Diabetic Retinopathy Pathophysiology

Article initiated by: Mário Lima Fontes

All authors and Manuel Falcão, Vítor Rosas, Fernando Falcão-Reis, Mário Lima Fontes, Robert A Hyde, MD, PhD, Jennifer I Lim MD, Neil
contributors: Sheth, MD, MBA

Assigned editor: Robert A Hyde, MD, PhD

Review: Assigned status Update Pending

 by Robert A Hyde, MD, PhD on February 8, 2022.

Contents
1 Introduction
1.1 Mechanisms of Diabetic Retinopathy Subtypes
1.1.1 NPDR
1.1.2 DME
1.1.3 PDR
2 Pathological Processes
2.1 Hyperglycemia and the regulation of metabolic pathways
2.1.1 The Polyol Pathway
2.1.2 AGEs Formation
2.1.3 PKC Activation
2.1.4 Hexosamine Pathway Flux
2.1.5 Poly(ADP-Ribose) Polymerase Activation
2.2 Oxidative stress
2.3 Inflammation
2.4 Vascular abnormalities and angiogenesis pathways
2.5 Retinal neurodegeneration
3 Conclusions
4 References

Introduction
Pathological Processes
Hyperglycemia and the regulation of metabolic pathways
Chronic hyperglycemia is the key promotor for the development and progression of DR due to its tissue-damaging effects, as described in the UKPDS[12] and
DCCT[13] trials. However, genetic factors may play a role in individual susceptibility to those effects and other clinical factors like hypertension, dyslipidemia
and pregnancy have also been implicated.[2] [3][14]

Hyperglycemia leads to the activation of alternative pathways of glucose metabolism[1] such as the polyol pathway, advanced glycation endproducts (AGEs)
formation, protein kinase C (PKC) activation, hexosamine pathway flux and Poly(ADP-ribose) polymerase activation.[15] The end result of these pathways is the
activation of cytokines and growth factors, leading to vascular endothelial dysfunction, increased vascular permeability, and eventual microvascular
occlusion.[1] Microvascular occlusion then leads to retinal ischemia, which promotes neovascularization and the formation of IRMAs.[1]

The Polyol Pathway

Excess glucose is metabolized via the polyol pathway to sorbitol.[16] Sorbitol is impermeable to cellular membranes, accumulating inside the cell and inducing
osmotic damage.[17] [18] It can also be metabolized to fructose and subsequently to fructose-3-phosphate and deoxyglucosone, both of which are strong
glycolyzing agents and lead to the deposition of AGEs.[16] In addition, upregulation of the polyol pathway results in a reduced availability of NADPH, thereby
enhancing the sensitivity of affected cells to oxidative stress.[19]

AGEs Formation
Due to the high availability of glucose, AGEs formation is markedly increased in diabetic patients.[20] AGEs have the capacity to cross-link proteins which alters
their structure and function, affecting basement membranes, cellular receptors, and blood vessel wall components. Moreover, AGEs receptors activation
induces prooxidant and pro-inflammatory cascades, thus exacerbating oxidative stress and leukocyte adhesion.[21] The accumulation of AGEs has also been
[22]
correlated to pericyte loss.[22]

PKC Activation
An increase in glycolysis activity also occurs during hyperglycemic episodes, elevating the synthesis of diacylglycerol (DAG) which in turn activates the PKC
pathway.[23] PKC activates the mitogen-activated protein kinase (MAPK) factors, leading to enhanced expression of stress-related proteins and mediators of
vascular function such as c-Jun kinases and heat shock proteins.[24] In particular, the PKC-β isoform increases VEGF expression.[25] PKC activation also drives
over-expression of NADPH oxidase and NFκB in vascular cells, exacerbating oxidative stress and inflammation.[26]

Hexosamine Pathway Flux

In the hexosamine pathway, fructose-6-phosphate (F6P) is converted into uridine-5-diphospho-N-acetylgalactosamine (UDP-GlcNAc).[27] O-GlcNAc
transferase (OGT) catalyzes the addition of GlcNAc to serine and threonine residues at phosphorylation sites on SP1, upregulating its transcriptional activity
and consequently the expression of transforming growth factor beta (TGFβ) and plasminogen activator inhibitor-1 (PAI-1) in vascular cells.[28] The
glycosylation of RNA polymerase-II transcription factors by OGT and UDP-GlcNAc affects the expression of multiple factors involved in DR pathophysiology,
representing a key regulatory mechanism of glucose-responsive gene transcription.[29]

Poly(ADP-Ribose) Polymerase Activation

Hyperglycemia-induced oxidative stress correlates to increased poly(ADP-ribose) polymerase (PARP) activation. The formation of ROS leads to NAD+
depletion and inhibition of glyceraldehyde phosphate dehydrogenase (GAPDH) through the depletion of the enzyme’s catalytic cofactor and PARP-mediated
ribosylation. In conjunction, these molecular mechanisms contribute to DNA damage and endothelial cell dysfunction in diabetic blood vessels.[30][31]

Oxidative stress
Several signaling pathways can be altered by having hyperglycemia in different tissues, which produces oxidative stress. Hyperglycemia activates a particular
pathway involving diacylglycerol (DAG), the activation of protein kinase C (PKC), and the NADPH-oxidase system. This particular signaling pathway is involved
in the control of angiogenesis, oxidative stress, and cell death.[32]

Inflammation
Increasing evidence points to inflammation as a key factor in the pathogenesis of DR, although the exact molecular mechanisms are not well understood. The
simultaneous course of multiple metabolic pathways, such as oxidative stress, AGEs, and increased VEGF expression all likely contribute to the inflammatory
response.[33] Chronic low-grade inflammation is a key driver of capillary occlusion and hypoxia that reinforces VEGF expression and concomitant hallmark
vascular abnormalities of DR.

Inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-8 and IL-1 were significantly up-regulated in diabetic patients, and
their expression level is correlated with the severity of DR.[34] [35] Leukostasis has been associated with occlusion of retinal microvasculature and is correlated
with endothelium damage and BRB impairment in diabetic rats, contributing to endothelial cell loss and breakdown of BRB.[36] [37]

Retinal glial cell dysfunction is also presumed to be involved in inflammation in DR. Under hyperglycemic stress, microglia activation increases secretion of
TNF-α, IL-6, MCP-1 and VEGF.[38] Numerous studies show that inflammation inhibition by using anti-inflammatory drugs such as intravitreal triamcinolone
acetonide and NSAIDs like nepafenac reduces VEGF expression and vascular permeability, inhibits retinal cell death, diminishes leukostasis, and ultimately
improves visual acuity.[39] [40] [41]

Vascular abnormalities and angiogenesis pathways

Hyperglycemia causes pericyte loss, apoptosis of endothelial cells and thickening of the basement membrane, which collectively contribute to the impairment
of the BRB.[42] Since pericytes are responsible for providing structural support for capillaries, their loss leads to microaneurysm formation.[43] Furthermore,
pronounced loss of pericytes and endothelial cells results in capillary occlusion and ischemia. Retinal ischemia/hypoxia leads to upregulation of VEGF through
activation of hypoxia-inducible factor 1 (HIF-1).[44]

Retinal neurodegeneration
Neural retina cells are also affected in DR pathophysiology. In fact, retinal neurodegeneration is an early event during the progression of DR that may even
precede vascular apoptosis. Upregulation of pro-apoptotic molecules has been detected in retinal neurons in diabetic animals and humans.[45] [46] [47]
Oxidative stress seems to be involved in the activation of these pathways.[48] Pro-apoptotic mitochondrial proteins such as cytochrome c and apoptosis-
inducing factor (AIF) were also found to be significantly increased, implicating mitochondrial dysfunction in retinal degeneration [47]In diabetic patients, inner
retinal thinning was detected with no DR or minimal DR.[49][50] This highlights the sensitivity of neuronal cell types to apoptotic stimuli such as oxidative stress
and mitochondrial dysfunction. Therefore, neuroprotective agents may play a role in preventing retinal neurodegeneration in early stages of DR.[51] Neuronal
and vascular cells interact with each other to regulate blood flow in the retina via an autonomic independent mechanism. New evidence shows that this
interaction is uncoupled in DR .[52]

Conclusions
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