Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

DOI 10.1007/s00417-006-0516-y

REVIEW ARTICLE

Mller cells as players in retinal degeneration and edema

Andreas Reichenbach & Antje Wurm &
Thomas Pannicke & Ianors Iandiev & Peter Wiedemann &
Andreas Bringmann

Received: 29 November 2006 / Accepted: 2 December 2006 / Published online: 12 January 2007
# Springer-Verlag 2007

Abstract
Background Under normal conditions, Mller cells support
neuronal activity and the integrity of the blood-retinal
barrier, whereas gliotic alterations of Mller cells under
pathological conditions may contribute to retinal degeneration and edema formation. A major function of Mller
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 Mller 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 Mller cells decrease the
expression of their major potassium channel (Kir4.1). This
alteration is associated with an impairment of the rapid
water transport across Mller cell membranes, as recognizable in the induction of cellular swelling under hypoosmolar conditions. Osmotic swelling of Mller 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 Mller 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 Mller 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 Mller 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 Mller cells.
Keywords Diabetes . Edema . Fluid transport . Ischemia .
Mller cells . Triamcinolone acetonide

Macular edema
A. Reichenbach : A. Wurm : T. Pannicke (*)
Paul Flechsig Institute of Brain Research, Faculty of Medicine,
University of Leipzig,
Jahnallee 59,
04109 Leipzig, Germany
e-mail: thomas.pannicke@medizin.uni-leipzig.de
A. Wurm : I. Iandiev : P. Wiedemann : A. Bringmann
Department of Ophthalmology and Eye Clinic,
Faculty of Medicine, University of Leipzig,
04103 Leipzig, Germany
I. Iandiev
Interdisziplinres Zentrum fr Klinische Forschung (IZKF),
Faculty of Medicine, University of Leipzig,
04103 Leipzig, Germany

Macular edema is one of the leading causes of visual

impairment in patients with uveitis or diabetes, and may
also occur after cataract surgery [13]. Retinal ischemia,
oxidative stress, and inflammation are pathogenic factors
implicated in the development of macular edema [48].
Though promising new therapeutical approaches arose from
the significantly increased knowledge regarding the factors
that cause retinal edema and neovascularization [810], the
pathogenic mechanisms underlying the development of
macular edema are still not fully understood. One major
pathogenic event in the development of edema is an
increase in the permeability of the blood retinal barrier
formed by vascular endothelial and retinal pigment epithe-

628

lial cells [11]. The leakage from perifoveal vessels and

pigment epithelium causes fluid accumulation in the foveal
tissue and subretinal space, respectively, resulting in serous
macular detachment and increased thickness of the retinal
tissue due to diffuse or cystoid edema. The fluid accumulation contributes to the degeneration of retinal neurons and
to a decrease in visual acuity, as it results in compression of
neurons, nerve fibers, and vessels (which exacerbates
ischemic conditions), and in an elongation of the routes
for the diffusion of metabolic substrates and oxygen.
Among the various vasoactive factors that induce vascular
leakage (e.g., prostaglandins, interleukin-1, tumor necrosis
factor [12]), the vascular endothelial growth factor (VEGF)
is thought to be the major cytokine causing the breakdown
of the blood-retinal barrier [8, 1315]. However, the
development of chronic edema depends on two factors:
the rate of fluid entry from leaky vessels into the retinal
tissue, and the rate of fluid absorption from the retina back
into the blood. An impairment of the fluid absorption from
the retinal tissue should be considered as a major
pathogenic mechanism of edema formation, for example
in patients which display macular edema without angiographic vascular leakage. In the preclinical stage of diabetic
retinopathy, two types of increased retinal thickness exist
that are or not associated with vascular leakage [16]. It has
been shown that clinically significant diabetic macular
edema develops only when (in addition to vascular leakage)
the active transport mechanisms of the blood-retinal barrier
are dysfunctional [17]. Obviously, any anomalies in vessel
permeability need to be accompanied by ineffective edemaresolving mechanisms to cause chronic edema [18].

Macular edema-a Mller cell disease?

Mller cells, the principal glial cells of the retina, constitute
a functional link between neurons and vessels. They
support neurons with blood-derived nutrients, remove
metabolic waste, and are responsible for maintaining the
homeostasis of the retinal extracellular milieu (ions, water,
neurotransmitter molecules, and pH) [19]. Retinal capillaries are closely ensheathed by glial cell processes arising
from astrocytes and Mller cells. Mller cells become
activated upon virtually all pathogenic stimuli [19]. In the
retina of diabetic animals, for example, Mller cells become
reactive at an early stage owing to disruption of the bloodretinal barrier [20, 21]. Normally, Mller cells participate in
the establishment of the blood-retinal barrier [22]; however,
under hypoxic conditions they impair the barrier function
[23]. Under hypoxic, inflammatory or glucose-deprivation
conditions, Mller cells secrete factors such as VEGF that
increase the vascular permeability [2427]. Mller cells are
also a source of matrix metalloproteinases [28, 29] which

Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

impair the barrier function of retinal endothelial cells, by

proteolytic degradation of the tight junction protein occludin [30]. Even under normoxic conditions, Mller cells
secrete factors that decrease the barrier permeability, such
as the pigment epithelium-derived factor (PEDF) [31]
which downregulates the expression of VEGF. Under
hypoxic conditions, the expression of PEDF is reduced in
the retina and Mller cells [31, 32].
In addition to the effects on the barrier state of the retinal
vasculature, Mller cells may also contribute to edema
development by another way. There are electron microscopic studies carried out in the early 1980s which suggest
thatin addition to ischemic changes in the retinal
microvasculatureswelling (i.e., intracellular edema) of
Mller cells may contribute to the development of cystoid
macular edema, with the cysts being formed by swollen and
necrotic Mller cells [33, 34]. In contrast, other authors did
not find Mller cell swelling [35]. In the brain, swelling of
astrocytes usually occurs concomitantly in vascular edema,
and represents a major mechanism of edema formation
under ischemic and various other conditions such as
hyponatremia [36]. There are further data suggesting that
dysfunctional Mller cells may be a causative factor in
edema development. Dominantly inherited cystoid macular
edema was suggested to represent a primary disease of
Mller cells since degenerated Mller cells were found to
be located around a virtually intact retinal vascular
endothelium [37]. In an animal model of retinal hypoxia,
it has been shown that vascular leakage is associated with
cellular edema of Mller cells [38]. In the present review
we discuss data which support the assumption that an
impairment in the fluid absorption from the retinal tissue
normally carried out by Mller cells may represent one
causative factor in edema development. Under distinct
circumstances, Mller cells may even swell.

Mller cells: fluid absorption from the retina

The fluid absorption from the subretinal space and from
retinal tissue into the blood is normally carried out by
pigment epithelial and glial cells. This is mediated via
transcellular water transport that is osmotically coupled to
the fluxes of osmolytes, particularly of ions [39, 40]. Fluid
absorption is carried out by both cell types under normal
conditions to redistribute water which accumulates in the
retinal tissue and subretinal space due to various processes
(Fig. 1): the influx of water from the blood into the retinal
parenchyma which is coupled to the uptake of metabolic
substrates such as glucose, and the formation of water
within the retinal tissue which is associated with the aerobic
energy production (per glucose molecule, 42 molecules of
water are formed). The water fluxes through the cells are

Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

Fig. 1 Water fluxes through the retina. Under normal conditions,

water accumulates in the neural retina and subretinal space due to
influx from the blood (coupled to the uptake of nutrients such as
glucose) and the oxidative synthesis of adenosine 5-triphosphate
(ATP) that generates carbon dioxide and water. The excess water is
redistributed into the blood by transcellular water transport through
Mller cells (yellow) and pigment epithelial cells (RPE). The transmembranous water transport is facilitated by aquaporin (AQP) water
channels. RPE cells express AQP1, whereas Mller cells express
AQP4. The transcellular water transport is osmotically coupled to the
transport of osmolytes, especially of potassium and chloride ions. The
ion fluxes across the cellular membranes are facilitated by transporter
molecules and ion channels. In Mller cells, the Kir4.1 potassium
channel is co-localized with AQP4 in membranes that surround the
vessels, and at both limiting membranes (compare Fig. 2)

facilitated by the polarized intramembranous expression of

specialized water transporting proteins, the aquaporins.
Aquaporins facilitate bidirectional water movements across
membranes, in dependence on the transmembranal osmotic
gradient and hydrostatic pressure, and are involved in the
maintenance of the ionic and osmotic balance in the tissue
[41, 42]. Pigment epithelial cells express aquaporin-1 [43]
whereas Mller cells express aquaporin-4 (Fig. 2a) [44].
The transcellular water transport is tightly coupled to fluxes
of osmolytes, in particular of potassium and chloride ions
(Fig. 1) [39, 40, 45]. Activated neurons release potassium
ions. To avoid potassium-induced depolarization of neurons
which may cause neuronal hyperexcitation resulting in
excess release of neurotransmitters and glutamate toxicity,
Mller cells take up excess potassium from the extracellular
space especially in the synaptic (plexiform) layers of the
retina, and release a similar amount of potassium into spaces
outside of the neural retina, especially into the blood and the
vitreous [46]. This spatial buffering of extracellular

629

Fig. 2 Experimental diabetes in rats alters the retinal expression of

Kir4.1 potassium channels. a Localization of Kir4.1 and AQP4
proteins in slices of the neural rat retina. The Kir4.1 potassium
channel is co-localized with AQP4 water channels in Mller cell
membranes that surround the vessels (arrows), and at both limiting
membranes (arrowheads). AQP4 is additionally expressed by Mller
cells in both plexiform layers, and in the ganglion cell layer. b The
prominent expression of the Kir4.1 protein around the vessels and at
both limiting membranes (control retina) is absent in the retina of a
diabetic animal. c View on the deep vascular plexus in the inner
nuclear layer (wholemount preparation). The vessels are surrounded
by AQP4 and Kir4.1 proteins in the control retina, but only by AQP4
in the retina of the diabetic animal. GCL, ganglion cell layer; INL,
inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear
layer. Bars, 20 m. With permission from ref. 52

potassium is mediated predominantly by passive currents

through potassium channels localized in Mller cell membranes. Mller cells express different types of potassium
channels. Under normal conditions, inwardly rectifying
potassium (Kir) channels of the Kir2.1 subtype are expressed
in neuron-abutting membranes through which Mller cells
take up excess potassium. Kir4.1 channels are expressed in
membranes which are in close contact with spaces outside of
the neural retina, i.e., in Mller cell processes enwrapping
blood vessels and at both limiting membranes of the retina
(Fig. 2a) [40, 47, 48]. Kir2.1 channels mediate only inward

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Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

Since the Mller cell-mediated fluid absorption from the

retinal tissue predominantly relies on channel-mediated cotransport of potassium ions and water, any dysfunction of
potassium channels should result in an impairment of the
retinal water clearance and, therefore, will contribute to the
development of chronic edema. Indeed we found in various
animal models of retinopathies, e.g., after transient ischemia of the retina [49, 50], during ocular inflammation [51],
in the retina of diabetic animals [52], and after retinal
detachment [53, 54], that a major response of Mller cells
under pathological conditions is an alteration in the
expression of Kir4.1 channels. The Kir4.1 channel protein
is redistributed from its prominent expression sites around
the vessels and at the limiting membranes of the retina, and
displays an even distribution in the retina at low level
(Fig. 2b,c). This disclocation of Kir4.1 may be associated
with a decrease in retinal expression of Kir4.1 protein [49],
and causes a general decrease in the potassium currents
flowing through Mller cell membranes [5054]. On the
other hand, the localization of Kir2.1 channels does not
change after retinal ischemia [48]. Thus, Mller cells can

take up potassium ions (via Kir2.1 channels), but the

extrusion of excess potassium by Mller cells into extraretinal spaces is impaired under pathological conditions.
Hence, this may lead to an intracellular potassium overload
and an increase in the osmotic pressure of the Mller cell
interior in the diseased retina. Disruption of glial potassium
homeostasis due to the downregulation of Kir4.1 channels
may contribute to the death of nerve cells in the retina under
pathological conditions [55], and should disturb the transport
of water through Mller cells. It has been shown that Mller
cells of patients with proliferative diabetic retinopathy
display a strong reduction of their potassium conductance
[56], suggesting that the downregulation of potassium
channels may represent a feature of Mller cells in the
human retina, as well as in animal models.
An increase in intracellular osmotic pressure and an
impairment of the rapid release of ionic osmolytes will
favor swelling of Mller cells under distinct conditions.
Indeed, we found that the swelling characteristics of Mller
cells from diseased retinas were altered. Under normal
conditions, Mller cells do not swell when isolated retinas
are perfused with a hypoosmolar solution (Fig. 3a).
However, Mller cells in pathologically altered retinas
display a time-dependent swelling of their cell bodies in a
hypoosmolar environment. Osmotic Mller cell swelling
was observed under all circumstances which are associated
with a downregulation of Kir4.1 channels, i.e., in retinas of
diabetic animals (Fig. 3a) [52], after retinal ischemia [49] or
detachment [54], and during endotoxin-induced ocular
inflammation [51]. There is a correlation between the
extent of osmotic swelling and the decrease of potassium
currents in Mller cells of detached retinas [54]. The
swelling of Mller cells indicates that the water transport
across Mller cell membranes in response to a transmembranal osmotic gradient is impaired due to the

Fig. 3 Experimental diabetes in rats affects the osmotic swelling

characteristics of Mller cells, suggesting an impaired water transport
across Mller cell membranes. Triamcinolone acetonide inhibits the
osmotic Mller cell swelling via stimulation of endogenous adenosine
signaling. a Mller cell bodies in retinal slices from control animals do
not change their size upon application of a hypoosmolar solution (60%
of control osmolarity). In contrast, Mller cell bodies in retinal slices

from diabetic animals increase their size under osmotic stress (see the
insets for an example; bar, 5 m). b The osmotic swelling of Mller
cell bodies in retinas from diabetic animals is inhibited in the presence
of triamcinolone acetonide (triam; 100 M). c The swelling-inhibitory
effect of triamcinolone is prevented by inhibitors of adenosine
transporters (NBTI) and adenosine A1 receptors (DPCPX), respectively. With permission from ref. 52

potassium currents into the Mller cells, whereas Kir4.1

channels mediate bidirectional currents between the extraretinal tissues and the Mller cell interior. The co-localization
of Kir4.1 potassium channels and aquaporin-4 water channels around vessels and at the limiting membranes of the
retina [40] indicates a coupling of water transport to
potassium currents in Mller cells. Moreover, aquaporin-4
channels are expressed by Mller cells in both plexiform
layers and in the ganglion cell layer (Fig. 2a) where the cells
take up excess potassium through Kir2.1 channels.

Mller cells: impairment of fluid absorption

Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

631

Fig. 4 Putative mechanisms of Mller cell swelling and the effect of

triamcinolone acetonide in the diabetic retina. a Under normal
conditions, Mller cells mediate the fluid absorption from the retinal
tissue into the blood by a co-transport of water (facilitated by AQP4
water channels) and osmolytes, especially potassium ions (facilitated
by Kir4.1 channels). b In the diabetic retina, vascular leakage occurs
due to the action of inflammatory mediators and VEGF. The Mller
cells downregulate the expression of functional Kir4.1 channels. This
downregulation impairs the release of potassium from Mller cells
into the blood, and may result in an accumulation of potassium ions
within the cells. The increase in the intracellular osmotic pressure
results in an osmotic gradient across the plasma membrane that draws
water into the Mller cells facilitated by AQP4 water channels. An
influx of sodium ions into the cells, evoked by inflammatory
mediators such as arachidonic acid (AA) and prostaglandins (PGs)

which are formed in response to oxidative stress, contributes to the

increase in intracellular osmotic pressure. The uptake of extravasated
serum proteins by Mller cells may further increase the osmotic
pressure of the cell interior. c Triamcinolone reduces edema by both
inhibition of the fluid inflow from the vessels (through blocking the
effects of inflammatory mediators and VEGF) and re-activation of the
fluid clearance function of Mller cells. The latter action is mediated
by triggering a release of endogenous adenosine and subsequent
activation of adenosine A1 receptors which results in the opening of
potassium channels (likely two pore domain [TASK] channels). The
efflux of potassium ions is associated with a water transport out of the
cells and, therefore, with a shrinkage of the cells. The triamcinoloneevoked stimulation of the potassium clearance by Mller cells
facilitates the fluid absorption from the retinal tissue

restriction of a rapid release of potassium ions after

downregulation of functional Kir4.1 channels. Moreover,
a causal relationship between the downregulation of
functional potassium channels and the osmotic swelling of
Mller cells is suggested by the observation that a blockade
of potassium channels in Mller cells of control retinas,
e.g., by barium ions, induces cellular swelling under
hypoosmolar conditions [49]. Both, the low potassium
channel expression and the inefficient cell volume regulation, resemble properties of undifferentiated Mller cells in
the young postnatal retina [57], suggesting that Mller cells
dedifferentiate under pathological conditions.
In addition to the decreased expression of functional
potassium channels, two further pathogenic factors are
implicated in the osmotic Mller cell swelling: inflammatory mediators and oxidative stress. Inhibition of enzymes
which produce arachidonic acid and prostaglandins (phospholipase A2 and cyclooxygenase) prevents the osmotic
swelling of Mller cells in pathologically altered retinas
[52, 54, 58]. Likewise, inhibition of oxidative stress by
application of a reducing agent impedes the swelling of
Mller cells under hypoosmolar conditions. Conversely, the
application of arachidonic acid or prostaglandin E2, or
oxidative stress evoked by H2O2, induces osmotic swelling

of Mller cells in control retinas [52, 54, 58]. Local

inflammation and oxidative stress are pathological factors
in retinal diseases known to be associated with edema, e.g.,
diabetic retinopathy [6, 8, 5965]. Under normal conditions, Mller cell bodies in the porcine retina do not
express immunoreactivity for cyclooxygenase-2, whereas
after experimental retinal detachment, they express this
enzyme [54], suggesting that (in addition to retinal neurons)
Mller cells increase the expression of enzymes that
produce inflammatory mediators. A similar up-regulation
of inflammatory-related proteins in Mller cells has been
described during experimental diabetes [64]. Retinas of
diabetic animals display an increased expression of
cyclooxygenase-2, and an increased production of prostaglandin E2 [66, 67]. Arachidonic acid and its metabolites,
especially prostaglandin E2, are major mediators of macular
edema [5, 7]. It is known that oxidative stress evoked by
acute application of H2O2 mimicks the edema-inducing
effect of retinal ischemia-reperfusion [68]. Therefore,
radical scavengers which inhibit vascular leakage in the
ischemic retina [69] should also inhibit Mller cell swelling.
Presumably, the osmotic swelling of Mller cells in
injured retinas is caused by oxidative stress, resulting in
activation of phospholipase A2 and cyclooxygenase, subse-

632

quent arachidonic acid- and prostaglandin-evoked lipid

peroxidation, and intracellular sodium overload. Simultaneously, the compensatory channel-mediated efflux of
potassium might be inhibited (Fig. 4b). Oxidative stress
can initiate lipid peroxidation, resulting in the release of
arachidonic acid from the cell membrane [70, 71]. Ischemia
in the neural tissue causes formation of free polyunsaturated
fatty acids, particularly arachidonic acid, from membrane
phospholipids, mainly by the action of phospholipase A2
[7275]. Free radicals and hydroperoxides produced during
ischemia-reperfusion stimulate the activity of lipoxygenase
and cyclooxygenase [76]. Arachidonic acid induces both
vascular and cellular edema in the brain [77, 78] and evokes
swelling of cultured astrocytes [79]. The increase in
intracellular sodium, being an effect of arachidonic acid
and prostaglandins, is mainly due to inhibition of the sodium
pump activity (Fig. 4b) [80, 81]. A similar increase in
intracellular sodium occurs during swelling of Mller cells
[82]. However, the intracellular sodium overload leads to
cellular swelling only when the cells lost their capability to
release osmolytes. Under normal conditions, retinal glial
cells release potassium ions via Kir4.1 channels and, thus,
avoid swelling despite of their increased sodium content.
However, when the channel-mediated release of potassium is
disturbed, they swell. It is known that arachidonic acid
blocks voltage-gated potassium channels in Mller cells [83]
which are the only channels that (under normal conditions)
mediate outward potassium currents across the Mller cell
membrane after downregulation of Kir4.1 [8486]. Arachidonic acid may also inhibit the swelling-activated efflux of
other osmolytes such as amino acids and chloride ions [87].
The induction of osmotic Mller cell swelling, which is
not observed in cells from control tissues, suggests that the
water transport across Mller cell membranes in response to
osmotic gradients is impaired under pathological conditions; a disturbance of this water transport should prevent
the resolution of retinal edema. The data suggest that an
insufficient fluid absorption by Mller cells, and even
Mller cell swelling under distinct conditions associated
with osmotic imbalances between retinal and extra-retinal
tissues, may represent an important factor contributing to
the development of edema.

Stimulation of fluid absorption

Chronic edema is caused by an imbalance between the fluid
influx into the tissue and the fluid absorption from the
tissue. Edema can be resolved by inhibition of vascular
leakage or by stimulation of the fluid clearance. Hitherto,
most of the research regarding clinically used edemaresolving therapies was focused on the inhibition of
vascular leakage. Reduction in fluid extravasation can be

Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

obtained by inhibition of the release, or of the effects of the

vessel-permeabilizing factors VEGF and inflammatory
factors. VEGF inhibitors, e.g., bevacizumab, reduce the
level of free VEGF. Ruboxistaurin blocks protein kinase-
which is an intracellular mediator involved in VEGFinduced increase in vascular permeability [88]. The antiinflammatory corticosteroid, triamcinolone acetonide,
inhibits vascular leakage [89, 90], reduces the vitreal level
of VEGF [91], the secretion of VEGF by retinal cells [92
94], and the cellular effects of VEGF, e.g., the VEGFevoked secretion of matrix metalloproteinases (own unpublished results). However, it is not known whether the
edema-resolving therapies used clinically stimulate the fluid
absorption from the retinal tissue concomitantly. This is
likely since anti-inflammatory steroids are also effective in
resolution of retinal edema in cases which are not
associated with angiographic vascular leakage.
Stimulation of the fluid clearance function of pigment
epithelial and Mller cells may represent an approach to the
development of novel edema-resolving drugs, as it has been
shown in experimentally detached retinas. Here, activation
of purinergic P2Y2 receptors stimulates the ion transport
and, therefore, the fluid absorption from the subretinal
space by the pigment epithelium, resulting in proper
attachment of the sensory retina [95, 96]. We found that
triamcinolone inhibits the osmotic swelling of Mller cells.
The swelling-inhibitory effect was observed in animal
models of retinal ischemia-reperfusion and detachment,
and in retinas of diabetic animals (Fig. 3b) [52, 54, 58].
Moreover, triamcinolone inhibits the swelling of Mller
cells in control retinas observed in the presence of the
potassium channel blocker barium, the inflammatory
mediators arachidonic acid or prostaglandin E2, as well as
under oxidative stress [52, 54, 58]. We found that
triamcinolone inhibits osmotic swelling of Mller cells by
stimulation of an autocrine purinergic signaling cascade
(Figs. 3c, 4c) [58]. Application of triamcinolone stimulates
the nucleoside transporter-mediated release of adenosine
from the cells. Adenosine activates adenosine A1 receptors
which leads to the opening of barium- and arachidonic
acid-insensitive potassium channels (likely, two poredomain channels [97]), as well as of chloride channels, in
the Mller cell membrane [54, 82]. The extrusion of ions
draws water out of the cells thereby preventing cellular
swelling under hypoosmolar conditions (Fig. 4c). The
action of adenosine on ion channels does not require
intracellular calcium but is mediated by cyclic adenosine
monophosphate, protein kinase A, and phosphatidylinositol-3 kinase (own unpublished results) [54, 82].
Two pore-domain potassium channels may function as
an osmolyte extrusion pathway that helps to maintain
proper Mller cell volumes when Kir4.1 channels are
downregulated under pathological conditions. Since the

Graefes Arch Clin Exp Ophthalmol (2007) 245:627636

potassium currents drive the water transport through

Mller cells, the activation of two pore-domain channels
by adenosine should facilitate the potassium clearence
and the water absorption from the edematous retinal
tissue. Stimulation of two pore-domain channels, either
indirectly by A1 receptor activation or directly by channel
openers, may represent a method to dissolve retinal
edema. It is known that activation of A1 receptors has
protective effects against retinal ischemic injury [98, 99];
a stimulatory effect on the fluid clearance through Mller
cells may contribute to this protective effect of A1 receptor
activation.

Conclusions: retinal edema- a dysregulation

at the glio-vascular interface
Retinal edema develops during ischemia/hypoxia and
inflammation; under both conditions, Mller cells alter
their potassium conductance and swelling characteristics
[4951]. The osmotic swelling of Mller cells indicates that
the fluid transport through Mller cell membranes is
impaired under conditions which are clinically associated
with macular edema (ischemia, ocular inflammation,
diabetes). In addition to vascular leakage, dysregulation
of the water movements across the glio-vascular interface
may represent a major causative factor of edema. Most
likely, there are different subtypes of macular edema in
individual patients, with differences in the relative
contribution of vascular leakage and dysfunction of
Mller cells. Additive effects of systemic diseases such
as hypertension [100] may increase the variability of
mechanisms for edema formation. In the presence of an
osmotic gradient across the glio-vascular interface, e.g.,
when the blood becomes hypoosmolar due to hyponatremia
or hypoalbuminemia associated with renal or hepatic
failures, or when neuronal hyperexcitation results in a
strong increase of the retinal osmotical pressure in
comparison to the blood and vitreous, Mller cells may
swell similar as described in brain astrocytes [101].
Pharmacological stimulation of the ion and water clearance
function of Mller cells should aid in resolution of both
vascular and cellular edema. It is suggested that triamcinolonevia stimulation of endogenous adenosine signaling
in Mller cellsfacilitates the fluid absorption from the
edematous tissue. Adenosine A1 receptors may represent a
promising target for the development of novel drugs that
stimulate the absorption of excesss fluid in edema.
Acknowledgements This work was supported by grants from the
Deutsche Forschungsgemeinschaft (GRK 1097/1) and from the Interdisziplinres Zentrum fr Klinische Forschung (IZKF) at the Faculty of
Medicine of the University of Leipzig (C21, Z10).

633

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