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Lechner 2017
Lechner 2017
Lechner 2017
Vision Research
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a r t i c l e i n f o a b s t r a c t
Article history: This review summarizes the pathological features of diabetic retinopathy. The lesions occurring in the
Received 14 March 2017 diabetic retina have been described over many decades using descriptive and experimental approaches
Received in revised form 4 April 2017 based on clinical studies on patients, human post-mortem material, animal models and various
Accepted 4 April 2017
in vitro systems. We have also accumulated a wealth of knowledge about basic molecular mechanisms
Available online xxxx
and key pathogenic processes that drive these abnormalities in diabetic retina. Despite these advances,
there are still limited therapeutic options for diabetic retinopathy with those currently available only
Keywords:
addressing late-stage disease. With a particular focus on the earlier stages of diabetes, there is growing
Diabetic retinopathy
Pathology
appreciation the complex neuronal, glial and microvascular abnormalities which progressively disrupt
Neurovascular unit retinal function. This is especially true from the perspective of the neurovascular unit during health
Microvascular and disease. Based on a strong appreciation of cellular and molecular pathology that underpins diabetic
retinopathy, further advances are anticipated as we drive towards development of efficacious therapeutic
options that can address all stages of disease.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Basic retinal neuronal structure and its oxygenation 2. Maintenance of retinal homeostasis by the vasculature
The human retina consists of three layers of nerve cell bodies Retinal capillaries are the key interface for exchange of nutri-
interspaced by two plexiform layers of synapses. Rod and cone ents, oxygen and metabolites between the neuropile and the circu-
photoreceptor cell bodies are located in the outer nuclear layer, lation. They are composed of non-fenestrated endothelial cells
bipolar, horizontal and amacrine cells are found in the inner surrounded by supporting pericytes and glial endfeet. Cell-cell
nuclear layer and ganglion cell bodies and displaced amacrine cells communication in the capillary unit is achieved via gap junctions
form the ganglion cell layer. Photoreceptor cells connect to second or through their shared basement membrane (BM). Together these
order neurons, primarily bipolar and horizontal cells, and second component cells regulate blood flow to compensate for changes in
order neurons connect to ganglion cells in the inner plexiform retinal oxygenation and ocular perfusion pressure (Flammer &
layer. Ganglion cell axons form the nerve fibre layer which trans- Mozaffarieh, 2008). While the choriocapillaris is under the influ-
ports the visual signal through the optic nerve to the visual cortex ence of autonomic innervation from sympathetic nerves, the
in the brain. The retina has exceptionally high metabolic demands intra-retinal vasculature is autoregulated in response to metabolic
with neural function being dependent on the constant availability demands of the neurons (a phenomenon known as neurovascular
of oxygen and nutrients. Therefore, two vascular beds nourish the coupling) (Kur, Newman, & Chan-Ling, 2012). Autoregulation
retinal neuropile, each with distinct anatomy and function. Lying ensures a constant retinal blood flow and ensures that delivery
beneath Bruch’s membrane, the choriocapillaris is a dense network of oxygen and nutrients matches the activity of defined regions
of highly fenestrated capillaries derived from the posterior ciliary of the neural retina. For instance, light to dark transition as well
artery which oxygenates the outer retina. The intra-retinal vascu- as light stimulation in certain areas of the retina results dynamic
lature is an end-artery, multi-layered capillary network perfusing changes to vessel diameter and blood flow (Kur et al., 2012).
the inner retina. Oxygen distribution varies across the retina and this corre-
sponds to the consumption rates of different cell-types. For exam-
ple, the photoreceptors have very high oxygen demands and thus
the highest levels of oxygenation occurs in the choroid (Caprara
⇑ Corresponding author at: McCauley Chair of Experimental Ophthalmology,
& Grimm, 2012). Photoreceptors remain depolarised in the absence
Centre for Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road,
Belfast BT9 7AE, Northern Ireland, UK.
of light and maintenance of the ‘‘dark current” requires the activity
E-mail address: a.stitt@qub.ac.uk (A.W. Stitt). of energy-consuming Na+-K+ ATPase pumps (de Gooyer et al.,
http://dx.doi.org/10.1016/j.visres.2017.04.003
0042-6989/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lechner, J., et al. The pathology associated with diabetic retinopathy. Vision Research (2017), http://dx.doi.org/10.1016/j.
visres.2017.04.003
2 J. Lechner et al. / Vision Research xxx (2017) xxx–xxx
Fig. 1. Clinical and histological perspective on diabetic retinopathy. A: Fundus photograph of the right eye of a patient with NPDR and central involvement clinically
significant macular edema. Exudates from the vasculature are observed around the foveal centre. B: Trypsin digest retinal specimen of a type-2 diabetic patient with NPDR
stained with PAS-haematoxylin (image courtesy of Dr Tom Gardiner, Queen’s University Belfast). A centrally placed radial artery is flanked above and below by retinal veins
and the intervening capillary beds. Numerous microaneurysms stain strongly with PAS and show a predominantly peri-arterial distribution (arrows).
Please cite this article in press as: Lechner, J., et al. The pathology associated with diabetic retinopathy. Vision Research (2017), http://dx.doi.org/10.1016/j.
visres.2017.04.003
J. Lechner et al. / Vision Research xxx (2017) xxx–xxx 3
in association with altered ion homeostasis in Müller cells. The health. Likewise, their activation in disease scenarios can evoke
macula is particularly susceptible to fluid accumulation that can profound changes to the normal function of the retina.
lead to edematous pathology (Ford et al., 2013). DME is commonly
associated with later stages of diabetic retinopathy and is observed
6. Key pathologies associated with the neurovascular unit
and quantified using Optical Coherence Tomography (OCT) which
can be used to non-invasively monitor retinal thickness and pro-
While diabetic retinopathy has been commonly considered as a
gression of edema. DME is traditionally classified as either focal
disease of the microvasculature, there is robust evidence showing
edema, with leakage associated with discrete areas of microa-
that dysfunctional neurovascular crosstalk plays a critical role in
neurysms and hard exudates, and diffuse edema, with leakage
this complication (Moran et al., 2016).
originating from dilated capillaries and IRMAs.
Please cite this article in press as: Lechner, J., et al. The pathology associated with diabetic retinopathy. Vision Research (2017), http://dx.doi.org/10.1016/j.
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Fig. 2. Capillary and glial changes during diabetic retinopathy. Transmission electron micrograph showing a typical normal retinal capillary (A) composed of an endothelial
cell (E) and pericyte (P) surrounded by BM (arrows). In a diabetic rat, the BM is thickened (arrows) (B). Acellular capillaries can be detected in diabetic rats using
immunofluorescent staining (green) (arrow, C) showing the persistence of the BM tube (Red, Collagen IV positive) but absence of Isolectin B4-positive endothelial cells (C). In
} ller cell activation can be detected
sections of non-diabetic rat retina, GFAP staining is limited to the astrocyte cells in the nerve fibre layer (E) however in diabetic animals Mu
as GFAP-positive across the whole inner retina (F). Red: GFAP, Blue: DAPI.
of this intermediate filament protein in Müller cells (Hammes, defect is reflected in the oscillatory potential implicit time (influ-
Federoff, & Brownlee, 1995; Mizutani, Gerhardinger, & Lorenzi, enced by the electrophysiological communication between the
1998). Indeed, Müller cell dysfunction is a consistent feature of dia- amacrine cells and the bipolar cells with interactions from gan-
betic retinopathy in animal models and is critical to dysfunction of glion cells to amacrine cells) (Tzekov & Arden, 1999). These
the neurovascular unit. For example, the capillary - Müller cell changes are important signposts to neural dysfunction as the dis-
interface becomes disrupted during diabetes (Biedermann et al., ease progresses (Bearse et al., 2006). The overall importance of
2004) as exemplified by changes to the inwardly rectifying chan- neuronal and glial dysfunction has led to a proposed ‘‘feed-
nels. In particular, the Kir4.1 channel in Müller cell end-feet at forward” hypothesis in which dysfunction in neural cells con-
the capillary interface is mislocalised in diabetic retina and this tributes to breakdown of the BRB which, in turn, promotes an
contributes to impaired water regulation and disruption of the iBRB inflammatory and oxidative environment that perpetuates vascu-
(Pannicke et al., 2006). Dysregulation of Kir4.1 and aquaporins on lar dysfunction (Antonetti et al., 2006).
Müller cells have been widely reported in diabetic animal models Overt degeneration of retinal neurons during diabetes is a con-
(Berner et al., 2012; Curtis et al., 2011; Vacca et al., 2014) which cept that was first described in the 1960s in post-mortem patient
may precede death of these glia which further exacerbates loss of samples. By the late 1990s experimental evidence reinforced this
normal retinal neuronal and vascular integrity. finding by demonstrating that depletion of some neuronal popula-
tions occured in diabetic rodent models, possibly even prior to
6.3. Neuronal pathology appearance of obvious microvascular lesions (Barber et al., 1998;
Reiter & Gardner, 2003). Histologically, apoptosis of the retinal
Compromise of the neural retina during diabetes can be demon- ganglion cells (RGCs) may be the initial losses observed in the
strated using electroretinography (ERG) and the most consistent diabetic retina. This may account for the reduced thickness of the
Please cite this article in press as: Lechner, J., et al. The pathology associated with diabetic retinopathy. Vision Research (2017), http://dx.doi.org/10.1016/j.
visres.2017.04.003
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retinal nerve fibre layer that has been detected in diabetic patients
without retinopathy or with only background disease
(Araszkiewicz et al., 2012; van Dijk et al., 2012). As reinforcing evi-
dence, several rodent models of diabetes have demonstrated apop-
tosis of RGCs as early as 5 (rat) or 10 (mouse) weeks after the onset
of hyperglycaemia (Kusari, Zhou, Padillo, Clarke, & Gil, 2007). In the
db/db type-two diabetic (T2D) mouse model, RGC apoptosis and
ERG deficits (reduction in OP and b-wave amplitudes) have been
reported, concurrent with evidence of retinal glutamate excitotox-
icity (Bogdanov et al., 2014). A growing body of evidence indicates
that hyperglycaemia-induced downregulation of a number of
important neurotrophic factors such as NGF, PEDF, IRBP and
somatostatin may have a central role in contributing to, or indeed
initiate, neuronal apoptosis and capillary dropout, In-depth discus-
sion of this experimental evidence is beyond the scope of this
review and is provided elsewhere (Simo & Hernandez, 2015).
Please cite this article in press as: Lechner, J., et al. The pathology associated with diabetic retinopathy. Vision Research (2017), http://dx.doi.org/10.1016/j.
visres.2017.04.003
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Fig. 4. Schematic overview of pathogenic mechanisms leading to the sight-threatening endpoints of DR. DR arises through a complex interplay between neuroglial and
vascular damage that results from hyperglycaemia-induced metabolic stress. From the microvascular perspective, hypoperfusion early in the disease due to loss of the cells
making up the endothelium ultimately leads to compensatory growth of new fragile and leaky blood vessels. Compromise of BRB integrity leads to the extravasation of fluid
and inflammatory mediators, creating sight threatening edema and exacerbating inflammatory conditions. Concurrent or preceding neuroglial dysfunction perpetuates
damage.
Please cite this article in press as: Lechner, J., et al. The pathology associated with diabetic retinopathy. Vision Research (2017), http://dx.doi.org/10.1016/j.
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