Biomedical subjects

Antje Wurm

Publications and source records attributed to Antje Wurm.

8 recordsLinked to original sources

PubMed2007

Müller cells as players in retinal degeneration and edema.

BACKGROUND: Under normal conditions, Müller cells support neuronal activity and the integrity of the blood-retinal barrier, whereas gliotic alterations of Müller cells under pathological conditions may contribute to retinal degeneration and edema formation. A major function of Müller cells is the fluid absorption from the retinal tissue, which is mediated by transcellular water transport coupled to currents through potassium channels. METHODS: Alterations of retinal Müller cells under pathological conditions were investigated by immunohistochemistry and recording their behavior under osmotic stress. RESULTS: In animal models of various retinopathies, e.g., retinal ischemia, ocular inflammation, retinal detachment, and diabetes, it was found that Müller cells decrease the expression of their major potassium channel (Kir4.1). This alteration is associated with an impairment of the rapid water transport across Müller cell membranes, as recognizable in the induction of cellular swelling under hypoosmolar conditions. Osmotic swelling of Müller cells is also induced by oxidative stress and by inflammatory mediators such as arachidonic acid and prostaglandins. CONCLUSIONS: The data suggest that a disturbed fluid transport through Müller cells is (in addition to vascular leakage) a pathogenic factor contributing to the development of retinal edema. Pharmacological re-activation of the retinal water clearance by Müller cells may represent an approach to the development of new edema-resolving drugs. Triamcinolone acetonide, which is clinically used to resolve edema, prevents osmotic swelling of Müller cells as it induces the release of endogenous adenosine and subsequent A1 receptor activation which results in the opening of ion channels. Apparently, triamcinolone resolves edema by both inhibition of vascular leakage and stimulation of retinal fluid clearance by Müller cells.

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PubMed2006

HB-EGF: increase in the ischemic rat retina and inhibition of osmotic glial cell swelling.

We determined whether the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the sensory rat retina alters during ischemia-reperfusion, and whether HB-EGF affects the osmotic swelling which is a characteristic feature of Müller glial cells after ischemia. Transient retinal ischemia was induced by elevation of the intraocular pressure for 1 h. Western blots revealed an upregulation of HB-EGF in the retina at 1, 3, and 7 days after reperfusion. HB-EGF inhibited the swelling of glial cells in retinal slices, via stimulation of the synaptic release of glutamate and subsequent activation of glial metabotropic glutamate receptors which resulted in an autocrine release of purinergic receptor agonists. Finally, activation of A1 receptors resulted in opening of glial K(+) and Cl(-) channels. It is suggested that the increased expression of HB-EGF and the inhibition of glial cell swelling may be parts of a protective role of HB-EGF in the ischemic retina.

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PubMed2006

Atrial natriuretic peptide inhibits osmotical glial cell swelling in the ischemic rat retina: dependence on glutamatergic-purinergic signaling.

Atrial natriuretic peptide (ANP) is a regulator of the water and electrolyte content in the brain which also mediates cell volume homeostasis. Here, we determined whether the expression of ANP in the retina of the rat undergoes changes during ischemia-reperfusion, and whether ANP affects the osmotic swelling of Müller glial cells in postischemic retinas under hypotonic conditions. Transient retinal ischemia was induced by elevation of the intraocular pressure above systolic blood pressure for 1h. At 1 and 3 days after reperfusion, there was an increased content of ANP protein in the retina, as determined by Western blotting. The increase of the retinal ANP content was markedly reduced when triamcinolone acetonide (10 mM in 2 microl vehicle) was intravitreally injected before ischemia. ANP inhibited the osmotic swelling of Müller cell somata in retinal slices. The effect of ANP was mediated by activation of NP receptors expressed by retinal neurons which evoked a release of glutamate. The stimulation of metabotropic glutamate receptors expressed by Müller cells evoked an autocrine purinergic signaling mechanism that resulted in the opening of K(+) and Cl(-) channels; the ion efflux counteracted the osmotic swelling of Müller cells. It is concluded that the expression of ANP is transiently upregulated in the postischemic retina of the rat. The increased expression of ANP may represent a part of the retinal response to transient ischemia and may inhibit cytotoxic glial cell swelling.

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PubMed2006

The developmental expression of K+ channels in retinal glial cells is associated with a decrease of osmotic cell swelling.

A major function of glial cells is the control of osmotic and ionic homeostasis, mediated by K+ and water movements predominantly through inwardly rectifying K+ (Kir) and aquaporin water channels. It has been suggested that K+ currents through Kir channels are implicated in the regulation of glial cell volume. Here, we investigated whether the developmental increase in Kir channel expression in Müller glial cells of the rat retina is associated with an alteration of cell volume regulation under anisoosmotic conditions. Around the time of eye opening at postnatal day (P) 15, developing retinal glial cells fully alter the profile of their membrane conductances, from a current pattern with prominent fast transient K+ and Na+ currents to a pattern of noninactivating currents through Kir and delayed rectifier K+ channels. Concomitantly, aquaporins-1 and -4 are expressed in the developing retina. This is accompanied by a conspicuous alteration of the swelling characteristics of cells; somata of immature glial cells in early postnatal retinas (P5-P15) swell under hypotonic stress but no swelling is inducible in mature cells at P18 and thereafter. However, glial cells at all developmental stages swell when their Kir channels are blocked by Ba2+. The postnatal maturation of Kir channel currents and volume regulation in retinal glial cells is delayed by visual deprivation. The data suggest that Kir channels are crucially involved in osmotic volume homeostasis of mature glial cells, and that the absence of Kir channels in immature cells is a major cause of their insufficient volume regulation.

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PubMed2006

Glial cell reactivity in a porcine model of retinal detachment.

PURPOSE: Detachment of the neural retina from the pigment epithelium causes, in addition to photoreceptor deconstruction and neuronal cell remodeling, an activation of glial cells. It has been suggested that gliosis contributes to the impaired recovery of vision after reattachment surgery that may involve both formerly detached and nondetached retinal areas. Müller and microglial cell reactivity was monitored in a porcine model of rhegmatogenous retinal detachment, to determine whether gliosis is present in detached and nondetached retinal areas. METHODS: Local detachment was created in the eyes of adult pigs by subretinal application of hyaluronate. Retinal slices were immunostained against glial intermediate filaments and K+ and water channel proteins (aquaporin-4, Kir4.1, Kir2.1), and P2Y receptor proteins. In retinal wholemounts, adenosine 5'-triphosphate (ATP)-induced intracellular Ca2+ responses of Müller cells were recorded, and microglial and immune cells were labeled with Griffonia simplicifolia agglutinin isolectin I-B4. K+ currents were recorded from isolated Müller cells. RESULTS: At 3 and 7 days after surgery, Müller cells in detached retinas showed a pronounced gliosis, as revealed by the increased expression of the intermediate filaments glial fibrillary acidic protein and vimentin, by the decrease of Kir4.1 immunoreactivity and of the whole-cell K+ currents, and by the increased incidence of cells that showed Ca2+ responses on stimulation of purinergic (P)2 receptors by ATP. By contrast, the immunohistochemical expression of Kir2.1 and aquaporin-4 were not altered after detachment. The increase in the expression of intermediate filaments, the decrease of the whole-cell K+ currents and of the Kir4.1 immunolabeling, and the increase in the Ca2+ responsiveness of Müller cells were also observed in attached retinal areas surrounding the focal detachment. The density of microglial-immune cells at the inner surface of the retinas increased in both detached and nondetached retinal areas. The immunoreactivities for P2Y1 and P2Y2 receptor proteins apparently increased only in detached areas. CONCLUSIONS: Reactive responses of Müller and microglial cells are not restricted to detached retinal areas but are also observed in nondetached regions of the porcine retina. The gliosis in the nondetached retina may reflect, or may contribute to, neuronal degeneration that may explain the impaired recovery of vision observed in human subjects after retinal reattachment surgery.

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PubMed2006

Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina.

The development of edema in the diabetic retina may be caused by vascular leakage and glial cell swelling. To determine whether diabetic retinopathy alters the swelling characteristics of retinal glial cells and changes the properties of the glial membrane K+ conductance, isolated retinas and glial cells of rats were investigated at 4 and 6 months of chemical diabetes. After 6 months of hyperglycemia, application of a hypotonic solution to retinal slices induced swelling of glial cell bodies, a response not observed in control retinas. The osmotic glial cell swelling was blocked by inhibitors of phospholipase A2 or cyclooxygenase and by a thiol-reducing agent. Glial cells from diabetic retinas displayed a decrease of K+ currents that was associated with an altered subcellular distribution of the K+ conductance and a loss of perivascular Kir4.1 protein. The observation that swelling of cells in control retinas was inducible with K+ channel-blocking Ba2+ ions suggests a relationship between decreased K+ inward currents and osmotic cell swelling in diabetic retinas. The data show that glial cells in diabetic retinas are more sensitive to osmotic stress, which is associated with a decrease of K+ currents, than cells in control retinas. It is suggested that these alterations may be implicated in the development of diabetic retinal edema.

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PubMed2006

Changes in membrane conductance play a pathogenic role in osmotic glial cell swelling in detached retinas.

Detachment of the neural retina from the pigment epithelium may be associated with tissue edema; however, the mechanisms of fluid accumulation are not understood. Because retinal detachment is usually not accompanied by vascular leakage, we investigated whether the osmotic swelling characteristics of retinal glial (Müller) cells are changed after experimental detachment of the porcine retina. Osmotic stress, induced by application of a hypotonic bath solution to retinal slices, caused swelling of Müller cell bodies in 7-day-detached retinas, but no swelling was inducible in slices of control retinas. Müller cell somata in slices of retinal areas that surround local detachment in situ also showed osmotic swelling, albeit at a smaller amplitude. The amplitude of osmotic Müller cell swelling correlated with the decrease in the K+ conductance, suggesting a causal relationship between both gliotic alterations. Further factors implicated in Müller cell swelling were inflammatory mediators and oxidative stress. We propose that a dysregulation of the ion and water transport through Müller cells may impair the fluid absorption from the retinal tissue, resulting in chronic fluid accumulation after detachment. This knowledge may lead to a better understanding of the mechanisms involved in retinal degeneration after detachment.

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PubMed2005

Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice.

PURPOSE: To obtain experimental in vivo information on the functional properties of myocilin for aqueous humor (AH) outflow and to study in vivo the processing of mutated Tyr437His myocilin. Myocilin is a secreted glycoprotein that is mutated in some forms of primary open-angle glaucoma (POAG), and patients with the Tyr437His mutation have severe phenotypes. METHODS: The chicken betaB1-crystallin promoter was used to overexpress wild-type human myocilin and mutated Tyr437His myocilin in the lenses of transgenic mice. Expression of transgenic mRNA was monitored by Northern blot analysis and in situ hybridization. The localization and secretion of transgenic myocilin was investigated by Western blot analysis and light and electron microscopy. Intraocular pressure (IOP) was measured by anterior chamber cannulation. RESULTS: Two independent lines were established with each of the constructs that showed a strong expression of transgenic mRNA in their lenses. Transgenic expression resulted in a 4.7 +/- 1.8-fold increase of secreted normal myocilin in mouse AH, compared with its concentration in human AH. Immunoreactivity for transgenic myocilin was observed along the surfaces of lens and corneal endothelium, and in the chamber angle. At 12 weeks of age, the ultrastructure of the trabecular meshwork in mice expressing normal myocilin was not different from that of control eyes, and IOP of transgenic animals did not significantly differ from that of control littermates. In contrast, mutated Tyr437His myocilin was not secreted from lens fibers, but accumulated in dilated cisterns of rough endoplasmic reticulum. Although no structural changes were observed in lenses of animals expressing normal myocilin, lenses with Tyr437His expression developed nuclear cataracts, completely lost transparency, and eventually ruptured. Structural changes in lenses of Tyr437His expressing mice were correlated with a significant increase in IOP. CONCLUSIONS: The results do not support the concept that increasing amounts of myocilin in the outflow tissues obstruct the system and directly cause an increase in outflow resistance. Mutated Tyr437His myocilin is not secreted in vivo and causes severe alterations of cellular structure and function. A comparable mechanism may cause POAG in patients with myocilin mutations.

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