Serum albumin induces osmotic swelling of rat retinal glial cells.

Edema in the ischemic neural tissue develops by increased vascular permeability associated with extravasation of albumin, and by glial swelling. Here, we show that bovine serum albumin acutely administered to slices of the rat retina causes swelling of glial somata under hypoosmotic conditions. The effect of albumin was dose-dependent, with half-maximal and maximal effects at 10 nM and 1 microM, respectively, and was mediated by activation of transforming growth factor-beta receptor type II, oxidative stress, and the production of arachidonic acid and prostaglandins. Albumin-induced glial swelling was prevented by glutamate and purinergic receptor agonists. The data suggest that serum albumin may induce glial swelling in the presence of osmotic gradients.

Glutamate release by neurons evokes a purinergic inhibitory mechanism of osmotic glial cell swelling in the rat retina: activation by neuropeptide Y.

Glial cell swelling is a central cause of ischemic edema in the brain and retina; however, the regulation of glial cell volume by endogenous factors in situ is largely unknown. In slices of the postischemic retina of the rat, the somata of glial (Müller) cells swell upon hypotonic stress that is not observed in slices of control retinas. We describe an endogenous signaling pathway that leads to inhibition of the osmotic glial cell swelling, and that is evoked by the release of glutamate from retinal neurons upon application of neuropeptide Y. Glutamate activates metabotropic glutamate receptors on swollen glial cells, which evokes a Ca2+ -independent purinergic signaling cascade that involves release of ATP, P2Y1 receptor activation, and transporter-mediated release of adenosine. Activation of A1 receptors causes the inhibition of osmotic glial cell swelling, by a protein kinase A-dependent activation of K+ and Cl- channels. It is proposed that the glutamate-evoked purinergic receptor signaling of glial cells is crucially involved in the cell volume homeostasis of the retina, and that this mechanism may contribute to the protective effect of adenosine in the ischemic tissue.

The glucocorticoid triamcinolone acetonide inhibits osmotic swelling of retinal glial cells via stimulation of endogenous adenosine signaling.

The glucocorticoid triamcinolone acetonide is clinically used for the treatment of macular edema. However, the edema-resolving mechanisms of triamcinolone are incompletely understood. Since cell swelling is a central cause of cytotoxic edema in the brain and retina, we determined the effects of triamcinolone acetonide on the swelling of retinal ganglion and Müller glial cells in acutely isolated retinas from rats and guinea pigs in situ. Triamcinolone acetonide (100 microM) had no effect on the swelling of ganglion cells that was evoked in isolated whole mounts of the guinea pig retina by acute application of glutamate (1 mM) or high K+ (50 mM). However, triamcinolone reversed the osmotic swelling of Müller glial cells in retinas of the rat that was observed under various experimental conditions: in retinas isolated at 3 days after transient retinal ischemia, in retinas of eyes with lipopolysaccharide-induced ocular inflammation, and in control retinas in the presence of Ba2+ (1 mM), H2O2 (200 microM), arachidonic acid (10 microM), or prostaglandin E2 (30 nM). The inhibiting effect of triamcinolone on osmotic glial cell swelling was mediated by stimulation of transporter-mediated release of endogenous adenosine and subsequent A1 receptor activation, resulting in an elevation of the intracellular cAMP level and activation of the protein kinase A, and, finally, in an opening of extrusion pathways for K+ and Cl- ions. The inhibitory effect on the cytotoxic swelling of glial cells may contribute to the fast edema-resolving effect of vitreal triamcinolone observed in human patients.

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

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 D(2) 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.