions of endothelial cells by phosphorylation of the tight junction protein occludin; (3) activation of protein kinase C, and (4) induction of fenestrations and vesiculovacuolar organelles.Prostaglandin PathwayA prostaglandin is any member of a group of lipid compounds that derives enzymatically from fatty acids. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects. Prostaglandins together with thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of eicosanoids. In the prostaglandin pathway, inflammation causes the enzyme phospholipase to release arachidonic acid from cell walls. Subsequently, arachidonic acid is converted into prostaglandins by the enzyme cyclooxygenase 2 and into leukotrienes by the enzyme 5-lipoxygenase. Prostaglandin E1 causes a breakdown of the BRB by opening the tight junctions.Ischemia and HypoxiaIschemic/hypoxic conditions play a central role in the development of macular edema. In neuronal cells, the rate of ATP synthesis is very high as compared to other cell types. This phenomenon results in excessive water production. The uptake of metabolic substrates such as glucose is related to an influx of water into cells. This fluid has to be cleared from the cells. Under physiological conditions, water leaves neuronal cells via uptake by glial cells and is released into the blood or into the cerebrospinal fluid (brain)/the vitreous body (retina). The water release from the glial cells into the retina occurs through their perivascular end-feet facing the vitreous. Aquaporin 4 (AQP4) water channels play a significant role in mediating these water fluxes.In postischemic brain edema, the swelling of glial cell end-feet around blood vessels is believed to be enhanced by an altered expression of the AQP4 water channels in cell membranes [...

    Stefan Schollet al. Pathophysiology of Macular Edema

    • ...K+ spatial buffering within the inner retina occurs via the redistribution (siphoning) of excess K+ from the extraneuronal space toward fluid reservoirs of low K+ (or sinks), such as vitreous body, subretinal space and blood vessels [47,48]...

    Adnan Dibaset al. Changes in ocular aquaporin-4 (AQP4) expression following retinal inju...

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