Molecular mechanisms of diabetic retinopathy: potential therapeutic targets.

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Diabetic Retinopathy Update Molecular Mechanisms of Diabetic Retinopathy: Potential Therapeutic Targets Maha Coucha1,2,3, Sally L. Elshaer1,2,3, Wael S. Eldahshan1,2,3, Barbara A. Mysona1,2,3, Azza B. El‑Remessy1,2,3

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ABSTRACT Diabetic retinopathy (DR) is the leading cause of blindness in working‑age adults in United States. Research indicates an association between oxidative stress and the development of diabetes complications. However, clinical trials with general antioxidants have failed to prove effective in diabetic patients. Mounting evidence from experimental studies that continue to elucidate the damaging effects of oxidative stress and inflammation in both vascular and neural retina suggest its critical role in the pathogenesis of DR. This review will outline the current management of DR as well as present potential experimental therapeutic interventions, focusing on molecules that link oxidative stress to inflammation to provide potential therapeutic targets for treatment or prevention of DR. Understanding the biochemical changes and the molecular events under diabetic conditions could provide new effective therapeutic tools to combat the disease.

Website: www.meajo.org DOI: 10.4103/0974-9233.154386 Quick Response Code:

Key words: Diabetic Retinopathy, Endoplasmic Reticulum‑stress, Nicotinamide Adenine Dinucleotide Phosphate Oxidase, Inflammation, Oxidative Stress, Peroxynitrite, Therapeutics

INTRODUCTION

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ver 29.1 million Americans, representing 9.3% of the population, had diabetes and over 86 million Americans age 20 and older had prediabetes.1 Diabetic retinopathy (DR), the most‑feared complication of diabetes mellitus, is the most frequent cause of new cases of blindness (28.5%) among adults aged 20–74 years.1 In 2012, an estimated $245 billion was spent on the direct healthcare and indirect consequences of diabetes in the United States.2 As compared to type‑2 diabetic patients, individuals with type‑1 diabetics are at higher risk for development of more severe retinal complications and visual loss. However, type‑2 diabetic patients account for approximately 90% of the population with diabetes, and they comprise a larger proportion of those affected with DR.3 DR is clinically classified into nonproliferative and proliferative disease stages. In nonproliferative DR (NPDR), intraretinal microvascular changes occur including microaneur ysms, altered retinal vascular permeability and eventual retinal vessel

closure and nonperfusion.3‑5 PDR involves the formation of new blood vessels on the retina or the optic disk. These new abnormal blood vessels erupt through the surface of the retina and proliferate into the vitreous cavity of the eye, where they can hemorrhage into the vitreous, resulting in visual loss.6 In assessing and managing diabetes, and specifically retinopathy, a comprehensive approach is recommended: Improved preventative care, earlier diagnosis, intensive disease management, and the use of new medical interventions could significantly reduce the complications of this disease. This review will summarize our current update on understanding of the specific biochemical pathways involved in the pathogenesis of diabetes and the potential molecular therapeutic targets for DR.

CURRENT AND NEW THERAPEUTICS Laser treatment for DR was the first intraocular treatment to provide a highly effective means for preventing visual loss

Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, 2Culver Vision Discovery Institute, Georgia Regents University, 3Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia 1

Corresponding Author: Dr. Azza B. El‑Remessy, Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta 30912, Georgia. E‑mail: [email protected]

Middle East African Journal of Ophthalmology, Volume 22, Number 2, April - June 2015

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Coucha, et al.: Targets for Diabetic Retinopathy

in diabetic patients and it remains the standard of care.7 While laser treatment for PDR usually does not improve vision, the therapy is designed to prevent further vision loss. The laser treats leaking blood vessels directly by sealing the area of leakage (photocoagulation) or by eliminating abnormal newly formed blood vessels in the periphery of the retina that is not required for functional vision. The peripheral retina is thought to be involved in the formation of vascular endothelial growth factor (VEGF) responsible for abnormal blood vessel formation. This concept was further supported by recent animal studies of decreased hypoxia and improved retina function in mice with degenerated or chemically‑ablated photoreceptors.8,9 Laser photocoagulation, an invasive procedure has been shown to reduce progression of visual loss, but vision is rarely improved or restored. Thus, anti‑angiogenic therapy was used in attempt to improve vision in patients with diabetic macular edema (DME) as well as PDR.10

A N T I ‑V A S C U L A R E N D O T H E L I A L GROWTH FACTOR THERAPY IN DIABETIC RETINOPATHY Intravitreal injection of ranibizumab, an anti‑VEGF, was proven to be effective for managing DME. This finding was based on the results of “RISE” and “RIDE” trials that are two parallel, phase 3, multicenter, double‑masked, sham injection‑controlled, randomized studies. Participants who were adults with vision loss from DME received monthly injections of ranibizumab for 2‑year. Overall, ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in diabetic patients, with low rates of ocular and nonocular side effects.11 Of note, the strong visual acuity gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained till month 36.12 Results from phase 3 RISE and RIDE trials showed that ranibizumab injection reduced the percentage of patients with an increase in posterior retinal nonperfusion assessed by fluorescein angiograms.13,14 For PDR, intravitreal ranibizumab in combination with panretinal photocoagulation was shown to be effective in a randomized controlled clinical trial done on 30 patients, assessing best‑corrected visual acuity and optical coherence tomography.15 Of note, chronic anti‑VEGF therapy may cause hypertension as well as renal side effects including proteinuria and glomerular thrombotic microangiopathy with preexisting hypertension.16 However, the use of ranibizumab in “as ‑ needed” treatment regimen over a 5‑year period for controlling neovascular DME was not associated with serious ocular or systemic effects.17 The approval of anti‑VEGF as the first pharmacotherapy for DR opens the door to develop new therapeutics that target other growth factors or molecules that are identified to play a critical role in the pathogenesis of the disease. 136

OXIDATIVE STRESS AND INFLAMMATION IN THE DIABETIC RETINA The imbalance between the levels of reactive oxygen species (ROS) and the antioxidants mechanisms is a hallmark in the pathogenesis of various diseases such as hypertension, ischemic cardiovascular diseases and DR.18‑20 Several lines of evidence support increased oxidative stress as a main cause for retinal inflammation in diabetic patients.21 ROS plays a crucial role in mediating the inflammatory response via modifying various inflammatory genes expression. The retina is a unique organ with its high concentrations of polyunsaturated fatty acids and high oxygen demand. Human retina consumes oxygen 300–600% higher than the cerebral cortex and cardiac muscle, respectively.22 Therefore, the retina and its vasculature are more susceptible to oxidative stress. Ample evidence from animal models as well as in clinical specimens supported the role of oxidative stress in the development and the progression of DR.23,24 However, in spite of overwhelming evidence supporting the damaging consequences of oxidative stress and its established role in experimental models of diabetes, the results of large‑scale clinical trials with general antioxidants have failed to show significant benefits for diabetic patients.25,26 The failure of the general and nonselective antioxidants triggered research to identify the specific sources of oxidative stress and how it can be linked to the specific pathology in diabetes. In the next section, we will summarize the current understanding of how diabetes induces oxidative stress in the retina and the possible therapeutic strategies for preventing the progression of DR.

NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE AND DIABETIC RETINOPATHY Reactive oxygen species is produced by various pathways including, the mitochondrial electron transport chain, xanthine oxidase, and uncoupled nitric oxide synthases.27 In addition protein kinase C (PKC) activation, hexosamine, polyol pathway and formation of advanced glycation end products (AGEs) can contribute to oxidative stress by reducing the activities or levels of antioxidant enzymes.28 Several studies have focused on determining the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs) in DR pathogenesis, given that their primary function is the production of superoxide anion that might give rise to peroxynitrite formation [Figure 1]. In the following section, we summarize what is known about the role of the Nox family in DR in relative to their specific retinal expression profile. Nicotinamide adenine dinucleotide phosphate oxidase catalyzes the transfer of electrons across biological membranes from NADPH to produce superoxide anion. In addition to the phagocytic Nox2/gp‑91 phox, six homologs of the cytochrome




angiogenesis39 and blood‑retinal barrier breakdown.40 Recently, photoreceptors were also shown to express Nox4 in response to stress in a living retinal explants.41 Taken together, these findings suggest that Nox 4 plays an important role in ROS production.

Figure 1: Schematic representation of the possible molecular pathways by which diabetes/high glucose induce generation of superoxide anion including nicotinamide adenine dinucleotide phosphate oxidase, mitochondrial oxidase, receptor for advanced glycation end products, protein kinase C, polylol, hexosamine pathway. Nitric oxide is generated by nitric oxide synthase to form the oxidant peroxynitrite and inhibit the thioredoxin (Trx) antioxidant defense resulting in increases in Trx interacting protein (TXNIP). Increases in TXNIP and endoplasmic reticulumstress have been linked to activation of proinflammatory cytokine production and development of diabetic retinopathy

subunits were discovered including: Nox1, Nox3, Nox4, Nox5, DUOX1, and DUOX2. Together, they are all known as the Nox family.29‑31 Experimental studies previously demonstrated the contribution of Nox to retinal neurovascular changes, which are hallmarks of DR. Treating rats with apocynin; a Nox inhibitor; nullified the retinal leukostasis mediated by intravitreal injection of angiotensin II in diabetic rats.32 These findings were consistent with studies that showed the involvement of Nox in retinal inflammation and the reduction of leukocyte adhesion and vascular permeability by inhibition of Nox.33 Ample of evidence supported the role of Nox2 in the vascular pathology of DR.34,35 Al‑Shabrawey et al. previously reported an up‑regulation in Nox2 expression and activity in diabetic mice and retinal endothelial cells treated with high glucose. In addition, they showed that inhibiting Nox or deleting Nox2 normalized ROS production and prevented retinal vascular injury.33,36,37 Similar findings were reported using human endothelial progenitor cells (EPCs). They found an increase in superoxide levels in EPC isolated from diabetic individuals, which was associated with an increase in Nox2 expression and activity. In addition, inhibiting Nox with apocynin or gp91 ds tat peptide enhanced blood vessel repair,38 emphasizing the role of Nox system in accelerating vascular dysfunction in diabetes. Nox4 is the most prevalent isoform in human retinal microvascular endothelial cells.39 Therefore, Nox4 is considered a promising therapeutic target to ameliorate vascular injury in DR. Several studies reported an association between increased Nox4 activity and various neurovascular features of DR including: Pathologic

The mRNA and the protein expressions of Nox1,2 and 4 were reported in primary retinal ganglion cells (RGCs) under normal conditions. However, exposing RGC to oxygen glucose deprivation led to the up‑regulation of Nox1 alone. Similar results were found in vivo after inducing unilateral retinal ischemia in mice.42 In an animal model of retinopathy of prematurity, knocking down Nox1 isoform reduced retinal neovascularization, retinal vascular leakage, avascular retina and vascular adherence of leukocytes.43 Taken together these findings provide evidence that Nox1 could be a therapeutic target in other neovascular ischemic retinopathies as DR. Nox5 expression and its role in DR have not been examined due to its absence from rodents.30 However, Nox5 expression has been reported in other species including human retina, bovine retinal endothelial cells and pericytes,43 indicating that Nox5 may be relevant to retinal vascular pathology. Clearly, there is differential expression of Nox isoforms throughout the retina,31 suggesting various roles of the different isoforms. Therefore, the targeted use of antioxidant is an important therapeutic strategy to achieve optimum levels of ROS required for correcting the pathology of DR without impairing the physiological retinal processes.

P E R OX Y N I T R I T E A N D N I T R AT I V E STRESS IN DIABETIC RETINOPATHY Mounting evidence supports the association of DR with increased nitrosative stress and peroxynitrite formation.44‑47 Peroxynitrite is a powerful oxidizing and nitrating agent, which results from the interaction of nitric oxide with the superoxide free radical. Increased nitrotyrosine levels; a detectable marker of peroxynitrite generation; were reported in retinas from diabetic animals44,48 and patients.49 Increased peroxynitrite generation contributes to DR via initiating various pathological processes including: (1) Decreased nitric oxide bioavailability (2) increased retinal vascular permeability46,50,51 (3) reduced endothelial and neuronal cell survival52‑54 and (4) retinal inflammation.50 Several studies have examined the therapeutic impact of inhibiting nitration during diabetes. Our group previously showed that peroxynitrite inhibits PI3 kinase/Akt survival pathway via inducing tyrosine nitration of p85 kinase in an ischemic retinopathy mouse model55 as well as in response to high glucose model.56 preventing nitration with epicatechin; a selective nitration inhibitor, which lacks antioxidant effects prevented retinal apoptosis, restored survival signal and reduced vaso‑obliteration. We showed that peroxynitrite‑mediated nitration of tyrosine kinase receptor A (TrKA), the survival receptor for the nerve growth factor (NGF) was associated with the inhibition of the prosurvival


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signaling and retinal neurodegeneration.49 Treatment of diabetic animals with FeTPPS; a selective peroxynitrite decomposition catalyst or the nitration inhibitor epicatechin restored survival signal and prevented retinal neuronal cell death.49,57,58 A recent study showed that tyrosine nitration of prostacyclin synthase was accompanied with increased retinal cell death in diabetic mice.59 Treatment with tempol, a superoxide scavenger reduced nitrotyrosine levels and prevented retinal apoptosis59 and vascular permeability in vivo.60

THIOREDOXIN INTERACTING PROTEIN LINKS OXIDATIVE STRESS TO INFLAMMATION Inflammation is the response of the body to pathogens, and it is prerequisite for tissue regeneration. Multiple studies using patient samples and various animal models confirmed the contribution of the inflammatory response in DR.21,61 Treatment with various anti‑inflammatory agents significantly slowed the progression of DR. However, how inflammation is generated in DR in the absence of pathogens is still unclear. Amelioration of oxidative stress is mediated via multiple antioxidants including the main thiol‑dependent thioredoxin (Trx) and glutathione‑glutaredoxin (Grxs) systems. Recent evidence suggests that Grxs acts as the backup of Trx system (reviewed in).62,63 The Trx system includes Trx, Trx reductase (TrxR) and Trx interacting protein (TXNIP). Trx is a multifunctional protein that binds to apoptosis signal– regulating kinase 1 (ASK1), leading to ASK1 inhibition and in turn the ASK1-dependent apoptosis. In addition, Trx is an oxidoreductase that controls cellular ROS through enhancing the reduction of various proteins by cysteine‑thiol disulfide exchange. TXNIP tightly regulates Trx activity via binding to Trx and limiting its ability to bind to other proteins. Therefore, TXNIP has been considered the physiological inhibitor of Trx, which regulates its expression and activity. Prior evidence showed the induction of TXNIP expression by high glucose and diabetes in neurons,64 renal65 and various retinal cells.66‑68 Studies by Singh group demonstrated that TXNIP contributes to the development and progression of DR via induction of retinal inflammation, fibrosis/gliosis and neurovascular injury.66‑68 They also showed that silencing TXNIP in vivo abolished diabetes‑induced retinal inflammation. In agreement with the aforementioned studies, we previously showed that TXNIP plays a critical role in augmenting retinal oxidative and inflammatory response in models of neurotoxicity,69,70 as well as high fat diet‑induced pre‑DR.71 TXNIP has been linked to inflammation both at transcriptional and posttranscriptional levels. At transcriptional levels, TXNIP results in activation of nuclear factor κB (NFκB) pathway, which leads to proinflammatory cytokine expression.66,69 At posttranscriptional levels, TXNIP acts as a direct activator of nod‑like receptor protein 3‑inflammasome, which is a 138

component of the innate immune system responsible for initiating the inflammatory response (reviewed in).62 Therefore, TXNIP is considered a promising therapeutic target in mitigating retinal inflammation during DR. Interestingly, we showed that TXNIP is essential for angiogenic response both in vivo and in vitro.72 In addition, in an animal model of oxygen‑induced retinopathy, we found that knocking down TXNIP resulted in activation of the apoptotic ASK1 signal, leading to exacerbated vaso‑obliteration.73 These results highlight the crucial role of TXNIP in regulating the homeostasis of Trx system. Based on literature, early modulation but not complete elimination of TXNIP expression is a promising therapeutic strategy for DR management.

PROINFLAMMATORY ROLE OF OXIDATIVE STRESS IN NEUROTROPHIN SYSTEM Changes in level of the NGF have been previously assessed in diabetic patients in relation to DR and neuropathy.74‑76 Our group previously showed that increased peroxynitrite generation in diabetic human and rat retinas impaired the NGF survival signal. NGF is usually released as the proform, proNGF, which is cleaved intracellularly by furins and extracellularly by several proteases including matrix metalloproteinases (MMPs‑7).57,77 Our group has identified diabetes‑induced peroxynitrite formation can impair MMP‑7 activity resulting in accumulation of proNGF at the expense of mature NGF in experimental and clinical PDR. 20,57 ProNGF binds favorably to p75 neurotrophin receptor (p75NTR), which in combination with its co‑receptor sortilin, generally activates inflammatory and apoptotic pathways (reviewed in).78,79 We and others have shown that overexpressing proNGF induced activation of NFκB and expression of tumor necrosis factor alpha (TNF‑α) and interleukin‑1β (IL‑1β) in rodent retina as well as in Müller glial cell treated with proNGF.80‑82 The proinflammatory response of proNGF was ameliorated by inhibiting its receptor; p75NTR. The proinflammatory role of proNGF in activated microglia has been documented also in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.83 It is not surprising that treatments that target peroxynitrite and oxidative stress were able to restore the balance between proNGF and NGF that coincided with decreases in retinal inflammation, vascular permeability, and neurodegeneration.57,58,80,81,84 These results support the notion that oxidative stress plays a critical role in driving proinflammatory pathway by favoring accumulation of proNGF in diabetic patients.

ENDOPLASMIC RETICULUM‑STRESS AND DIABETIC RETINOPATHY The endoplasmic reticulum (ER) is a multifunctional intracellular organelle. It is essential for the synthesis, folding and trafficking of proteins. Therefore, ER‑stress is involved in various disorders




including neurodegenerative diseases and diabetes.85,86 ER‑stress results from the disturbance in the folding capacity of the ER causing an accumulation of unfolded protein in the lumen of ER. ER‑stress activates the unfolded protein response (UPR), which is initiated by the three ER‑stress transducers: Protein kinase RNA‑like ER kinase, inositol‑requiring enzyme‑1, and activating transcription factor 6. These proteins act to reestablish the ER homeostasis via: (1) Reducing protein synthesis and translocation into the ER, (2) enhancing the ability of ER to handle the unfolded protein, and (3) by increasing the clearance of the misfolded protein from the ER. However, programmed cell death occurs upon the failure of UPR to resolve the ER‑stress reviewed in.87‑90 In addition, ER‑stress contributes to increased oxidative stress and inflammatory response.87-90 It is well‑documented that the ER‑stress is involved in retinal neurodegeneration and vascular damage in various ocular disorders.91 Zhong et al. previously reported that hyperglycemia induces ER‑stress in retinal Muller cells both in vitro and in vivo. These effects were associated with induction of inflammatory gene expression as intercellular adhesion molecule‑1 and VEGF. Interestingly, they showed that periocular injection of the chemical chaperone 4‑phenyl butyric acid; an ER‑stress inhibitor; reduced retinal VEGF expression and vascular permeability in diabetic mice.92 Consistent with the aforementioned study, another study reported an increase in the proinflammatory factors in the retina of the animal model of type‑1 diabetes, and human retinal microvascular endothelial cells after exposure to hypoxia.93 Inhibiting ER‑stress mitigated the proinflammatory factors expression both in vivo and in vitro. In a follow‑up study, the authors examined the impact of ER‑stress preconditioning on retinal inflammation. Interestingly, the results showed that diabetic rats treated systemically with tauroursodeoxycholic acid; an ER‑stress modulator; were protected from neuronal death and vascular abnormalities.94 Recently, it has been shown that intravitreous injection of tunicamycin; an ER-stress inducer; led to an up‑regulation of VEGF expression, which was associated with an increase in vascular permeability.95 In addition, low doses of tunicamycin; were able to increase cell proliferation and migration in human retinal endothelial cells. However, high doses of tunicamycin led to severe ER‑stress and hence apoptotic cell death.96 In agreement with the in vitro results, treatment with tunicamycin enhanced retinal neovascularization in an animal model of oxygen‑induced retinopathy. These findings suggest the contribution of ER‑stress in the formation of leaky vessels and the abnormal vasculature in ischemic retinal diseases. Interestingly, a recent study demonstrated that intermittent high glucose led to ER‑stress enhancement in human retinal pericytes, which was accompanied with an increase in inflammatory mediators.97 These findings highlight the detrimental role of ER‑stress in retinal inflammation after episodes of poor glycemic

control. Together, these studies support the contribution of ER‑stress to retinal inflammation and vascular impairment in DR. Therefore, modifying ER‑stress to favor adaptive response rather than detrimental response in the pathogenesis of DR is of clinical interest.

PROTEIN KINASE C Protein kinase C family, including eight isozymes, is ubiquitously expressed in many cell types and has distinct signaling roles in both health and disease including DR (reviewed in).98 In particular, two PKC isozymes, PKCδ and PKCβ, have been implicated in the pathogenesis of diabetes. PKCδ plays a role in diabetes by influencing beta‑islet cell function and insulin resistance, it is PKCβ that plays an important role in diabetic microvascular complications.99 In diabetes, hyperglycemia induces elevated levels of diacyl glycerol that results in increased activation of PKCβ. Abnormal PKCβ signaling plays a role in cytokine activation and inhibition, vascular alterations, abnormal angiogenesis associated with diabetic microvascular complications.100 Increased activation of PKCβ occurs in retinal endothelial cells exposed to high glucose as well as in retinas of diabetic animals (reviewed in).101 The multiple effects of elevated PKCβ signaling, suggest that it may be a promising therapeutic target for DR. Experimentally, inhibiting PKC using both intravitreal and oral administration of the specific PKCβ inhibitor ruboxistaurin as well as the general PKC inhibitor GF109203X prevented retinal vascular permeability.100 In addition, ruboxistaurin was well tolerated and had no adverse effects in a multicenter, randomized, placebo‑controlled clinical trial (PKC‑Diabetic Retinopathy Study) in subjects with moderately severe to a very severe NPDR.102 However, while ruboxistaurin treatment was found to improve visual acuity in patients with DME, clinical trials showed that it did not reduce or reverse the progression of DME or prevent the development of PDR. The fact that the FDA‑approved primary endpoint was not altered by ruboxistaurin, resulted in a failure to have the drug approved for marketing for the treatment of DR.102

HEXOSAMINE BIOSYNTHESIS PATHWAY Recent studies suggest that the metabolism of glucose through the hexosamine biosynthesis pathway (HBP) is responsible in part for insulin resistance and DR.103 After entering the cell, glucose is converted to glucose‑6‑phosphate that is in turn converted to fructose‑6‑phosphate. Under euglycemia, only small fraction of glucose is metabolized through HBP, while, in hyperglycemia, HBP is highly activated in order to consume excess fructose 6‑phosphate formed.104 The first and the rate‑limiting step of HBP is the conversion of fructose‑6‑phosphate to N‑acetylglucosamine‑6‑phosphate by glutamine fructose‑6‑phosphate amidotransferase.105 Ultimately, the flux of glucose through the HBP leads to the formation of


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uridine diphosphate N‑acetylglucosamine (GlcNAc) which is a substrate for O‑linked glycosylation of serine and threonine residues of a number of proteins leading to changes in gene expression and protein function which adversely affect the retina.28,106 Therefore, HBP is a viable target for the treatment of DR. A prior study showed protective effects of inhibiting HBP using benfotiamine that acts by converting fructose‑6‑phosphate to pentose‑5‑phosphates.107 Recent studies demonstrated increased O‑GlcN acylation in retina vasculature that impaired migration of retinal pericytes108 and pericyte apoptosis in diabetes.109 Another study correlated O‑GlcNAc glycosylation to the detrimental effects of hypoxia and hyperglycemia in a model of DR.110

POLYOL PATHWAY Another pathway contributing to DR is the polyol pathway in which aldose reductase reduces glucose into sorbitol using NADPH as a cofactor and sorbitol is converted to fructose by the action of sorbitol dehydrogenase and NAD+ as a cofactor.111,112 Under euglycemic conditions, sorbitol level is low, while, during hyperglycemia, sorbitol level increases due to the flux of glucose through the polyol pathway.113 Sorbitol accumulation in tissues such as the retina causes osmotic damage as sorbitol cannot readily diffuse through plasma membrane.113 Aldose reductase (AR) is the rate‑limiting enzyme in the polyol pathway.111,112 Therefore, several studies have examined the protective effect of either pharmacological inhibition or genetic deletion of AR. Fidarestat, an AR inhibitor showed promising results for the treatment of DR in vitro and in vivo.114‑116 Studies with the specific AR inhibitor, zoloperstat showed protective effects in preventing ROS generation and preventing retinal endothelial cell death.56,117 Genetic deletion of AR in diabetic mice showed protective effects on ROS production and retinal acellular capillaries but not on adhesion molecules.118 Interestingly, AR deletion also resulted in preserving retinal neuronal function by preventing diabetes‑induced defects in contrast sensitivity and spatial frequency threshold.119 A recent report showed that glucose flux via AR triggers activation, histone acetylation, and prolonged expression of genes linked to proinflammatory responses in diabetic mice.120 Together, these reports revive AR, an old and classic contributor to hyperglycemia, to be reconsidered as an attractive therapeutic target for diabetic complication.

to activate mitogen‑activated protein kinase and NFκB pathways leading to increased expression of proinflmmatory cytokines such as TNF‑α and IL‑1β.122‑124 Accumulation of AGEs is accelerated in diabetes and is implicated in DR.125‑128 In addition to the effect of benfotiamine on HBP pathway; the drug also inhibits AGE formation to prevent the development of DR.107 Benfotiamine has been shown in animal models to decrease retinal capillary changes and increase extracellular matrix turnover, and to prevent human pericyte apoptosis emphasizing the promising effects of the drug in DR.129‑131

SUMMARY We have attempted to review the evidence from experimental models that support a pivotal and a specific role of oxidative stress in driving inflammation, ER‑stress and other damaging neuro‑ and vascular changes involved in the progression of DR. Multiple pathways have been identified including activation of Nox, peroxynitrite, polyol pathway, RAGE, PKC and hexoseamine pathway (figure 1 for schematic representation). Possible molecular links between inflammation and oxidative stress or ER‑stress have also been elucidated. Based on these studies, there is urging need to develop and assess the efficacy of specific modulators of the aforementioned pathways in clinical trials instead of the general and nonselective antioxidants that proven unsuccessful in diabetic patients. So far, the only FDAapproved pharmacological treatment for DR is the anti-VEGF therapy. Therefore, understanding the biochemical changes and the molecular events under diabetic conditions are essential to develop novel therapeutic tools to combat DR disease.

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Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets.

Diabetic retinopathy: reversibility of epigenetic modifications and new therapeutic targets.

Epigenetic modifications as potential therapeutic targets in age-related macular degeneration and diabetic retinopathy.

Epigenetic modifications and potential new treatment targets in diabetic retinopathy.

Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets.

Myocardial metabolism in diabetic cardiomyopathy: potential therapeutic targets.

MicroRNAs are potential prognostic and therapeutic targets in diabetic osteoarthritis.

Diabetic Cardiomyopathy: Current Approach and Potential Diagnostic and Therapeutic Targets.

Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets.

Cellular and Molecular Mechanisms of Diabetic Atherosclerosis: Herbal Medicines as a Potential Therapeutic Approach.

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New Therapeutic Approaches in Diabetic Retinopathy.

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Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential.

Molecular Imaging of Subclinical Diabetic Retinopathy.

Mechanisms of ATP release--future therapeutic targets?

Anti-diabetic potential of chromium histidinate in diabetic retinopathy rats.

Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy.

Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets.

Inflammation in gout: mechanisms and therapeutic targets.

Molecular Markers of Diabetic Retinopathy: Potential Screening Tool of the Future?

Potential therapeutic targets of Guggulsterone in cancer.

MicroRNAs: potential therapeutic targets in diabetic complications of the cardiovascular and renal systems.