Physiol Rev 85: 845– 881, 2005;
doi:10.1152/physrev.00021.2004.
The Retinal Pigment Epithelium in Visual Function
OLAF STRAUSS
Bereich Experimentelle Ophthalmologie, Klinik und Poliklinik fuer Augenheilkunde,
Universitaetsklinikum Hamburg-Eppendorf, Hamburg, Germany
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I. Introduction
II. Embryonic Origin of the Retinal Pigment Epithelium
A. First phase: establishment of two layers
B. Second phase: differentiation of RPE and photoreceptors
III. Absorption of Light and Protection Against Photo-Oxidation
A. The RPE is able to absorb light energy focused by the lens onto the retina
B. Increasing imbalance of protective and toxic factors with aging leads to retinal degeneration
IV. Transepithelial Transport
A. The RPE transports nutrients and ions between photoreceptors and the choriocapillaris
B. Increases in epithelial transport help to treat edema: reductions in epithelial transport cause
retinal degeneration
V. Spatial Buffering of Ions in the Subretinal Space
A. Spatial buffering of ions in the subretinal space maintains excitability of photoreceptors
B. Spatial buffering gives rise to wave forms in the ERG: monitoring of metabolic status
VI. Visual Cycle or Retinoid Cycle
A. Exchange of retinal between photoreceptors and RPE: isomerization and reisomerization
between 11-cis and all-trans
B. Inherited retinal degenerations are caused by mutations in a variety of genes of the visual cycle
VII. Phagocytosis
A. Photoreceptor outer segment renewal: phagocytosis of shed photoreceptor membranes
by the RPE
B. Failure of photoreceptor outer segment phagocytosis leads to retinal degeneration
VIII. Secretion
A. The RPE secretes a variety of growth factors
B. Changes in the secretory activity are associated with proliferative diseases in the retina
IX. Summary
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Strauss, Olaf. The Retinal Pigment Epithelium in Visual Function. Physiol Rev 85: 845– 881, 2005;
doi:10.1152/physrev.00021.2004.—Located between vessels of the choriocapillaris and light-sensitive outer segments
of the photoreceptors, the retinal pigment epithelium (RPE) closely interacts with photoreceptors in the maintenance of visual function. Increasing knowledge of the multiple functions performed by the RPE improved the
understanding of many diseases leading to blindness. This review summarizes the current knowledge of RPE
functions and describes how failure of these functions causes loss of visual function. Mutations in genes that are
expressed in the RPE can lead to photoreceptor degeneration. On the other hand, mutations in genes expressed in
photoreceptors can lead to degenerations of the RPE. Thus both tissues can be regarded as a functional unit where
both interacting partners depend on each other.
I. INTRODUCTION
The retinal pigment epithelium (RPE) is a monolayer
of pigmented cells forming a part of the blood/retina
barrier (72, 372, 492, 558). The apical membrane of the
RPE faces the photoreceptor outer segments (Fig. 1).
Long apical microvilli surround the light-sensitive outer
segments establishing a complex of close structural interwww.prv.org
action. With its basolateral membrane the RPE faces
Bruch’s membrane, which separates the RPE from fenestrated endothelium of the choriocapillaris (Fig. 1).
As a layer of pigmented cells the RPE absorbs the
light energy focused by the lens on the retina (72, 86).
The RPE transports ions, water, and metabolic end
products from the subretinal space to the blood (144,
236, 369, 402, 558). The RPE takes up nutrients such as
0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society
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OLAF STRAUSS
glucose, retinol, and fatty acids from the blood and
delivers these nutrients to photoreceptors. Importantly,
retinal is constantly exchanged between photoreceptors and the RPE (30, 58, 596). Photoreceptors are
unable to reisomerize all-trans-retinal, formed after
photon absorption, back into 11-cis-retinal. To maintain the photoreceptor excitability, retinal is transported to the RPE reisomerized to 11-cis-retinal and
transported back to photoreceptors. This process is
known as the visual cycle of retinal. Furthermore, the
voltage-dependent ion conductance of the apical membrane enables the RPE to stabilize ion composition in
the subretinal space, which is essential for the maintenance of photoreceptor excitability (144, 558, 559). Another function in the maintenance of photoreceptor
excitability is the phagocytosis of shed photoreceptor
outer segments (72, 170, 187, 575). The photoreceptor
outer segments are digested, and essential substances
such as retinal are recycled and returned to photoreceptors to rebuild light-sensitive outer segments from
the base of the photoreceptors. In addition, the RPE is
able to secrete a variety of growth factors helping to
maintain the structural integrity of choriocapillaris endothelium and photoreceptors. Furthermore, the secretory activity of the RPE plays an important role in
establishing the immune privilege of the eye by secreting immunosuppressive factors (280, 581). With these
complex different functions, the RPE is essential for
visual function. A failure of any one of these functions
can lead to degeneration of the retina, loss of visual
function, and blindness. In the following sections these
functions will be described in more detail.
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II. EMBRYONIC ORIGIN OF THE RETINAL
PIGMENT EPITHELIUM
The development and differentiation of RPE and photoreceptors reflects the unique relationship between both
tissues (372, 373, 484, 487, 492). First, the RPE is essential
for the proper development of the retina (260, 565). For
this purpose, the RPE was found to secrete factors that
promote photoreceptor survival and differentiation (3,
126, 306, 531–534). Second, the development of both tissues occurs in concert with developmental steps where
the RPE depends on the specific stages in photoreceptor
development, and vice versa (373, 484, 487, 492). In the
case of a selective loss of the RPE, neuronal retina and
photoreceptors are the most affected tissues in the eye
(50, 51, 339). Third, the proper development of the retina
appears to be dependent on the genes involved in the
proper development of the melanogenesis pathway in
RPE cells (286). Human albino eyes show abnormal fovea
and chiasmatic projections (159, 361).
A. First Phase: Establishment of Two Layers
The development of both tissues can be divided into
two main events. In the first stage, the structure of the two
layers, the prospective RPE and prospective neuronal
retina, is established. After invagination of the optic cup,
cells of the neuroepithelium which, on one hand, are
designated to become RPE cells and, on the other hand,
cells which are determined to become the neuronal retina
are building two layers opposed to each other (Fig. 2) and
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FIG. 1. Summary of retinal pigment epithelium (RPE) functions. PEDF, pigment epithelium-derived growth factor; VEGF, vascular epithelium
growth factor; Epithel, epithelium.
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
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separated by a thin remnant of lumen (487). The remnant
of the lumen is filled by a new material, the interphotoreceptor matrix, the IPM (204, 206, 207). Before this stage,
the RPE is a ciliated and pseudostratified epithelium
(179). After the IPM is formed, the RPE starts to mature.
At this stage both layers are still able to differentiate into
RPE or neural retina if the IPM is disturbed (204, 206, 207,
224). Several factors were found to be essential for determination of RPE differentiation. The expression of the
transcription factors OTX2 (homeodomain-containing
transcription factor) and MITF (microphthalmia-associated transcription factor) appears to be critical initial
steps of determination and differentiation of the RPE
(384). In early development, before formation of the two
layers, the region destined to form the anterior parts of
the eye express cellular retinol binding protein (CRBP),
cellular retinaldehyde binding protein (CRABP), and several enzymes in the retinal metabolism pathway. The
embryonic retina anlage releases retinoic acid. RPE cells,
in turn, express receptors for retinoic acid (RAR-␤2),
CRBP, and CRABP (see sect. VI for a more detailed description of these proteins) (396, 513, 515). In addition, it
has been shown that retinoic acid alone can promote RPE
differentiation (100, 145, 393, 396, 563), although an exchange of retinoic acid between the developing RPE and
developing neural retina also seems to be of importance.
This exchange and retinoic acid buffering are mediated by
interphotoreceptor retinal binding protein (IRBP) (204).
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IRBP is present in the IPM from the onset of IPM formation, which is at embryonic day 19 in rodents, for example
(110, 112, 156, 204, 206, 207, 562). IRBP is synthesized in
cells destined to become photoreceptors and also those
that will become RPE cells. Thus IRBP is produced long
before it is needed in the visual cycle (see sect. VI) and
must play an important role in development. This is supported by the finding that the IRBP concentration is much
lower in the IPM of the developing eye than in the adult
eye in which the visual cycle is fully functional. Onset of
expression of the RPE specific protein of the visual cycle,
RPE65, occurs in the same time frame as the synthesis of
the IPM. RPE65 expression in the rat steadily increased
from the first expression at embryonic day 18 to postnatal
day 12, just before eye opening (364). Another important
signaling pathway essential for the development of both
tissues is the hedgehog signaling pathway (462, 623). Different hedgehog signaling pathways are active in the RPE
and in the retina. As mentioned above, the selective differentiation of RPE cells mostly affects the development
of photoreceptors and neuronal retina. However, the inactivation of the retina-specific hedgehog signaling leads
to improper development of the retina (623). Thus the
proper development of the retina is not solely dependent
on the presence of the RPE.
The following developmental steps depend on the interaction of retina and RPE. As in the adult eye, the interface
for this interaction is the IPM. The maturation of the RPE
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FIG. 2. Initiation of RPE and retina development: frontal section through the center of the optic cup (region of the optic fissure). The arrows
indicate how neuroepithelium designated to become the RPE and neuroepithelium designated to become retina move into an opposed position. The
space between the two layers will then be filled with interphotoreceptor matrix, the important interface for cross-talk between these two tissues
and proper development. The ocular field of the neural plate shows the fate of various regions. [From Reichenbach and Pritz-Hohmeier (487), with
permission from Elsevier.]
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OLAF STRAUSS
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Another important factor for the establishment of the
apical to basolateral polarity is the formation of tight
junctions between RPE cells. Three stages of tight junction development have been described (34, 36, 314, 456,
481, 494, 634). In the early stage, key proteins for tight
junction formation are expressed. Because these tight
junction complexes are only rudimentary at this point, the
RPE forms a leaky barrier at this stage. This corresponds
with the stage of a partial apical to basolateral polarity.
The tight junctional complexes define the apical and basolateral parts of the membrane because they decrease a
free exchange of membrane proteins over the cell membrane (492). In this phase ␥-tubulin was found in the
apical membrane, whereas ␣1␤3-integrin is present in the
basal membrane (494, 496). At the end of the early phase,
defined as late early phase by Rizzolo (492), the Na⫹-K⫹ATPase becomes apically polarized in the central region
(493, 495) and apical microvilli start to elongate (89, 90).
The second stage is designated the intermediate stage.
During this stage tight junctions have constant tight junctional connections but develop a constant decrease in
permeability. This is due to a major change in the isoform
composition of tight junction proteins. Now tight junctions not only prevent free diffusion of membrane proteins over the cell membrane but also the underlying
maturation of the cytoskeleton additionally defines the
apical to basolateral polarity (492). In this phase a remodeling of the basal membrane occurs (490 – 492, 495). In the
third or late stage of tight junction development, the
composition of tight junction protein isoforms stabilizes
and the tight junction permeability decreases to that characteristic of a tight epithelium. This is primarily due to an
increase in the number and branching of tight junction
strands. According to studies using chick RPE, mature
tight junctions are composed of ZO-1, occludin, and the
claudins 1, 2, 5, 12, and AL (481). The formation of tight
junctions establishes the blood retina barrier and signifies
coincident onset of epithelial transport. Thus, following
completion of tight junctions, the RPE starts to express
transporters like the glucose transporter, which is essential for transepithelial glucose transport (35).
B. Second Phase: Differentiation of RPE
and Photoreceptors
With the differentiation properties acquired by the end
of the first developmental phase, the RPE is prepared to
interact with photoreceptors. Now primordial photoreceptors can start to differentiate (179). It is in this second
developmental phase that the photoreceptors and RPE undergo the last differentiation events and become a functional
unit. Primordial photoreceptors start to extend their outer
segments. The RPE responds by elongating its apical microvilli into the subretinal space. The microvilli start to
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begins with activation of the tyrosinase promoter, which
marks the onset of melanogenesis (286). From that point,
neuroectodermal cells begin to differentiate into the RPE.
The RPE basement membrane and basement membrane of
the endothelium form Bruch’s membrane. Over the whole
time of embryonic development, Bruch’s membrane develops into a five-layered structure: the basement membrane of
the RPE, the inner collagenous layer, the elastin layer, the
outer collagenous layer, and the basement membrane of the
choriocapillaris (195, 220, 257, 338, 381, 583). The formation
of Bruch’s membrane starts near the RPE (448, 588), which
is capable of synthesizing most of the extracellular matrix
components present in Bruch’s membrane (102). The elastin
layer is connected with the ciliary epithelium (318). During
the development of the chick embryo, the expression of
elastin could only be detected in the ciliary epithelium,
which indicates that a part of Bruch’s membrane is possibly
not only built by the RPE/choriocapillaris complex (606).
By now the RPE is a pigmented epithelium showing
almost complete apical to basolateral polarity (372) but
with short microvilli and small basolateral membrane
infoldings. At this stage ⬃75% of the RPE apical architecture has developed (372–374). The surface of the apical
membrane is now three times greater than the one of the
basolateral membrane. Na⫹-K⫹-ATPase, ␣V␤5-integrin
(phagocytosis receptor), N-CAM-140 (a morphoregulator), and EMMPRIN (inducers of matrix metalloproteinase secretion) are now primarily localized in the apical
membrane (265, 372, 374, 490, 493, 494, 582, 631). Later,
the maturation of the apical surface is promoted by the
presence of ezrin. Ezrin seems to be essential for the
development of long apical microvilli (76, 78). In the
developed RPE, ezrin and its associated proteins radixin
and moesin might play a role in 11-cis-retinoid transport
and, thus, in the visual cycle (see sect. VI). A key role is
played by EBP50 [ERM (ezrin, radixin, moesin)-binding
phosphoprotein 50], which interacts with CRBP (75, 425).
This polar distribution of these proteins is thought to be
achieved by a suppression of basolateral sorting mechanisms. This may be due to masking of a basolateral targeting signal by its serine/threonine phosphorylation (92,
116). Furthermore, active apically directed transcytosis
adds to the suppression of basolateral sorting mechanisms. This was shown using the influenza hemagglutinin
(77). A second mechanism may be the suppression of
gene expression of basolateral sorting adaptors. If this is
the case, the suppression modulates several different
sorting mechanisms at different times. For example, NCAM is already localized exclusively to the apical membrane, whereas EMMPRIN is still detectable in the basolateral membrane (372, 374). In addition to intracellular
factors, several receptors interacting with extracellular
signaling molecules such as integrins and cadherins also
play a role in the formation of this special apical to
basolateral polarity (25, 122, 125, 379, 394).
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
III. ABSORPTION OF LIGHT AND PROTECTION
AGAINST PHOTO-OXIDATION
A. The RPE Is Able to Absorb Light Energy
Focused by the Lens Onto the Retina
The RPE increases optical quality by forming a dark
pigmented wall cover of the inner bulbus, which aids in
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absorption of scattered light. In addition, RPE pigmentation is essential for maintenance of visual function. Light
enters the eye via the pupil and is focused onto the
macula lutea by the lens. This concentrates light energy
onto the retina. The outer retina is also exposed to an
oxygen-rich environment. The blood perfusion of the choriocapillaris is 1,400 ml · min⫺1 · 100 g tissue⫺1, which is
even higher than the perfusion in the kidney (17, 19).
Venous blood from the choriocapillaris shows a 90% O2
saturation, indicating that there is a negligible O2 extraction during the passage through the choriocapillaris (16 –
19). By comparison, venous blood from retinal vessels
shows a O2 saturation of 45% (16 –19). The retina is
thought to float on the choriocapillaris, which appears to
function as a bed of blood-filled vessels. This combination
is ideal to allow photo-oxidation and subsequent oxidative damage. This photo-oxidative activity is increased by
the load of reactive oxygen species produced by phagocytosis of shed photoreceptor outer segments (see sect.
VII) (399). As elegantly reviewed by Boulton and DayhawBarker (86), the RPE has three lines of defense against
this damage and toxins. The first line is absorption and
filtering of light. For this purpose, the RPE contains a
complex composition of various pigments that are specialized to different wavelengths and the special wavelength-dependent risks (44 – 46). General light absorption
occurs via melanin in melanosomes (85). This is supplemented by additional light absorption by photoreceptors.
Photoreceptors contain as the most important pigments
the carotenoids lutein and zeaxanthin (74, 244, 245, 332,
435). These pigments form a kind of biological sunglasses
that absorb blue light (44 – 46). Blue light appears to be
most dangerous for RPE cells in the adult eye because it
permits the photo-oxidation of lipofuscin components to
cell toxic substances (52, 53, 352, 503, 504, 547, 549, 550,
552–554). The exposure of the adult retina to ultraviolet
light is rather low because the lens absorbs most of the
ultraviolet light. However, melanosomes and blue light
absorbing pigments are only responsible for the absorption of ⬃60% of light energy (84, 85). This implies the
presence of other pigments that have not been described
yet. One of these pigments might be lipofuscin, which
accumulates in the RPE during life (140, 625). As a lightabsorbing pigment lipofuscin might first be beneficial for
visual function. In the older eye, lipofuscin concentration
seems to reach a toxic concentration for the RPE. The
second line of defense is made by antioxidants. As enzymatic antioxidants, the RPE contains high amounts of
superoxide dismutase (185, 399, 428, 447) and catalase
(399, 594). As nonenzymatic antioxidants, the RPE accumulates carotenoids, such as lutein and zeaxanthin (45,
46), ascorbate, ␣-tocopherol, and ␤-carotene (45, 429).
This is supplemented by glutathione and melanin, which
itself can function as an antioxidant. The third line of
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surround the growing outer segments of photoreceptors. By
the end of differentiation, the RPE has developed two types
of microvilli (84, 179): long microvilli (5–7 ␮m) that maximize the apical surface for epithelial transport (see sect. IV)
and shorter microvilli that form photoreceptor sheaths for
phagocytosis of photoreceptor outer segments (see sect. VII).
Accompanying onset of microvilli growth at the apical membrane is the formation of deep basal infoldings in the basolateral membrane. Thus RPE and photoreceptors are interacting as they undergo their last maturation steps. This tight
coordination of differentiation is also reflected in differential
gene expression in these cells. For example, in the RPE, the
expression of the visual cycle protein RGR opsin (591) and
the putative Cl channel bestrophin is coordinated with the
onset of the electrical activity in the retina including photoreceptors (33).
The coordinated maturation requires the adaption of
RPE cells to different functional properties of the retina.
Differentiated RPE cells in the macula are smaller with 14
␮m in diameter and a height of 12 ␮m than cells in the
periphery which have a diameter of 60 ␮m and which
show a variable height (380, 580, 665). Together with a
higher melanin content (625), the different cell morphology in the macula leads to organization of melanosomes,
which is essential for a more efficient light absorption
(85). This is believed to be the reason for the observation
that the RPE in the macula appears darker (85, 86). For
interaction with photoreceptors, RPE cells develop
sheaths that closely surround photoreceptor outer segments (31, 555, 560). Because cones and rods are surrounded by different types of sheaths, the RPE cells in the
macula have a different apical architecture (555, 560).
Due to the higher number of photoreceptors per RPE cell
in the macula, macular RPE cells (143, 194, 544) are
adapted to a higher turnover rate of shed photoreceptor
outer segments (595) (see sect. VI). For example, macular
RPE cells display higher enzyme activities that are required for degradation processes (87, 93, 249).
The RPE is essential for the development of retinal
structures partly because of its capability to secrete a
variety of growth factors. Growth factors secreted by the
RPE function in both endothelial cell differentiation and
photoreceptor differentiation (3, 48, 94, 282, 306). This
secretion of growth factors is maintained in the adult eye
and helps to stabilize the structural integrity of the retina
(described in detail in sect. VIII).
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defense is the cell’s physiological ability to repair damaged DNA, lipids, and proteins.
B. Increasing Imbalance of Protective and
Toxic Factors With Aging Leads
to Retinal Degeneration
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A reduced capability to absorb light energy is an
important factor in the cascade of events leading to agerelated macular degeneration (AMD), the most common
cause for blindness in industrialized countries (20, 45, 52,
84, 86, 261, 311, 659). An increase in oxidative stress due
to a reduction in protective mechanisms or an increase in
number and concentration of active photo-oxidative reaction species are believed to contribute to the pathogenesis
of AMD (84, 86, 87). One starting point is the accumulation of lipofuscin in the RPE (139 –141). The onset of this
chain of events is based in age-dependent changes of the
RPE. This includes a reduction in the cell density of RPE
cells while the epithelial layer remains intact (143, 226,
415). The reduction in cell density itself may result from
apoptosis, which is caused by accumulation of toxic substances. This is enhanced by an age-related reduction in
one of the most important antioxidants, ␣-tocopherol
(186). Additional important age-related alterations are
changes in pigmentation. These changes include age-dependent reduction of melanosomes as well as an increase
in the number of lipofuscin granules (165, 166, 521, 625).
New types of pigmented organelles can also be detected.
These are melanolysosomes, which are a sign of melanin
degradation and melanolipofuscin granules, which are a
result of accumulation of lipofuscin in melanosomes
(165). The increase in the amount of reactive oxygen
species destabilizes intracellular membrane compartments such as lysosomes and mitochondria. The resulting
decrease in metabolic efficiency produces more lipofuscin and reactive oxygen species. It has been reported that
oxidative stress can be seen as the accumulation of advanced-glycation end products (AGEs) in Bruch’s membrane (243). These AGEs may also play an important role
in the induction of choroidal neovascularization (CNV).
The developing neovascular tissue contains high amounts
of AGE and active receptors for AGEs (RAGE) expressed
on RPE cells (242). RPE cells are able to secrete vascular
endothelial growth factor (VEGF), the major angiogenic
factor in CNV, in response to AGE exposure (360). One
important constituent of lipofuscin is derived from the
inability of the RPE to convert all all-trans-retinol into
11-cis-retinal (see sect. VI) (548, 550). An additional source
is photoreceptor outer segments that form the precursor
of this compound (see sect. VI) This precursor enters RPE
cells by phagocytosis of photoreceptor outer membranes.
The resulting compound, N-retinyl-N-retinylidene ethanolamine, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-
yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hydroxyethyl)-4-[4methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5Ehexatrienyl]-pyridinium or A2E, increases the sensitivity
of the RPE to blue light and has several toxic effects on
RPE cells (55, 56, 262, 523, 524, 548, 549, 552, 553). Coupled with oxygen, A2E is converted by light of the wavelength 430 nm into A2E-epoxides (53, 553). In this reaction, oxygen reacts with the carbon-carbon double bonds
of A2E to form epoxides. Studies of a mouse model for
Stargradt’s disease (see sect. VI) showed the light-dependent accumulation of A2E photoreactivity in the RPE
(479). The light-dependent toxic effect of A2E was demonstrated in vitro when RPE cells were fed A2E (53,
503–505, 524, 553). This had a toxic effect on the RPE cell
only when coupled to exposure to blue light. The active
compound is able to destabilize mitochondrial membranes and lysosomal membranes (55, 56, 262, 523). In
addition, A2E can inhibit cytochrome oxidase in a lightdependent manner which results in interruption of electron flow in the respiratory chain (529, 530, 586). This not
only reduces efficiency of energy metabolism but also
produces more reactive oxygen species. However, the
importance of A2E photoreactivity for AMD in vivo is not
entirely proven. Pawlak and co-workers (454, 455) reported that compared with other related compounds A2E
showed a low photoreactivity that was insufficient to
account for reactive oxygen species in the human RPE.
Thus other components of lipofuscin A2E must be the
principal photo-inducible generators of a range of reactive oxygen species (503, 505). Destabilization of lysosomal and mitochondrial membranes has also been shown
without light exposure (261, 262, 523). Nonoxidized A2E
was capable of inducing comparable effects in studies
with isolated mitochondria and lysosomes (84, 87, 262,
523, 548, 586). An alternative toxic pathway for A2E was
described by Finnemann et al. (172). In this study A2Eladen RPE cells did not show destabilized lysosomes, but
the cells failed to complete the digestion of phagocytosed
photoreceptor outer segments in 24 h. Because the phagocytosis (see sect. VII) is a circadian-regulated process, this
would constantly increase nondegraded phospholipids,
which represents a source for reactive oxygen species.
The destabilization of mitochondria and the incomplete
digest of proteins and lipids by destabilized lysosomes
lead to a subsequent increase in accumulation of reactive
oxygen species and free radicals. In a vicious cycle, these
mechanisms further destabilize RPE cells leading to a loss
of RPE cells, which denotes the beginning of the formation of Drusen (20, 226 –228). Drusen is the most important symptom of age-related macular degeneration and
consists of basal laminar deposits that are located between RPE and Bruch’s membrane and basal linear deposits that are located inside Bruch’s membrane. These
deposits include metabolic end products such as lipoproteins and other hydrophobic materials (227). These might
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
IV. TRANSEPITHELIAL TRANSPORT
A. The RPE Transports Nutrients and Ions
Between Photoreceptors and
the Choriocapillaris
1. Transport from subretinal space to blood
There is a large amount of water produced in the
retina derived primarily as a consequence of the large
metabolic turnover in neurons and photoreceptors. Furthermore, intraocular pressure leads to a movement of
water from the vitreous body into the retina (236, 366,
369). This establishes the need for constant removal of
water from the retina. Water in the inner retina is transported by Müller cells (411, 418), and water in the subretinal space is eliminated by the RPE. Furthermore, the
water transport is required for close structural interaction
of the retina with its supportive tissues in establishment
of an adhesive force between RPE and the retina (308,
366, 370).
The RPE transports ions and water from the subretinal space or apical side to the blood or basolateral side
(Fig. 3A) (268). Therefore, the RPE has the structural
properties of an ion transporting epithelium. Tight junctions establish a barrier between the subretinal space and
choriocapillaris (34, 313, 315, 434, 492). The paracellular
resistance is 10 times higher than the transcellular resistance, classifying the RPE as a tight epithelium (404, 405).
Furthermore, the RPE has an apical to basolateral polarity by structure, organization of organelles, and distribution of the membrane proteins (72, 107, 136, 189, 219, 290,
372–374, 477, 490 – 494). On the apical side, the RPE extends long microvilli, and on the basolateral side, the
membrane is thrown into deep foldings. The majority of
mitochondria are located near the basolateral side (372).
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The Na⫹-K⫹-ATPase, which is located in the apical
membrane, provides the energy for transepithelial transport (218, 372, 374, 450, 490, 491, 493– 495, 631). This
localization is achieved during embryonic development
from the first expression of the Na⫹-K⫹-ATPase and likely
results from suppression of basolateral sorting mechanisms (see sect. II). Constant elimination of water from
the subretinal space produces an adhesion force between
retina and RPE that is lost by inhibition of Na⫹-K⫹-ATPase by ouabain (181). The transport of water is mainly
driven by a transport of Cl⫺ and K⫹ (71, 83, 144, 180 –182,
190, 191, 236, 264, 272, 298, 301, 325, 333, 363, 366, 369,
402– 404, 426, 477, 478, 511, 558, 603, 629, 632). The Cl⫺
transport results in an apical positive transepithelial potential of ⬃5–15 mV (404, 405).
The Na⫹-K⫹-ATPase establishes a gradient for sodium from the extracellular space to the intracellular
space. At the apical membrane this gradient facilitates
⫹
⫺
uptake of HCO⫺
3 via the Na -HCO3 cotransporter and
⫹
⫺
⫹ ⫹
uptake of K and Cl via the Na -K -2Cl⫺ cotransporter
(5, 236, 267, 290, 295, 297, 298, 327, 346). Accumulation of
Cl⫺ results in a high intracellular Cl⫺ activity of ⬃20 – 60
mM (290, 325 , 402, 477, 632). The intracellular Cl⫺ activity
is increased by coupling Cl⫺ transport to HCO⫺
3 transport
for regulation of intracellular pH. For this purpose, a
⫺
basolateral Cl⫺/HCO⫺
3 exchanger extrudes HCO3 from
⫺
the cell and increases the intracellular Cl concentration
(150, 151, 295, 346, 347). Cl⫺ leaves the cell via Ca2⫹dependent Cl channels (248, 475, 574, 577, 585, 607) and
via ClC-2 channels (80, 248, 287, 629). In addition, immunohistochemical analysis shows the expression of cystic
fibrosis transmembrane conductance regulator (CFTR) in
the RPE, which might provide an additional efflux pathway for Cl⫺ over the basolateral membrane (71, 401, 482,
629, 635). CFTR is known to function as a Cl channel
activated by protein kinase A (PKA) (2). The observation
of a cAMP-dependent increase in transepithelial Cl⫺
transport indicates the functional role of CFTR in the RPE
(71, 401). In the regulation of intracellular pH, the activity
of the Cl⫺/HCO⫺
3 exchanger and the activity of the Cl
channels are combined resulting in a cycling of Cl⫺ over
the basolateral cell membrane. In addition, the Cl⫺/HCO⫺
3
exchanger also decreases the efficiency of extrusion of
Cl⫺ from the cytosol and, thus, the efficiency of transepithelial Cl⫺ transport. Intracellular acidification results in
a decrease in the transport activity of the Cl⫺/HCO⫺
3
exchanger (150, 347). Thus intracellular acidification results in an increase in epithelial Cl⫺ transport, which
might be important in elimination of water from the retina
during increased metabolic activity. This is of importance
because increased metabolic activity may cause intra- and
extracellular edema in response to increased formation
of lactic acid as well as increased uptake of glucose
(80, 369).
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be a consequence of incomplete degradation of metabolic
end products from both photoreceptors and RPE. However, a more detailed analysis of the protein composition
of Drusen led to alternative theories of Drusen formation
(128, 226, 519). In one theory, the formation of Drusen
begins with loss of RPE cells that are removed by an
inflammatory event. The resulting gap in the epithelial
barrier is actively closed by adjacent RPE that secretes a
new extracellular matrix (226). The major matrix component is vitronectin (228). The theory is supported by
detection of active dendritic cells and active components
of the complement system in Drusen (414, 415). The
hydrophobic material and lipoproteins could be the debris left over by incomplete degradation of cells. The end
stages of the disease are either geographic atrophy (GA),
a loss of RPE and photoreceptors over large areas, or
CNV with subsequent intraocular bleeding and formation
of a disciform scar (20, 99, 659).
851
852
OLAF STRAUSS
K⫹ entering the RPE on the apical site by Na⫹-K⫹ATPase and Na⫹-K⫹-2Cl⫺ cotransporter can leave the cell
through the basolateral or the apical membrane via K⫹
channels. Normally, the basolateral K⫹ conductance is
higher than the apical K⫹ conductance establishing the
basis for the net transepithelial K⫹ transport from the
subretinal space to the choroidal site (64, 189, 213, 250,
290, 328, 405, 477). Depending on changes in the K⫹
concentration in the subretinal space, this transport direction can be changed (see below) (328). The apical K⫹
conductance is primarily provided by inward rectifier K⫹
channels of the Kir 7.1 subtype (274, 276, 323, 528, 536,
571, 576, 593, 649). These K⫹ channels are located in the
apical microvilli of the RPE (323, 536). Two main functions have been attributed to these inward rectifier K⫹
channels. The close colocalization of Kir 7.1 and Na⫹-K⫹ATPase suggests that these act synergistically. Kir 7.1
promotes a cycling of K⫹ through the apical membrane
(214, 215, 250, 273, 275, 276, 323, 436 – 438, 528, 536). The
resulting decrease in intracellular K⫹ concentration together with decreasing gradient of K⫹ against which the
Physiol Rev • VOL
Na⫹-K⫹-ATPase is transporting facilitates the Na⫹ transport out of the cell through the apical membrane. In this
way, the Kir 7.1 increases the efficiency of Na⫹-K⫹ATPase for transporting Na⫹ across the apical membrane.
As mentioned above, the transepithelial transport of ions
is linked to pH regulation. The inward rectifier K⫹ channels appear to be dependent on extra- and intracellular pH
(657). Acidification results in an activation of these K⫹
channels and therefore facilitates Na⫹ transport by Na⫹K⫹-ATPase, thereby transepithelial transport. With these
properties, Kir channels can help the transepithelial transport adapt to increases in metabolic activity and pH regulation required for transport of lactic acid. A second
function of Kir 7.1 is to react in response to changes in the
subretinal K⫹ concentration, which will be described in
detail in section V (276, 528). Channels responsible for
efflux of K⫹ over the basolateral membrane have not been
clearly identified. Candidates include the large-conductance Ca2⫹-dependent K⫹ channel (508, 592) or the Mtype K⫹ channel (587). These K⫹ channels can both provide a K⫹ conductance over a broad voltage range, and
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⫺
FIG. 3. Epithelial transport and pH regulation. A: transepithelial transport of ions across the RPE is shown. Cl is predominantly transported
from the subretinal space to the choriocapillaris. This transport drives water through aquaporins from the subretinal space to the choriocapillaris.
The driving force for epithelial transport is provided by the apically located Na⫹-K⫹-ATPase. K⫹ transported by the ATPase recycles through the
apical membrane and facilitates establishment of a Na⫹ gradient into the cell. The Na⫹ gradient serves to drive uptake K⫹ and Cl⫺ on the apical
side resulting in a high intracellular Cl⫺ activity. Cl⫺ is extruded from the cell on the basolateral side through Cl channels. The efficiency of Cl⫺
⫺
extrusion from the cell is reduced by activity of a Cl⫺/HCO⫺
3 exchanger, which transports Cl back into the cell. B: transport of lactic acid and pH
regulation is also shown. Lactic acid is removed from the subretinal space by the lac⫺-H⫹ cotransporter. Through the basolateral membrane lactic
acid leaves the cell using a different subtype of lac⫺-H⫹ cotransporter. The necessary pH regulation occurs using Na⫹/H⫹ exchanger and Na⫹/HCO⫺
3
⫺
⫺
exchanger in the apical membrane and a Cl⫺/HCO⫺
3 exchanger at the basolateral membrane. The activity of Cl /HCO3 exchanger is supported by
⫺
⫺
basolateral Cl channels, which result in a cycling of Cl across the basolateral membrane. In the case of intracellular acidification, the Cl /HCO⫺
3
exchanger is inhibited whereas Cl channels are activated. This increases the net water transport. ClC-2, voltage-dependent Cl channels of the ClC
family; CFTR, cystic fibrosis transmembrane conductance regulator; Kir7.1, inwardly rectifying K⫹ channel 7.1; maxi-K, large-conductance Ca2⫹dependent K⫹ channel; MCT1, monocarboxylate transporter 1; MCT3, monocarboxylate transporter 3.
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
Physiol Rev • VOL
ing in a HCO⫺
3 transport from the choroid to the subretinal space. The coupling of transepithelial HCO⫺
3 transport
with pH regulation and Cl⫺ transport is explained above.
There is a small amount of transepithelial Na⫹ transport by the RPE, and the pathway controlling this is not
fully understood. Na⫹ is extruded from the cell through
the apical membrane via Na⫹-K⫹-ATPase, but it enters the
cell primarily through the Na⫹-2Cl⫺-K⫹ cotransporter.
Therefore, most of the transported Na⫹ recycles through
the apical membrane. However, for the small amount of
transepithelial transported Na⫹ which leaves the RPE cell
through the basolateral membranes, the basolateral transport mechanism is not clear. This transmembrane transport is coupled to other metabolites and has to occur
against a Na⫹ gradient. A Na⫹-coupled lactic acid transporter and an additional Na⫹-HCO⫺
3 cotransporter have
been proposed to mediate this function in bovine RPE
(301, 302). Using the Na⫹/HCO⫺
3 cotransporter seems unlikely because the other HCO⫺
3 transport mechanisms in
the basolateral membrane should not support the establishment of a large enough HCO⫺
3 -dependent driving force
to transport Na⫹ against its concentration gradient.
RPE-mediated removal of water from the retina and
the subretinal space is coordinated with the neuronal
retina. The regulation of water and ion transport by neuropeptide Y and serotonin imply such a coordination.
Neuropeptide Y stimulates both transport of Cl⫺ and water via stimulation of Ca2⫹-dependent Cl channels (23).
Serotonin increases transepithelial potential, which
mainly results from transport of Cl⫺ from the subretinal
space to the choroid (91, 269 –272, 424, 449). Furthermore,
the stimulating effect of epinephrine on fluid absorption
suggests that there is a sympathetic influence (49, 289,
478, 511). At least purinergic stimulation of RPE cells
results in activation of several types of ion channels
as well as in an enhancement of fluid absorption (363,
406, 508).
2. Transport from blood to the photoreceptors
In one direction, the RPE transports electrolytes and
water from the subretinal space to the choroid, and in the
other direction, the RPE transports glucose and other
nutrients from the blood to the photoreceptors. To transport glucose, the RPE contains high amounts of glucose
transporters in both the apical and the basolateral membranes. Both GLUT1 and GLUT3 are highly expressed in
the RPE (35, 54, 582). GLUT3 mediates the basic glucose
transport while GLUT1 is responsible for inducible glucose transport in response to mitogens or oncogenes and
can, thus, adapt glucose transport to different metabolic
demands.
Another important function of the RPE is the transport of retinol to ensure the supply of retinal to the
photoreceptors. The bulk of the retinal is exchanged be-
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they are coupled to second messenger signaling pathways
making them good candidates for function in transepithelial transport of K⫹.
Epithelial transport of Cl⫺ and K⫹ drives epithelial
transport of water. The transport rate of water was estimated between 1.4 and 11 ␮l · cm⫺2 · h⫺1 (123, 152, 271,
602, 604, 640). Because the RPE is a tight epithelium,
water cannot pass through the paracellular transport
route. Thus movement of water occurs mainly by transcellular pathways. In a recent publication, expression of
aquaporin-1 was detected in the RPE. Furthermore, it
was shown that the transepithelial transport of water
is facilitated by the functional presence of aquaporin-1
(238, 556).
In the RPE’s role to support photoreceptor function,
it is responsible for elimination of metabolic end products
from the photoreceptors (237, 302, 330, 660). The most
important metabolic end product seems to be lactic acid
for which a subretinal concentration of 19 mM has been
reported (4). Photoreceptor outer segments are known to
produce lactic acid and might represent the major source
for lactic acid (263, 637). A smaller part of lactic acid
might come from inner segments, which react to transient
changes in illumination with increases in lactate production (21, 67, 620). The transport of lactic acid by the RPE
(Fig. 3B) requires an efficient regulation of intracellular
pH (452). Lactic acid is removed from the subretinal
space by the lactate-H⫹ cotransporter MCT1 (54, 345, 467)
and the Na⫹-dependent transporter for organic acids
(302). Protons are delivered to the subretinal space by the
apically located Na⫹/H⫹ exchanger (150, 295, 658). Thus
uptake of lactic acid by MCT1 is by tertiary active transport. Lactic acid is extruded through the basolateral membrane from the intracellular space to the choroid by MCT3
(467, 650) and the Na⫹/lac⫺ exchanger (302). The subretinal pH as well as intracellular pH of the RPE are regulated
by transepithelial transport of HCO⫺
3 (295, 296, 346). In
the apical membrane the Na⫹/HCO⫺
3 cotransporter transports HCO⫺
into
the
cell
(267,
290,
295,
301, 326, 327, 329,
3
346). This is an electrogenic cotransporter which transports 1 Na⫹ with 2 HCO⫺
3 (326, 327, 329). Thus the transport direction is dependent on the apical transmembrane
potential and intracellular HCO⫺
3 concentration. This enables the HCO⫺
transport
system
to regulate the transport
3
direction in response to pH changes. At high intracellular
and subretinal pH, HCO⫺
3 is taken into the RPE cells by
the Na⫹/HCO⫺
cotransporter
in the apical membranes
3
and leaves the cell through the basolateral membrane in
exchange with Cl⫺ mediated by the Cl⫺/HCO⫺
3 exchanger
(144). This results in a subretinal to choroid directed
HCO⫺
3 transport. At low intracellular and subretinal pH,
new driving forces for HCO⫺
3 are established. In this case
HCO⫺
is
taken
up
by
the
Cl⫺/HCO⫺
3
3 exchanger in the
basolateral membrane and leaves the cell through the
Na⫹-HCO⫺
3 cotransporter in the apical membrane result-
853
854
OLAF STRAUSS
Physiol Rev • VOL
between RPE and photoreceptors. Even though this alternative function has not been established, detailed structure/binding correlation studies support its existence.
IRBP isolated from dark-adapted retinas carries larger
quantities of 11-cis-retinal and 11-cis-retinol than from
light-adapted retinae (348). This suggests that IRBP has a
11-cis-retinal buffering function and that it protects this
essential compound from oxidative damage. With this
buffering function, photoreceptors could take up 11-cisretinal from a pool and would therefore not be dependent
on the numerous reactions of the visual cycle pathway to
supply 11-cis-retinal, which would be much slower. This
would result in faster regeneration of rhodopsin after the
onset of light.
Delivery of docosahexaenoic acid to photoreceptors
is a third kind of transport of importance for visual function (41). Membranes of neurons and photoreceptors as
well as photoreceptor disk membranes are selectively
built from phospholipids that are highly enriched with
docosahexaenoic acid, a 22:6␻3 fatty acid (26, 29, 178,
566, 621, 633). This compound cannot be synthesized by
neuronal tissue. Thus neuronal tissue is dependent on the
delivery of 22:6␻3. New photoreceptor outer segments
that are rebuilt from the base, the inner segment of photoreceptors, selectively require 22:6␻3 fatty acid (26, 29,
566, 621, 633). This compound is synthesized from the
precursor, linolenic acid, in the liver and transported in
the blood bound to plasma lipoprotein (26, 29, 566, 621,
633). The RPE preferentially takes up docosahexaenoic
acid in a concentration-dependent manner (41– 43, 208,
209). In the RPE this fatty acid is incorporated into glycerolipids in de novo synthesis reactions for storage and
connection into the recycling pathways during the phagocytosis process (see sect. VII)(499).
B. Increases in Epithelial Transport Help to Treat
Edema: Reductions in Epithelial Transport
Cause Retinal Degeneration
In diabetic retinopathy or in some forms of inherited
macular degeneration, a clinically important complication
is the formation of macular edema (369). Macular edema
is most likely caused by damage to the blood/retina barrier, which is formed by the RPE and the endothelium of
retinal vessels. In the case of diabetic retinopathy, the site
of damage is in the endothelium of retinal vessels. Macular edema is successfully treated by administration of
inhibitors of carbonic anhydrase (119, 176, 369, 561, 639,
641). This results in a reduction of intracellular pH and
intracellular HCO⫺
3 concentration (180, 293, 371, 404, 604,
648). As a result, transport activity of the Cl⫺/HCO⫺
3 exchanger is reduced, and the uptake of Cl⫺ via the basolateral membrane is reduced. This increases the efficiency
of Cl⫺ release through the basolateral membrane and
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tween RPE and photoreceptors during the visual cycle in
which all-trans-retinol is taken up from photoreceptors,
isomerized to 11-cis-retinal, and redelivered to photoreceptors (30). The vitamin A (all-trans-retinol) uptake
from the bloodstream through the basolateral membrane
constitutes a smaller, additional supply to this process.
The uptake of vitamin A occurs in a receptor-mediated
process with recognition by a serum retinol-binding protein/transthyretin (RBP/TTR) complex (466, 476, 615).
Within the RPE cell, all-trans-retinol binds to CRBP (513–
515) and enters the isomerization and oxidation steps of
the visual cycle (30). The subsequent reactions are described in detail in section VI. Once vitamin A is converted
to 11-cis-retinal, it is transported to the photoreceptors
where it binds to opsin and can serve in its function to
initiate the phototransduction cascade (30). The direction
of transepithelial transport of vitamin A from the blood to
the photoreceptors is achieved by binding retinal to specific binding proteins that ensure absence of free retinol
inside the cell (254). In addition, the rapid transfer
through the visual cycle maintains a constant gradient of
retinol from inside the RPE cell and the bloodstream and
drives the directed transport (392, 512).
The space between the RPE and photoreceptors, the
IPM, forms an important interface for interaction between
RPE and photoreceptors. The IPM mediates adhesion
between the RPE and photoreceptor layer, phagocytosis
by the RPE (described in more detail in section VII), and
nutrient exchange between RPE and the photoreceptors
(204, 224). The IPM is a complex structure containing
IRPB, growth factors such as basic fibroblast growth
factor (bFGF), hyaluronan and hyaluronan binding proteoglycans, sulfated glycosaminoglycans, and matrix metalloproteases (1, 225, 253, 258, 259, 320). The IPM changes
its structure between light and dark (610). In spite of its
importance, the exchange of retinal and retinol between
RPE and the photoreceptors is not understood (204). A
very promising candidate to mediate exchange of retinal
and retinol was IRBP (72, 107, 111, 113, 114, 206, 207, 254,
532, 562). IRBP functions to solubilize retinal and retinol,
which are otherwise insoluble in water and mediates
targeting of these compounds and defines the transport
direction (107, 108, 130, 445, 446, 457, 458, 518). This role
for IRBP is further supported by the observation that
IRBP is not only present in the IPM but also in endosomes
of the RPE (131). The transport direction is then defined
by the rapid turnover of IRBP between the IPM and the
RPE. However, this model was recently challenged by
investigation of IRBP⫺/⫺ mice (453). These mice still
have an intact visual cycle and a normal regeneration of
retinal that can be interpreted in one of two ways: either
there is an efficient alternative retinoid transport pathway
between RPE and photoreceptors which can compensate
for the loss of the IRBP-dependent pathway, or IRBP has
a function other than transport of retinal and retinol
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
Physiol Rev • VOL
phin mutations a loss of Cl channel function (585). Thus
reduction in the light-peak amplitude in the patients’s
EOG results from reduction in basolateral Cl⫺ conductance. However, studies searching for more bestrophin
mutations described patients with bestrophin mutations
that show normal light peaks or an onset of the light-peak
reduction that occurs later than the onset of macular
dystrophy (12, 157, 319, 358, 525, 617). In addition, in a
recently published rat model for Best’s disease, overexpression of wild-type bestrophin did not change lightpeak amplitude but desensitized luminance response
while two investigated mutant bestrophins could generate
the expected decrease in light-peak amplitude (376).
These observations cannot be easily explained by the
theory that Best’s disease is caused by a lack of Cl channel function.
Another example of Cl⫺ transport alteration in the
RPE that might result in disease is cystic fibrosis (287,
482). Patients with cystic fibrosis have reduced amplitudes of the fast oscillation in the EOG (71, 629). Like the
light peak, the fast oscillation represents a signal in the
EOG that is generated by activation of Cl channels in the
basolateral membrane of the RPE. The expression of
CFTR has been established in RPE cells. Furthermore,
part of the transepithelial transported Cl⫺ is dependent
on cAMP-activated Cl conductance (269 –272, 321, 325,
342, 401, 403, 422). Thus patients with cystic fibrosis have
additional reduction in the transepithelial Cl⫺ transport
by the RPE. However, patients with cystic fibrosis do not
develop retinal degeneration perhaps because there is a
compensatory activation of other Cl channels, such as the
Ca2⫹-dependent Cl channel, in the RPE.
Alteration of transepithelial transport may function
in the pathogenesis of age-related macular degeneration.
As described above, the development of Drusen is required for diagnosis of this disease (20). In 20 –25% of
patients, Drusen become large and confluent (311) and
establish large diffusion barriers between blood vessels
and the RPE. This may lead to development of areas with
reduced supply of oxygen and glucose, mimicking hypoxia (183, 360). These regions of hypoxic stress may
cause degeneration of adjacent photoreceptors and subsequent loss of vision in areas of Drusen. A further consequence of metabolic stress might be the induction of
choroidal neovascularization, the most severe complication in the etiology of age-related macular degeneration
(311). Hypoxia reduces the secretion of pigment epithelium-derived growth factor (PEDF) by the RPE (134).
PEDF is a potent antiangiogenic factor. The development
of choroidal neovascularization can lead to intraocular
bleeding, which is the main cause for vision loss (20). This
theory is supported by the observation that choroidal
neovascular membranes contain high amounts of advanced glycation end products that are generated by reactive oxygen species during reduced metabolism (242).
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enhances transepithelial Cl⫺ transport. Epithelial transport of Cl⫺ drives the transport of water and eliminates
the fluid of the edema.
Epithelial transport of Cl⫺ was found to be essential
for visual function. This was shown in a transgenic mouse
model with a disrupted gene for ClC-2 Cl channels (80,
287). The resulting phenotype has a retinal degeneration
comparable to retinitis pigmentosa. The disease is caused
by a lack of epithelial transport of Cl⫺, the RPE shows no
transepithelial potential. It is likely that this results in the
inability to extrude lactic acid from the photoreceptor
side leading to subsequent metabolic stress and loss of
photoreceptors (80). However, the exact mechanism for
the retinal degeneration is not fully understood and needs
further evaluation. A second example of retinal degeneration associated with defective Cl⫺ transport is Best’s
vitelliform macular degeneration (12, 32, 98, 129, 157, 198,
210, 358, 375, 377, 378, 416, 464, 470, 567, 624). In this
disease the retinal degeneration is caused by degeneration of RPE (198). This results in the formation of a bull’s
eye shaped lesion that resembles an egg yolk. The shape
of the lesion gave rise to the name of this disease. The
bull’s eye lesion primarily contains extracellular fluid,
suggesting there is a reduction in epithelial Cl⫺ transport
(624). The leading symptom for diagnosis of Best’s vitelliform macular degeneration is a reduction in the light
peak-to-dark ratio in the patient’s electro-oculogram
(EOG) (198). The light peak results from the activation of
basolateral Cl⫺ conductance (188, 190, 191, 193). Lightdependent stimulation of the retina leads to release of a
light peak substance from the inner retina or photoreceptors (188). The light peak substance diffuses to the RPE
and leads to activation of basolateral Cl⫺ channels via
activation of intracellular second messenger pathways
(192, 193). Because it is likely that the underlying second
messenger pathway results in an increase in intracellular
Ca2⫹, the basolateral Cl⫺ conductance is provided by
Ca2⫹-dependent Cl channels. The as yet unidentified light
peak substance is very likely ATP, which is known to
activate the inositol 1,3,4-trisphosphate (InsP3)/Ca2⫹ second messenger system. Furthermore, an increase in intracellular InsP3 increases the concentration of cytosolic
free Ca2⫹ and subsequently Ca2⫹-dependent Cl channels
(573, 577). Thus the reduction of the light peak in patients’
EOG points to a reduction in epithelial Cl⫺ transport,
which might be the cause for the pathology of the disease.
The gene responsible for Best’s vitelliform macular degeneration has been isolated and identified as VMD2 gene
(378, 464). The VMD2 gene product is named bestrophin
(32, 98, 157, 358, 378, 416, 464, 567). Recent data suggest
on several lines of evidence that bestrophin itself represents a new family of Ca2⫹-dependent Cl channels (175,
473– 475, 585, 605). This elegantly explains the cause for
the light peak reduction in the patient’s EOG. Heterologous expression studies showed for 15 different bestro-
855
856
OLAF STRAUSS
Finally, reduction in the delivery of retinal to photoreceptors was found to induce a form of photoreceptor
dystrophy (526). This rare disease was described as a
symptom of the retinol binding protein deficiency syndrome. Here, patients show mutations in the retinol binding protein 4, RBP4, gene. This protein appears to be
essential for uptake of retinol into the RPE cells. Because
of the reduced retinol uptake, patients have no detectable
rod function in dark adaption or in their scotopic ERG.
However, these patients do not have a very severe degenerative phenotype, suggesting that there must be an alternative tissue source for vitamin A.
A. Spatial Buffering of Ions in the Subretinal
Space Maintains Excitability of Photoreceptors
The RPE not only stabilizes the ion homeostasis in
the subretinal space by transepithelial transport of
ions, but it is also able to compensate for fast occurring
changes in the ion composition in the subretinal space
(558). This function is comparable to the ability of glia
cells for spatial buffering of ions. In fact, a major part
of the spatial buffering is enabled by Müller glia cells
(427, 486, 644). Another part is controlled by the RPE.
Stimulation of photoreceptors by light reduces the dark
current, which consists of an influx of Na⫹ via open
cGMP-gated cation channels in the outer segments
which is counterbalanced by an efflux of K⫹ via K⫹
channels in the inner segment (39). The reduction of
the K⫹ efflux results in a decrease of the subretinal K⫹
concentration from ⬃5 to 2 mM (144, 558, 559). This
leads to a change in the equilibrium potential for K⫹,
which in turn disturbs the phototransduction cascade
in the outer segments of the photoreceptors. The RPE
compensates for these changes in the following manner: the decrease in the subretinal K⫹ concentration
hyperpolarizes the apical membrane of the RPE (436 –
438), which causes activation of inward rectifier K⫹
channels (276, 528, 536, 649, 657). These inward rectifier channels respond with a mild rectification and an
increase in activity in response to a decrease in the
extracellular K⫹ concentration (276). The activation of
inward rectifier K⫹ channels then causes a change in
the ratio of apical and basolateral K⫹ conductance
(328). Normally, the basolateral K⫹ conductance is
higher than the apical conductance which results in
directed epithelial transport of K⫹ from the subretinal
space to the choroidal site (328). The rise in apical K⫹
conductance increases the portion of K⫹ that is transported back to the subretinal space. As a result, K⫹ is
secreted to the subretinal space and compensates for
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V. SPATIAL BUFFERING OF IONS IN THE
SUBRETINAL SPACE
the light-induced decrease of subretinal K⫹. Application of K⫹ channel blocker can prevent the hyperpolarization-induced decrease in intracellular K⫹ (215, 273).
The compensation for the light-induced decrease in
subretinal K⫹ is supported by the Na⫹-K⫹-2Cl⫺ cotransporter that appears to work in the early phase of apical
membrane hyperpolarization in the opposite direction,
leading to an additional K⫹ outflow of the cell (64, 65).
In addition, the decrease in subretinal K⫹ concentration changes the Cl⫺ transport (64, 151, 213, 214). The
decrease in subretinal K⫹ concentration decreases the
uptake of Cl⫺ via the Na⫹-K⫹-2Cl⫺ cotransporter in the
late phase of apical membrane hyperpolarization. The
subsequent decrease in intracellular Cl⫺ activity
changes the equilibrium potential for Cl⫺ through the
basolateral membrane which has a high Cl⫺ conductance (64, 65). This results in a hyperpolarization of the
basolateral membrane and decreases the driving force
for Cl⫺ to leave the cell via the basolateral membrane.
These compensatory mechanisms can be monitored in
the electroretinogram (ERG) as the c-wave and delayed
hyperpolarization (214, 436, 558). The c-wave results
from the hyperpolarization of the apical RPE cell membrane, and the delayed hyperpolarization results from
hyperpolarization of the basolateral membrane. Lightdependent activation of photoreceptors closes cation
channels in the outer segments and thus increases the
subretinal Na⫹ concentration, which is compensated
for by the Na⫹/H⫹ exchanger and by the Na⫹-K⫹-2Cl⫺
cotransporter in the apical membranes of the RPE. The
subsequent decrease in the subretinal Na⫹ concentration after closing of cation channels during the transition from light to darkness is compensated for by Na⫹K⫹-ATPase in the photoreceptor’s inner segments and
by the Na⫹-K⫹-ATPase of the RPE (255). It is believed
that this might be why the Na⫹-K⫹-ATPase is localized
to the apical membrane of the RPE.
The light-induced changes in ion transport do not
only maintain ion homeostasis in the subretinal space.
The changes in the transport direction also imply lightdependent changes in water transport (268). This effect is
based on the fact that the activity of the apical Na⫹-HCO⫺
3
cotransporter is dependent on the membrane potential
(326). Light-induced hyperpolarization of the apical membrane results in a decrease of its transport activity, which
subsequently leads to intracellular acidification (301, 344,
346). This increases Cl⫺ efflux through the basolateral
membrane (see sect. IV) and results in an increase in Cl⫺
and water transport from subretinal space to choroid. The
light-induced increase in water absorption seems to be of
importance to control subretinal space volume during
changes in illumination. With the use of measurements of
the concentration of tetramethylammonium (TMA⫺) ions
by a TMA⫺-sensitive electrode, it was shown that illumination leads to transient volume increases in the retina
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
B. Spatial Buffering Gives Rise to Wave Forms in
the ERG: Monitoring of Metabolic Status
To date, changes in the ability of the RPE to mediate
spatial ion buffering have not been linked to degenerative
disease of either the photoreceptors or the RPE. However, the action of spatial buffering can be monitored in
recordings of the ERG. Changes in signals that arise at the
RPE can give information about diseases caused by alterations of RPE function. These alterations can be attributed to changed metabolic activity of the RPE (133, 291,
349 –351, 558). The c-wave of the ERG arises from an
increase in the apical K⫹ conductance in the RPE and
correlates with the function of K⫹ buffering in the subretinal space that is reduced under hypoxic conditions
(349, 351). However, many of these changes arise in the
interaction between RPE and neuronal retina and reveal
the tight interactive function of both tissues. The current
detailed picture of the energy metabolism-associated
events leading to retinal degenerations has been drawn
primarily from methods investigating RPE/retina interactions in the ERG.
Physiol Rev • VOL
VI. VISUAL CYCLE OR RETINOID CYCLE
A. Exchange of Retinal Between Photoreceptors
and RPE: Isomerization and Reisomerization
Between 11-cis and all-trans
Photoreceptors lack cis-trans isomerase function for
retinal and are unable to regenerate all-trans-retinal into
11-cis-retinal after transduction of light energy into electrical impulses (30). Therefore, retinal is converted by two
major metabolic pathways. One pathway includes binding
of retinal to opsin as 11-cis-retinal and release from opsin
as all-trans-retinal during recovery of rhodopsin after
light absorption. The second pathway serves for the regeneration or better reisomerization of all-trans-retinal
into 11-cis-retinal (Fig. 4). The reisomerization occurs in
the RPE. Thus retinal entering the second pathway is
cycled between photoreceptors and the RPE to ensure
constant excitability of photoreceptors. This shows how
closely photoreceptors and RPE interact in the process of
vision. However, recent studies have described a second
pathway of retinal reisomerization (28, 386). It appears
that cones can regenerate a part of their photoisomerized
retinal in a second visual cycle occurring in Müller cells.
The metabolic pathways of the visual cycle are not completely understood. Most of the understanding comes
from studies on mechanisms of retinal degenerations.
Excellent reviews on this topic have been published by
Thompson and Gal (596, 597) and by Besch et al. (58).
Much in the following description of the metabolic pathway of retinal regeneration will need to be further verified
by extensive future studies.
Light transduction is initiated by absorption of light
by rhodopsin which is composed of a seven transmembrane domain G-coupled receptor protein, opsin, and the
chromophore 11-cis-retinal (247). Absorption of light
changes the conformation of 11-cis-retinal into all-transretinal. The conformational change of retinal results in
formation of active rhodopsin, meta-rhodopsin, which in
turn is able to activate transducin in the next step in the
phototransduction cascade (256, 444). The active state of
rhodopsin is terminated by phosphorylation by rhodopsin
receptor kinase and subsequent binding with arrestin (39,
40). Inactivated rhodopsin releases all-trans-retinal and
binds 11-cis-retinal again in several subsequent steps so
that rhodopsin can again be activated by absorption of
light. Accumulating all-trans-retinal leaves the intradiscal
space facilitated by the activity of an ATP-binding cassette protein (ABCR) (584, 628) known as ABCA4 (9 –11,
13–15, 340, 537). It functions in rods and cones as ATPdependent flippase for N-retinylidine-phosphatidylethanolamine (N-retinylidine-PE). This requires the reaction
of all-trans-retinal with phophatidylethanolamine (352).
After hydrolysis, N-retinylidine-PE is released to the cy-
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that were most pronounced in the region between outer
nuclear layer and subretinal space (266, 341). It is likely
that changes in the extracellular volume of the inner
retina are compensated for by Müller cells, whereas the
RPE compensates for the changes in the subretinal space.
In the dark, the apical membrane of the RPE is depolarized. Now the activity of the Na⫹-HCO⫺
3 cotransporter
rises causing intracellular alkalinization (267, 346). In
consequence, less Cl⫺ leaves the cell through the basolateral membrane. This reduces fluid absorption in the
dark (301). Studies on epithelial transport indicate a more
severe consequence (65, 603). A decreased efflux of Cl⫺
out of RPE cells increases intracellular Cl⫺ concentration
providing a driving force for Cl⫺ to leave the cell through
the apical membrane. Indeed, an apical Cl⫺ secretion was
observed when K⫹ concentration at the apical site was
increased from 2 to 5 mM (151, 347). Because apical Cl
channels have not yet been described, the Cl⫺ efflux
mechanism through the apical membrane is unclear.
However, the postulated Cl⫺ secretion in the dark should
result in a fluid secretion in the dark into the subretinal
space. Indeed, a corresponding fluid movement from the
basolateral side to the apical side has been observed in
transepithelial transport studies but is not proven in vivo.
The physiological significance of a fluid secretion into the
subretinal space in the dark is not clear. However,
the secretion likely occurs only for a short time until
the increase in subretinal K⫹ concentration has been
compensated and the apical membrane is no longer depolarized.
857
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OLAF STRAUSS
tosol of the photoreceptors as all-trans-retinal. Here, it is
reduced to all-trans-retinol by a membrane-bound retinol
dehydrogenase that requires NADPH (221, 483). The allretinol dehydrogenase (RDH) belongs to the family of
membrane-bound short-chain alcohol dehydrogenases
(SCAD or short chain acetyl-CoA dehydrogenase). Alltrans-retinol is then translocated to the RPE on a carrier
protein that may be IRBP (204, 206). The exact mechanism for uptake into the RPE is not known but might be
a trapping of all-trans-retinol inside the RPE by formation
of insoluble fatty acid retinyl ester. Inside the RPE alltrans-retinol is bound to CRBP (513, 514, 516). The reisomerization is initiated by an esterification step which
includes transfer of an acyl group to retinol catalyzed by
lecithin:retinol transferase (LRAT) (387, 407, 507, 601,
666). The isomerization requires in addition the participaPhysiol Rev • VOL
tion of a chaperone. This chaperone, RPE65 (retinal pigment epithelium-specific protein 65 kDa), was first isolated as a RPE-specific protein (239 –241, 432, 485). Studies of RPE65 loss of function implicate its role in the
retinol isomerization cycle (217, 278, 292, 357, 485, 527,
598, 614). In recent publications it has been suggested that
RPE65 functions as a retinylester binding protein (124,
200 –203, 284, 385, 645) and as a chaperone for all-transretinylesters (202, 645). Furthermore, RPE65 can adapt
the visual cycle on the different retinoid requirements in
dark and light (202, 645). A membrane-bound form
mRPE65 is triply palmitoylated, has high affinity to alltrans-retinylesters, and is a palmitoyl donor for the acylgroup transfer by LRAT (645). This form ensures 11-cisretinal production during light. The soluble form, sRPE65,
is not palmitoylated and has high affinity to vitamin A.
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FIG. 4. Visual cycle. Light transduction starts with photon absorption by rhodopsin. The process of light absorption underlies the stereochemical change of 11-cis-retinal into all-trans-retinal. All-trans-retinal is metabolized into all-trans-retinol and transported to the RPE. In the RPE retinol
reisomerized to 11-cis-retinal and then redelivered to the photoreceptors. The regeneration seems to follow two pathways. One occurs through an
as yet unidentified enzyme thought to function as a isomerohydrolase. The second pathway involves a light-dependent pathway using the RPE-retinal
G protein-coupled receptor which isomerizes all-trans-retinal to 11-cis-retinal following light absorption. IRBP, interstitial retinal binding protein;
CRBP, cellular retinol binding protein; CRALBP, cellular retinaldehyde binding protein; atRDH, all-trans-retinol dehydrogenase; 11cRDH, 11-cisretinol dehydrogenase; LRAT, lecithin retinol acyltransferase; RPE65, RPE specific protein with molecular mass of 65 kDa; RGR, RPE-retinal G
protein-coupled receptor; RBP/TTR, retinol-binding protein/transthyretin complex. [From Thompson and Gal (597), with permission from Elsevier.]
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
Physiol Rev • VOL
ulates 11-cis-retinal for recovery from light exposure. The
RGR knock-out mice cannot maintain 11-cis-retinal levels
in ambient light. Exposure of Rgr⫺/⫺ mice leads to a
drop in the levels of 11-cis-retinal and rhodopsin (120). In
addition, the RGR pathway can better compensate for
loss of function in the RDH5 pathway versus the RDH5
pathway, which incompletely compensates for loss of
function of RGR. That there is the capacity for a partial
compensation can be seen in the fact that Rgr⫺/⫺ mice
show a rather late onset (9 mo) of retinal degeneration
(120) compared with other animal models for retinal degeneration (222).
The transport of 11-cis-retinal back to photoreceptors occurs through binding to IRBP in the subretinal
space. How 11-cis-retinal leaves the RPE and enters photoreceptor cells is not understood. With this last step of
retinal regeneration, retinal reenters the other metabolic
pathway by binding to opsin and serves in its function for
light transduction.
B. Inherited Retinal Degenerations Are Caused
by Mutations in a Variety of Genes
of the Visual Cycle
Reduction in the activity of the visual cycle is responsible for several types of retinal and RPE degenerations.
To date the cause of many retinal degenerations has been
identified as gene defects leading to reduced function of a
broad range of proteins involved in the visual cycle reaction cascade.
Mutations in the ABCA4 gene can lead to a variety of
diseases (9 –11, 13, 14, 57, 340, 383, 416, 537, 539, 540, 584,
661– 663). These mutations lead to different degrees of
reduced function. Reduced ABCA4 protein function decreases the efficiency of all-trans-retinal elimination from
the intradiscal space decreasing amounts of retinal that
can enter the visual cycle to be isomerized back to 11-cisretinal. Interestingly, the degree of functional loss of
ABCA4 protein leads to different types of retinal degeneration (11). A total loss of function causes retinitis pigmentosa, a photoreceptor degeneration which is characterized by a loss of vision from the periphery to the center
of vision due to rod photoreceptor followed by cone
photoreceptor cell death and accumulation of pigment
granules in the fundus (11, 383). A different type of photoreceptor degeneration, collectively referred to as conerod dystrophies, are caused by mutations causing a severe
reduction in the transport activity versus a total loss of
function (540). The most common disease that results
from mutations in ABCA4 is Stargardt disease or fundus
flavimaculatus, inherited forms of macular degeneration,
and loss of vision occurring early in life (10, 14, 15, 27, 68,
141, 210, 390, 416, 539, 661– 663). This disease can be
regarded as a RPE disease because it starts with the
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This form is responsible for a reduced 11-cis-retinal production in the dark. The palmitoyl switch between these
two RPE65 forms is controlled by the activity of LRAT
and the concentration of 11-cis-retinol in the RPE (645).
With these characteristics RPE65 function is a rate-limiting step for the visual cycle. The enzyme that catalyzes
the isomerization of all-trans-retinyl ester to 11-cis-retinol
is called isomerohydrolase and has not yet been identified
(137). Isomerohydrolase uses the energy from ester hydrolysis in a reaction that might occur in two separate
reaction steps. In the first step hydrolysis of retinylester
occurs via the retinylester hydrolase function of the enzyme complex. In the second step isomerization occurs
through a carbocation intermediate. The next step in the
regeneration process of retinal is the oxidation of 11-cisretinol to 11-cis-retinal. This NAD and NADP-requiring
reaction step is catalyzed by 11-cis-retinol dehydrogenase
or RDH5, which belongs to the family of short-chain
dehydrogenases (146, 285, 538). This reaction is supported by a cellular retinylaldehyde-binding protein
(CRALBP) that accelerates the enzymatic reaction (517).
Immunoprecipitation studies suggest that RDH5, RPE65,
LRAT, and CRALBP form complexes in which CRALBP
positions retinol for optimal enzymatic turnover (63, 120,
121, 538). This pathway to regenerate retinal is supplemented by an alternative pathway involving the activity of
RPE-retinal G protein-coupled receptor (RGR) (120, 121,
246, 288, 535, 591). RGR converts all-trans-retinal into
11-cis-retinal, in an inverted light-induced rhodopsin
isomerization reaction (121). The substrate for RGR is
produced from all-trans-retinol of the retinylester pool. A
retinol dehydrogenase, presumably not RDH5, produces
all-trans-retinal, which will be subsequently transformed
into 11-cis-retinal by RGR using light energy. Analysis of
RGR knock-out mice (see below) suggests that the RGRdependent, alternative pathway serves to adapt the retinal
turnover to changes in ambient light (120). Thus two
pathways are responsible to regenerate 11-cis-retinal. For
clearer presentation, these pathways will be considered
separately and referred to as the RDH5 or the RGR pathway. It is not clear if a RGR-dependent pathway can be
separated from a RDH5-dependent pathway in normal
individuals. The data from studies of knock-out mice
indicate some independence because of the compensatory effects (120, 147). RGR functions to maintain constant levels of 11-cis-retinal independent of different levels of ambient light (362). The RDH5 pathway is important
for the fluctuating acute turnover of retinal during the
process of vision. Thus the loss of function of RGR reduces and destabilizes the overall levels of 11-cis-retinal
and leads to photoreceptor degeneration. In contrast, loss
of function of RDH5 results in a delayed recovery from
light exposure and, thus, to night blindness. The RGR
pathway is important to maintain the 11-cis-retinal levels
after the onset of light, whereas the RDH5 pathway reg-
859
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OLAF STRAUSS
Physiol Rev • VOL
phenotype resulting from RGR mutations and from RDH5
mutations show again the relative functional importance
of the two retinal regenerating pathways.
A severe phenotype, retinal dystrophy, also arises
from mutations in the RPE65 gene (167, 200, 217, 239 –
241, 357, 359, 409, 460, 461, 541, 598, 600, 614, 622, 643). As
described above, RPE65 function is rate limiting for the
visual cycle by enhancing or decreasing 11-cis-retinal production in dependence of the illumination (202, 645). A
lack of RPE65 leads to abnormally low levels of chromophore and increased levels of phosphorylated opsin
(612). The disturbance of retinal turnover also results in
an accumulation of lipofuscin in RPE cells (292). Lipofuscin appears to play an important role in the etiology of
age-related macular degeneration by destabilizing RPE
cells and increasing their susceptibility to photo-oxidative
damage (202). Mice with a disrupted RPE65 gene show
dramatically reduced light- and dark-adapted ERGs before onset of photoreceptor degeneration (485, 527, 612,
613). The remaining visual function comes from rod photoreceptors (527). This residual activity suggests that
there is either an additional, not yet described pathway, to
regenerate all-trans-retinal or that there could be an incomplete compensation by RGR-dependent and/or RDH5dependent pathways. Because RGR can directly isomerize
all-trans-retinal into 11-cis-retinal, it is likely that this
pathway is responsible for the remaining retinal regeneration. However, in RPE65 ⫺/⫺ mice, without the retinyl
ester binding protein RPE65, all-trans-retinal must reach
the RPE directly and not via the ABCR-mediated pathway.
This very likely occurs during phagocytosis of photoreceptor outer segments, which is described in more detail
in the next section. In humans, mutations of the RPE65
gene lead to retinal dystrophies including Leber’s congenital amaurosis (142, 167, 217, 240, 241, 357, 359, 409, 460,
461, 541, 596, 598, 600, 622, 643). These diseases are early
onset showing the importance of RPE65 in the visual
cycle. In animals, such as the RPE65 transgenic mouse or
the naturally occurring retinal dystrophy in Briard dogs,
mutations in the RPE65 gene result in retinitis pigmentosa. However, RPE65 mutations represent examples of
diseases caused by a gene expressed in the RPE leading to
disease which initially affects photoreceptors.
A comparable phenotype to the one of RPE65 mutations results from mutations in the LRAT gene, the gene
encoding lecithin:retinol transferase (597, 599). Patients
with LRAT mutations have an early-onset, severe retinal
dystrophy. The visual field becomes restricted to tiny
islands. LRAT mutations include changes that cause
amino acid changes resulting in loss of function or truncated proteins due to missense mutations. The net effect
is the accumulation of toxic levels of vitamin A in RPE
cells. This can be explained by the fact that LRAT is
responsible for the palmitoyl switch of RPE65 to the form
with high affinity to vitamin A. In patients with LRAT
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degeneration of the RPE. Thus mutations in a gene expressed in photoreceptors can result in degeneration of
the RPE. In addition, ABCA4 mutations have been associated with age-related macular degeneration (9, 13, 57,
210, 416). How loss of function in the ABCA4 transporter
protein leads to retinal degeneration is best understood in
the case of Stargardt disease. The reduced ABCA4 function causes accumulation of all-trans-retinal and N-retinylidine-PE (see above) in the disks of the photoreceptor
outer segments (480). Photoreceptor outer segments are
shed from the photoreceptors in a circadian regulated
process and are phagocytosed by the RPE constituting
another important function of the RPE for the maintenance of visual function (see sect. VII). The phagocytosed
outer segments undergo enzymatic digestion within the
RPE. In the case of Stargardt disease, the RPE is confronted with photoreceptor outer segments that contain
abnormally high levels of all-trans-retinal and N-retinylidine-PE. As a consequence, during enzymatic digestion
within phagosomes N-retinylidine-N-retinylethanolamine
(A2E) is generated (197, 388, 479). A2E is a major fluorophore of lipofuscin and has several toxic effects on the
RPE that are described in section III. Thus, with reduced
function of ABCR, the RPE is poisoned by A2E. The
resulting loss of function of the RPE and the possible loss
of RPE cells secondarily leads to photoreceptor degeneration and subsequent loss of vision (548, 552, 611). As
mentioned above, some forms of age-related macular degeneration have been associated with mutations of ABCR
gene (9, 11). Also in age-related macular degeneration,
accumulation of A2E appears to be a hallmark for the
induction of the disease (52, 530). Here, ABCR show only
a small loss of function leading to a slower poisoning of
RPE cells.
Within the RPE, retinal and retinol are transported by
binding to retinol binding proteins. CRALBP mutations
have been described that lead to an early-onset retinal
dystrophy known as retinitis punctata albescens, which is
characterized by the appearance of uniform white dots in
the fundus picture (391, 408, 545). In these patients a
delayed dark adaption and elevated dark adaption thresholds leading in the beginning to night blindness show the
importance of CRALBP in the visual cycle, since these
mutations lead to a decreased efficiency to regenerate
retinal (205).
As mentioned earlier, mutations in the 11-cis-retinal
dehydrogenase gene RDH5 cause less severe phenotypes.
RDH5 mutations lead to decreased protein stability, mislocalization in the cytosol, and decreased enzyme activity
(343). The patients suffer from fundus albipunctatus, a
congenital night blindness caused by a delayed rod-cone
pigment regeneration after strong bleaches and white
dots in the fundus picture (109, 367, 368). In contrast,
mutations in the RGR gene cause the much more severe
retinitis pigmentosa (410, 622). The differences in the
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
disease-causing mutations, the loss of photoreceptors
cells is secondary to loss of the RPE cells.
VII. PHAGOCYTOSIS
A. Photoreceptor Outer Segment Renewal:
Phagocytosis of Shed Photoreceptor Membranes
by the RPE
Physiol Rev • VOL
has not been identified. In addition, initiation and intracellular regulation of phagocytosis can be studied in isolated cells by challenging RPE cell cultures with isolated
POS (171, 229, 235, 251, 417). Thus it seems that the
presence of shed POS is sufficient to initiate phagocytosis. Thus the basis of coordination between POS shedding
and phagocytosis is the presence of POS. The initial step
in phagocytosis (Fig. 5) is the specific binding of POS at
the apical membrane of the RPE (229). In the next step,
the recognition of POS binding is transferred to the intracellular space by activation of a second messenger cascade, which in turn activates the ingestion of bound POS
(229). CD36, MerTK, and integrin receptors have all been
described as regulators of POS phagocytosis. The macrophage scavenger receptor CD36 was found to regulate the
rate of POS internalization (174, 509, 510, 551). A recent
study suggests an interaction between CD36 and the tolllike receptor TLR4 adapting the metabolism of RPE cells
to handle ingested POS (305). The receptor tyrosine kinase c-mer (MerTK) transduces the specific binding of
POS to the RPE into activation of the second messenger
cascade that initializes internalization of POS (118, 135,
154, 199, 233, 235, 251). Binding of POS requires the
activation of ␣V␤5-integrin receptors (170, 171, 173, 174,
400, 664). MerTK and ␣V␤5-integrin receptors interact in
the initialization of phagocytosis (170). An essential role
of MerTK is evident (148, 168, 616). Cells lacking the
MerTK receptor are able to bind POS but are not able to
ingest them (118). It is noteworthy, however, that al-
FIG. 5. Phagocytosis. The molecules involved in the initiation of
photoreceptor outer segment phagocytosis are shown. The initiation
starts with binding of photoreceptor outer membranes. The event of
binding is transduced into an intracellular signal, a rise in intracellular
inositol 1,4,5-trisphosphate (InsP3), which in turn leads to ingestion of
the bound photoreceptor outer segment membranes. Binding is likely
mediated by integrins, and signal transduction occurs through the receptor tyrosine kinase MerTK. Ingestion involves the macrophage receptor CD36. Coordinate signal transduction occurs through integrin
and MerTK interaction through the focal adhesion kinase. CD36, macrophage phagocytosis receptor; FAK, focal adhesion kinase; Gas6,
growth-arrest-specific protein 6; MerTK, receptor tyrosine kinase c-mer;
PLC, phospholipase C; POS, photoreceptor outer segment.
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Photoreceptors contain high amounts of photosensitive molecules. As discussed in section III, photoreceptors
are exposed to intense levels of light. This leads to accumulation of photo-damaged proteins and lipids. In addition, retinal itself can generate photo-oxidative radicals.
Thus, during each day, the concentration of light-induced
toxic substances increases inside the photoreceptors
(45). The light transduction by photoreceptors is dependent on the proper function and structure of proteins,
retinal, and membranes. Therefore, to maintain the excitability of photoreceptors, the photoreceptor outer segments (POS) undergo a constant renewal process (72, 73,
232, 430, 558, 652, 654 – 656). In this renewal process POS
are newly built from the base of outer segments, at the
cilium. The tips of the POS that contain the highest concentration of radicals, photo-damaged proteins, and lipids
are shed from the photoreceptors. Through coordinated
POS tip shedding and formation of new POS, a constant
length of the POS is maintained. Shed POS are phagocytosed by the RPE. In the RPE, shed POS are digested and
important molecules, such as retinal or docosahexaenoic
acid, are redelivered to photoreceptors in a manner comparable to the visual cycle (66, 72). For recycling, docosahexaenoic acid is removed from phospholipids and redelivered to photoreceptors as a fatty acid (26, 41, 42, 208,
209, 499). Retinal undergoes the RPE-specific part of visual cycle and is redelivered as 11-cis-retinal to photoreceptors. Here again, RPE and photoreceptors are closely
interacting partners. This interaction is essential for maintaining the structural integrity of photoreceptors and,
thus, visual function. Furthermore, the process of disk
shedding and phagocytosis must be tightly coordinated
between both the RPE and the photoreceptors. A failure
in this regulation would result in POS that are either too
long or too short. The process of POS shedding and
phagocytosis is under circadian control (334 –337, 439,
651). In the process of phagocytosis every RPE cell is
facing an average ranging between 20 and 45 photoreceptors in Rhesus monkeys (544, 653). In humans, the ratio
was estimated in the fovea with 23 photoreceptors
per RPE cell average over 9 decades (194). The turnover
rate for one entire photoreceptor outer segment is 10
days (653).
A substance permitting the communication between
photoreceptor and RPE that controls phagocytic activity
861
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OLAF STRAUSS
Physiol Rev • VOL
Osborne and co-workers (423, 424, 449) demonstrated
coregulation by both systems by serotonin via protein
kinase C. Interestingly, bFGF (or FGF-2) can stimulate
POS phagocytosis. This might result from a bFGF-dependent reduction in the cAMP production in RPE cells. Nash
and Osborne (423) showed that bFGF decreases the forskolin-induced cAMP production. This effect is even more
remarkable because bFGF can also increase POS phagocytosis activity in RPE cells lacking MerTK (395). However, because bFGF has no effect on cAMP production in
RPE cells lacking MerTK (423), the rescue effect of bFGF
is mediated by another pathway.
It has been proposed that the rate of phagocytosis is
dependent on the rate in which apical POS phagocytosis
receptor containing cell membrane cycles between the
extracellular and intracellular space (79). This theory was
derived from the measurement of overlapping binding
and ingestion kinetics (229). Kinetic studies have shown
that inhibition of ingestion reduces binding of POS, and
vice versa.
There is also a circadian regulation of POS phagocytosis (60, 177, 335, 337, 469). The major burst of rod outer
segment phagocytosis takes place with the onset of light
(61). However, extensive studies on the circadian regulation of photoreceptor outer segment shedding and phagocytosis revealed a more complex pattern with differences
between cones and rods (595) and with differences
among different species (59). The circadian control is
dependent on a circadian clock in the retina which (95–
97) is known to regulate adaptive changes in the retina
(211). How this circadian clock controls the onset of POS
phagocytosis is also not entirely understood (430). An
important transmitter to coordinate phagocytosis and the
circadian clock seems to be dopamine (62, 469). The
negative regulation of phagocytosis by increasing cAMP
levels and the presence of dopamine receptors linked to
adenylate cyclase activation suggest that circadian regulation may be mediated through the dopamine/melatonin
system (59, 95–97, 430, 431, 433, 442, 488, 489). In a recent
paper an additional role of integrin receptors was shown
(421). Mice lacking ␣v␤5-integrin lack a synchronized
phagocytosis of shed POS with no burst of phagocytosis
after onset of light (421).
B. Failure of Photoreceptor Outer Segment
Phagocytosis Leads to Retinal Degeneration
Inability of the RPE to phagocytose POS causes an
autosomal recessive form of retinitis pigmentosa (148,
154, 187, 413, 420, 600, 616, 622). This was first described
in an animal model for retinitis pigmentosa, the Royal
College of Surgeons or RCS rat (73, 88, 118, 154, 199, 355,
413, 575). The genetic defect in this animal results in
synthesis of a truncated, unfunctional MerTK protein and,
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though RPE cells lacking MerTK cannot ingest POS, these
cells are capable of nonspecific phagocytosis (154, 251).
In RPE cells with intact MerTK, the binding of POS leads
to an increase in intracellular InsP3, which does not occur
in RPE cells with disrupted MerTK receptor tyrosine kinase (251). The lack of InsP3 activation in cells with
disrupted MerTK is responsible for the inability to ingest
POS. Thus MerTK is essential for transfer of this signal
into the intracellular space. The binding of POS to RPE
cells seems to be mediated by ␣V␤5-integrin receptors
(170, 171, 174, 400). Antibody-induced inhibition of ␣V␤5integrin receptors dramatically reduced binding and as a
consequence ingestion of POS (171). In a recent publication, Finnemann (170) could show that activation of ␣V␤5integrin receptor is not only essential for POS binding but
also plays a role in activation of MerTK. Thus both the
receptors MerTK and ␣V␤5-integrin interact. This interaction is mediated by activation of focal adhesion kinase
(FAK). In this model, POS binding to ␣V␤5-integrin receptor activates FAK, in turn phosphorylates MerTK, and
then activates the subsequent second messenger cascade.
If both receptor types are involved in binding and recognition of POS, then additional proteins are also required
for this process. ␣V-Integrin receptor predominantly recognizes vitronectin (125). Finneman et al. (171) found that
in an in vitro POS phagocytosis assay that vitronectin
itself did not change POS phagocytosis. The group concluded that other surface proteins on POS that are capable of binding to ␣V␤5-integrin receptor mediate this process. The specific binding partner of MerTK is growtharrest-specific protein 6 (Gas6). Hall and co-workers (234,
235) could demonstrate that Gas6 is required for proper
phagocytosis of POS. However, the interaction of phagocytosis receptors, intermediate proteins, and POS has not
been entirely elucidated.
As mentioned above, the binding and recognition of
POS activates the second messenger InsP3 (251). The
activation of this second messenger cascade results in an
increase in the number of phosphorylated proteins (252).
Initiation of phagocytosis requires tyrosine phosphorylation (170). An increase in intracellular InsP3 also causes a
subsequent increase in intracellular free Ca2⫹. Both in
concert seem to regulate phagocytosis, whereas an increase in InsP3 alone activates the ingestion of POS (251,
498). The increase in intracellular free Ca2⫹ coupled to
subsequent activation of protein kinase C may act as a
shut-off signal for phagocytosis (231). While the InsP3/
Ca2⫹ second messenger system functions in initiation of
phagocytosis, the cAMP second messenger system is an
important modulator of the rate of phagocytosis (153,
230). An increase in intracellular cAMP reduces phagocytic activity. This is physiologically achieved by ␤-adrenergic stimulation and by stimulation of adenosine A2 receptors (49, 212, 230). Both the InsP3/Ca2⫹ and the cAMP
second messenger systems can interact. The group of
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
Physiol Rev • VOL
the macula (86, 87, 93). This could result from a higher
rate of photon absorption by photoreceptors in macula
compared with the periphery (58, 546). Furthermore, the
predominant photoreceptors in the macula, cones, have a
higher energy demand and production than rods (21, 127,
316, 317, 459, 468, 522, 642), which are the predominant
photoreceptors in the periphery. The increased metabolic
activity supports the need for increased phagocytic activity in this region. Finally, there are also reports of a higher
number of photoreceptors per RPE cell in the macula
(143). However, this has not been supported by other
studies (194).
VIII. SECRETION
A. The RPE Secretes a Variety of Growth Factors
As already noted, RPE and photoreceptor development are interdependent. The mechanisms controlling
this may not be limited solely to the presence of corresponding surface proteins and their interaction with complimentary receptors, including integrins (373, 394, 492).
This can also be controlled by growth factors that can act
over a longer distance. The RPE is known to produce and
to secrete a variety of growth factors (589) as well as
factors that are essential for maintenance of the structural
integrity of retina (104, 557) and choriocapillaris (638),
e.g., different types of tissue inhibitor of matrix metalloprotease (TIMP) (8, 138, 155, 451, 471, 472, 506, 646). Thus
the RPE makes factors that support survival of photoreceptors and ensure a structural basis for optimal circulation and supply of nutrients. The RPE is able to secrete
fibroblast growth factors (FGF-1, FGF-2, and FGF-5) (81,
82, 115, 126, 149, 225, 281, 283, 303, 309, 310, 564, 619),
transforming growth factor-␤ (TGF-␤) (303, 324, 389, 590),
insulin-like growth factor-I (IGF-I) (382, 542), ciliary neurotrophic factor (CNTF) (106, 619), platelet-derived
growth factor (PDGF) (101, 103), VEGF (3, 322, 356, 360,
419, 638), lens epithelium-derived growth factor (LEDGF)
(7), members of the interleukin family (280, 581, 630), and
pigment epithelium-derived factor (PEDF) (134, 306, 440,
441, 557).
In the healthy eye, the RPE secretes PEDF (134, 306,
557), which helps to maintain the retinal as well as the
choriocapillaris structure in two ways. PEDF was described as a neuroprotective factor because it appeared to
protect neurons against glutamate-induced or hypoxiainduced apoptosis (105, 441, 557). In addition, PEDF was
shown to function as an antiangiogenic factor that inhibits
endothelial cell proliferation and stabilizes the endothelium of the choriocapillaris (134, 306, 440). These effects
on vascularization also play an important role in the embryonic development of the eye (48, 282). Another vasoactive factor made in the RPE is VEGF, which is secreted
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thus ultimately, to loss of POS phagocytosis receptor
function (135). Furthermore, biochemical studies have
shown that the truncated MerTk protein cannot be directed to the cell membrane. The lack of MerTK blocks
POS phagocytosis and therefore leads to subsequent loss
of photoreceptors (118, 148, 154, 199, 335). As proof that
the defect in the RCS rat is truly due to lack of MerTK, the
transfection of RCS rat RPE with normal MerTK rescues
the loss of function (616). Comparable mutations in
MerTK have also been identified in humans with autosomal recessive retinitis pigmentosa (187, 600).
A defect in RPE POS phagocytosis may also cause
retinal degeneration in Usher type 1B patients (196).
Usher syndrome is a congenital concomitant and progressive loss of hearing and vision (6, 161, 294, 304, 463). The
gene product of the Usher type 1B gene is myosin VIIa.
Defects in myosin VIIa function were initially thought to
affect photoreceptor outer segment structure through disturbed vesicular transport outer segment components
along the cilium. However, recent in vitro analysis of RPE
cells isolated from mice lacking myosin VIIa showed that
these RPE cells display a reduced ability to ingest bound
POS due to disturbed vesicle trafficking and fusion between phagosomes and lysosomes. However, the capability per se to bind and ingest POS is in myosin VIIa⫺/⫺
mice comparable to that of wild-type mice. Thus the
intracellular machinery to handle ingested POS is compromised in RPE cells from myosin VIIa-deficient mice
and that the primary defect is in the RPE instead of the
photoreceptors (196).
POS phagocytosis might also contribute to the onset
of age-related macular degeneration (84). As described
above, POS are shed because they accumulate high
amounts of oxidized lipids and proteins which therefore
end up within the RPE after phagocytosis. In addition, the
RPE itself is exposed to high amounts of oxygen radicals
due to exposure to high light energy in combination with
the high oxygen concentration in the choriocapillaris and
must, thus, compensate for very high photo-oxidative activity (see sect. III). Thus POS phagocytosis could be
considered as an additional burden on the RPE by oxidative stress that might over time ultimately poison the RPE.
An important “early” event of AMD is the loss of RPE cells
likely due to oxidative damage (143, 226). In eyes without
eye disease, the RPE cell density remains stable until the
ninth decade of life (194). As a result, the remaining RPE
cells face a higher number of photoreceptors shedding
more outer segments increasing their oxidative stress
even further, eventually snowballing and causing large
regions of RPE atrophy (58, 84, 86). In addition, there are
observations suggesting that this process might also be
one of the reasons that AMD starts in the macula because
a higher lysosomal activity has been detected in RPE cells
of the macula compared with RPE cells from the periphery, suggesting there is a higher rate of phagocytosis in
863
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OLAF STRAUSS
However, the cross talk between the blood cells and the
RPE is not fully understood.
The mechanisms involved in the regulation of secretion by the RPE are comparable to other known secretory
tissues (Fig. 6). For example, RPE cells express L-type
Ca2⫹ channels of the neuroendocrine subtype, which corresponds with the ␣1D- or CaV1.3 subunit of Ca2⫹ channels
(397, 500, 501, 568, 577–579, 608, 609). The same subtype
of L-type Ca2⫹ channels is responsible for controlling the
secretory activity of, for example, beta islet cells of the
pancreas (37, 38, 117, 520, 647). In vitro studies revealed
that VEGF secretion by RPE cells is dependent on the
activity of L-type channels (569). Direct stimulation of
L-type channels by the L-type channel opener BAY K 8644,
a substance which directly binds to the channel, increases
VEGF secretion while the inhibition of L-type channels by
nifedipine reduces VEGF secretion (569). L-type channels
belong to the group of high-voltage activated Ca2⫹ channels. RPE cells express a splicing variant of the CaV1.3
subunit which has not been published for other tissues
(636). The electrophysiological properties of this splice
variant permit these L-type channel to function in epithelial cells by being activated at lower voltages. Normally,
RPE cells do not undergo changes in their membrane
potential more positive than ⫺30 mV (192, 405, 571, 609,
626). To function under these conditions, L-type channels
in the RPE show very negative activation thresholds (398,
501, 608, 609). Another unusual feature of the RPE L-type
channels is that their voltage dependence is regulated by
tyrosine kinase (398, 501, 568, 570), which allows a mode
of activation that differs from that in excitable cells.
Unlike L-type channels in excitable cells, L-type channels
in RPE cells are not activated by changes in the membrane voltage. These channels are activated by tyrosine
kinase-dependent shifts in their voltage-dependent activa-
FIG. 6. Secretion. In the healthy eye, the RPE
secretes the neurotrophic factor pigment epithelium-derived factor (PEDF) into the subretinal space
at the apical side of the RPE. The angiogenic factor
vascular endothelial growth factor (VEGF) is secreted from the basolateral side into the extracellular matrix where it stabilizes the endothelium of
the choriocapillaris and helps to keep it fenestrated. RPE cells express the neuroendocrine subtype of L-type Ca2⫹ channels. Activation of these
channels increases intracellular free Ca2⫹, which
triggers the release of growth factors. This is terminated by either deactivation of L-type channels
via activation of delayed rectifier K⫹ channels and
hyperpolarization of the cell or by transport mechanism which decrease intracellular free Ca2⫹ such
as Ca2⫹-ATPase or Na⫹/Ca2⫹ exchanger. Delayed
rectifier (KV1.3), outwardly delayed rectifying K⫹
channel composed of KV1.3 subunits; L-type (CaV1.3),
L-type Ca2⫹ channel of the neurendocrine subtype
defined by the CaV1.3 or ␣1D-subunit; maxi-K, largeconductance Ca2⫹-dependent K⫹ channel; NCX-1,
cardiac sodium/calcium exchanger-1; PMCA, plasma
membrane Ca2⫹-ATPase.
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in low concentrations by the RPE in the healthy eye (3,
356, 638) where it prevents endothelial cell apoptosis and
is essential for an intact endothelium of the choriocapillaris (94). VEGF also acts as a permeability factor stabilizing the fenestrations of the endothelium (497). The
secretions of TIMP-1 and TIMP-3 are additional factors
that stabilize the endothelium as well as the extracellular
matrix (8, 24, 138, 155, 162, 451, 471, 472, 506, 646). In a
healthy eye, PEDF and VEGF are secreted at opposite
sides of the RPE: PEDF to the apical side where it acts on
neurons and photoreceptors and the majority of VEGF is
secreted to the basal side where it acts on the choroidal
endothelium (47, 69). Growth factor secretion changes in
response to damage or injury, which stimulates the RPE
to also secrete neuroprotective factors including bFGF or
CNTF (70, 106, 627). This is thought to protect photoreceptors from light-induced damage. The group of Reme
and co-workers (216, 223, 278) has demonstrated that
following a range of intensified light exposures photoreceptors started to show signs of apoptosis that were fully
reversible. This may be due to increased secretion and de
novo synthesis of different neuroprotective factors by the
RPE such as PEDF, CNTF, and bFGF, which are known to
be protective against light damage (105, 619).
As the part of the epithelia that separates the inner
eye from the bloodstream, the RPE functions in establishing immune privilege of the eye (280, 581, 630). There are
several lines of evidence that point to an immunosuppressive function of the RPE. RPE cells can suppress activation of CD4⫹ and CD8⫹ T cells (164) as well as inducing
apoptosis in the Jurkat T-cell line (163). Because in vivo
the RPE is physically separated from the bloodstream by
Bruch’s membrane, these immunosuppressive effects
must be due to secretion of soluble factors and not by
direct interaction with blood cells (160, 164, 280, 353).
THE RETINAL PIGMENT EPITHELIUM IN VISUAL FUNCTION
B. Changes in the Secretory Activity Are
Associated With Proliferative Diseases
in the Retina
The healthy ability of the RPE to secrete growth
factors can protect photoreceptors from damage, but dysregulated growth factor secretion can also be involved in
Physiol Rev • VOL
the pathogenesis of retinal diseases (99, 183, 261, 307, 465,
589, 638, 659). These forms of retinal degenerations are
characterized by proliferation of cells. One important disease with a proliferative component is age-related macular degeneration. The most severe complication in agerelated macular degeneration is the development of choroidal neovascularization (CNV) (20, 22, 99, 132, 183, 184).
Although the initiation of this neovascularization is not
understood, several mechanisms have been implicated
including local hypoxia, wound healing processes subsequent to RPE cell loss, and inflammatory processes (99,
132, 226, 300, 412). To date, analysis of CNV membranes
has identified several different types of growth factors
within the CNV membranes (184, 279, 331, 618). In each
case the major angiogenic factor causing the development
of choroidal neovascularization is VEGF. Many studies
have shown that the major source of VEGF seems to be
RPE cells (3, 183, 312, 356, 360, 412, 419, 638). For example, RPE cells in neovascular tissues obtained from patients with age-related macular degeneration secreted
VEGF at a higher rate compared with RPE cells from eyes
without neovascularization (569). The increased rate of
RPE-derived VEGF secretion was due to intracellular signaling mediated by increased activity of L-type Ca2⫹ channels (569). Many extracellular stimuli have been proposed
to induce increased VEGF secretion. These include
growth factors such as IGF-I (331, 502, 542) or tumor
necrosis factor-␣ (TNF-␣) (443), the intregrin ligand vitronectin (158, 227, 228, 412), and AGEs, which act via
stimulation of the receptor for AGE’s RAGE (242, 243,
360). Because IGF-I is produced by photoreceptors in
healthy eyes but by RPE cells and photoreceptors in eyes
with age-related macular degeneration, it can contribute
to a signaling pathway in which photoreceptors can stimulate VEGF secretion by RPE cells (502, 542, 543).
IX. SUMMARY
Initially only regarded as the dark cover of the inner
wall of the bulbus, today’s understanding of the RPE
shows it is essential for visual function providing multiple
functions that support normal photoreceptor function.
This role was unraveled in studies on normal RPE function as well as in studies of retinal degeneration. The view
of the RPE has been refined to the point that RPE and
photoreceptors are together considered a functional unit.
This is supported by studies of diseases resulting from
defects in genes normally expressed in photoreceptors
that lead to degeneration of the RPE, such as ABCR. Or
vice versa, studies showed that defects of genes expressed in the RPE results primarily in degeneration of
photoreceptors, such as MerTK or RPE65. This is due to
the synergistic interaction of these tissues. Integrated
interaction includes, for example, the visual cycle in
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tion towards more negative potentials, towards the resting potential of RPE cells (398). The receptor tyrosine
kinase, bFGF receptor FGFR-2, coprecipitates with L-type
channels and leads to their activation (501). The same
properties have been observed for the cytosolic subtype
of tyrosine kinase, pp60c-src (568). The activation by
pp60c-src tyrosine kinase links these Ca2⫹ channels to the
InsP3/Ca2⫹ second messenger system (398). Thus L-type
channels in the RPE are ideal targets for growth factordependent signaling, implicating an influence of growth
factors on the secretory activity of the RPE. In fact, bFGF
was found to stimulate both L-type channels and VEGF
secretion (501, 569).
To allow rapid changes in intracellular Ca2⫹ homeostasis, L-type channels are under the control of outwardly rectifying K⫹ channels (274, 277, 571, 572, 587,
593, 626). These K⫹ channels were identified as K⫹ channels mainly composed of Kv1.3 subunits (572). The outwardly rectifying channels activate at the same potentials
as L-type channels and thereby limit activation of L-type
channels by stabilizing the resting potential (572). In addition, outwardly rectifying K⫹ channels are also stimulated by tyrosine kinase (572). Thus concomitant with
each stimulation of L-type channels by activation of tyrosine kinase there is also stimulation outwardly rectifying K⫹ channels. Because outwardly rectifying K⫹ channels activate more slowly than the L-type channels, an
influx of Ca2⫹ through L-type channels can occur until it
is terminated by hyperpolarization from K⫹ channel activation. This regulation prevents an overload of Ca2⫹ in
the cell after L-type channel activation. In addition, intracellular Ca2⫹ homeostasis is controlled by transport molecules that eliminate Ca2⫹ from the intracellular space.
The RPE expresses the cardiac subtype of Na⫹/Ca2⫹ exchanger (NCX-1), which shows a transport stoichiometry
of 3Na⫹ to 1Ca2⫹ (169, 354, 365). Expression of this
Na⫹/Ca2⫹ exchanger in RPE cells gives these cells a
comparable transport efficiency to cells like myocardial
cells, which are dependent on fast and efficient termination of Ca2⫹ signals. RPE cells also express Ca2⫹-ATPase
that functions as a very efficient transport molecule to
terminate rises in intracellular free Ca2⫹ (299). In summary, the combination of specific Ca2⫹ channels, a Na⫹/
Ca2⫹ exchanger, and the Ca2⫹-ATPase enables RPE cells
to generate fast and very distinctive intracellular Ca2⫹
signals as second messenger.
865
866
OLAF STRAUSS
This article would not have been possible without the help,
scientific input, and stimulating fruitful discussions with Catherine Bowes Rickman, Andreas Reichenbach, Silvia Finnemann,
Subratha Tripathi, Sönke Wimmers, and Mike Karl. I thank
Claudia Nickels for the editorial help and Armin J. Wulf for
providing Figure 1.
This work is supported by Deutsche Forschungsgemeinschaft Grants STR 480/8 –2 and STR 480/9 –1.
Address for reprint requests and other correspondence: O.
Strauss, Bereich Experimentelle Ophthalmologie, Klinik und Poliklinik fuer Augenheilkunde, Universitaetsklinikum HamburgEppendorf, Martinistrasse 52, 20246 Hamburg, Germany (E-mail:
[email protected]).
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which retinal cycles between photoreceptors and the
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