|DIABETIC RETINOPATHY UPDATE
|Year : 2015 | Volume
| Issue : 2 | Page : 135-144
Molecular mechanisms of diabetic retinopathy: Potential therapeutic targets
Maha Coucha, Sally L Elshaer, Wael S Eldahshan, Barbara A Mysona, Azza B El-Remessy
Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, Georgia; Culver Vision Discovery Institute, Georgia Regents University, Georgia; Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia, USA
|Date of Web Publication||1-Apr-2015|
Azza B El-Remessy
Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta 30912, Georgia
Source of Support: AHA, NEI RO-1EY-022408., Conflict of Interest: None
| 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.
Keywords: Diabetic Retinopathy, Endoplasmic Reticulum-stress, Nicotinamide Adenine Dinucleotide Phosphate Oxidase, Inflammation, Oxidative Stress, Peroxynitrite, Therapeutics
|How to cite this article:|
Coucha M, Elshaer SL, Eldahshan WS, Mysona BA, El-Remessy AB. Molecular mechanisms of diabetic retinopathy: Potential therapeutic targets. Middle East Afr J Ophthalmol 2015;22:135-44
|How to cite this URL:|
Coucha M, Elshaer SL, Eldahshan WS, Mysona BA, El-Remessy AB. Molecular mechanisms of diabetic retinopathy: Potential therapeutic targets. Middle East Afr J Ophthalmol [serial online] 2015 [cited 2020 Aug 11];22:135-44. Available from: http://www.meajo.org/text.asp?2015/22/2/135/154386
| Introduction|| |
Over 29.1 million Americans, representing 9.3% of the population, had diabetes and over 86 million Americans age 20 and older had prediabetes.  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.  In 2012, an estimated $245 billion was spent on the direct healthcare and indirect consequences of diabetes in the United States.  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.  DR is clinically classified into nonproliferative and proliferative disease stages. In nonproliferative DR (NPDR), intraretinal microvascular changes occur including microaneurysms, altered retinal vascular permeability and eventual retinal vessel closure and nonperfusion. ,, 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.  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 in diabetic patients and it remains the standard of care.  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. , 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. 
| ANTI-VASCULAR ENDOTHELIAL 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.  Of note, the strong visual acuity gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained till month 36.  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. , 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.  Of note, chronic anti-VEGF therapy may cause hypertension as well as renal side effects including proteinuria and glomerular thrombotic microangiopathy with preexisting hypertension.  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.  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.
| 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. ,, Several lines of evidence support increased oxidative stress as a main cause for retinal inflammation in diabetic patients.  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.  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. , 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. , 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.  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.  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.
|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 reticulum-stress have been linked to activation of proinflammatory cytokine production and development of diabetic retinopathy|
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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 subunits were discovered including: Nox1, Nox3, Nox4, Nox5, DUOX1, and DUOX2. Together, they are all known as the Nox family. ,, 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.  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. 
Ample of evidence supported the role of Nox2 in the vascular pathology of DR. , 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. ,, 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,  emphasizing the role of Nox system in accelerating vascular dysfunction in diabetes.
Nox4 is the most prevalent isoform in human retinal microvascular endothelial cells.  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 angiogenesis  and blood-retinal barrier breakdown.  Recently, photoreceptors were also shown to express Nox4 in response to stress in a living retinal explants.  Taken together, these findings suggest that Nox 4 plays an important role in ROS production.
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.  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.  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.  However, Nox5 expression has been reported in other species including human retina, bovine retinal endothelial cells and pericytes,  indicating that Nox5 may be relevant to retinal vascular pathology. Clearly, there is differential expression of Nox isoforms throughout the retina,  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.
| Peroxynitrite and nitrative stress in diabetic retinopathy|| |
Mounting evidence supports the association of DR with increased nitrosative stress and peroxynitrite formation. ,,, 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 animals , and patients.  Increased peroxynitrite generation contributes to DR via initiating various pathological processes including: (1) Decreased nitric oxide bioavailability (2) increased retinal vascular permeability ,, (3) reduced endothelial and neuronal cell survival ,, and (4) retinal inflammation.  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 model  as well as in response to high glucose model.  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 signaling and retinal neurodegeneration.  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. ,, A recent study showed that tyrosine nitration of prostacyclin synthase was accompanied with increased retinal cell death in diabetic mice.  Treatment with tempol, a superoxide scavenger reduced nitrotyrosine levels and prevented retinal apoptosis  and vascular permeability in vivo. 
| 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. , 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). , 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,  renal  and various retinal cells. ,, 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. ,, 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, , as well as high fat diet-induced pre-DR.  TXNIP has been linked to inflammation both at transcriptional and posttranscriptional levels. At transcriptional levels, TXNIP results in activation of nuclear factor kB (NFkB) pathway, which leads to proinflammatory cytokine expression. , At posttranscriptional levels, TXNIP acts as a direct activator of nod-like receptor protein 3-inflammasome, which is a component of the innate immune system responsible for initiating the inflammatory response (reviewed in).  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.  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.  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. ,, 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). , 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. , ProNGF binds favorably to p75 neurotrophin receptor (p75 NTR ), which in combination with its co-receptor sortilin, generally activates inflammatory and apoptotic pathways (reviewed in). , We and others have shown that overexpressing proNGF induced activation of NFkB 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. ,, The proinflammatory response of proNGF was ameliorated by inhibiting its receptor; p75 NTR . The proinflammatory role of proNGF in activated microglia has been documented also in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.  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. ,,,, 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. , 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. ,,, In addition, ER-stress contributes to increased oxidative stress and inflammatory response. ,,,
It is well-documented that the ER-stress is involved in retinal neurodegeneration and vascular damage in various ocular disorders.  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.  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.  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. 
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.  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.  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.  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).  In particular, two PKC isozymes, PKCd and PKCβ, have been implicated in the pathogenesis of diabetes. PKCd 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.  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.  Increased activation of PKCβ occurs in retinal endothelial cells exposed to high glucose as well as in retinas of diabetic animals (reviewed in).  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.  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.  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. 
| 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.  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.  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.  Ultimately, the flux of glucose through the HBP leads to the formation of 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. , 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.  Recent studies demonstrated increased O-GlcN acylation in retina vasculature that impaired migration of retinal pericytes  and pericyte apoptosis in diabetes.  Another study correlated O-GlcNAc glycosylation to the detrimental effects of hypoxia and hyperglycemia in a model of DR. 
| 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. , Under euglycemic conditions, sorbitol level is low, while, during hyperglycemia, sorbitol level increases due to the flux of glucose through the polyol pathway.  Sorbitol accumulation in tissues such as the retina causes osmotic damage as sorbitol cannot readily diffuse through plasma membrane.  Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway. , 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. ,, Studies with the specific AR inhibitor, zoloperstat showed protective effects in preventing ROS generation and preventing retinal endothelial cell death. , Genetic deletion of AR in diabetic mice showed protective effects on ROS production and retinal acellular capillaries but not on adhesion molecules.  Interestingly, AR deletion also resulted in preserving retinal neuronal function by preventing diabetes-induced defects in contrast sensitivity and spatial frequency threshold.  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.  Together, these reports revive AR, an old and classic contributor to hyperglycemia, to be reconsidered as an attractive therapeutic target for diabetic complication.
| Receptor for advanced glycation end products axis|| |
Advanced glycation end products (AGEs) are a group of compounds formed as a result of a cascade of reactions starting with the nonenzymatic reaction between the carbonyl group of reducing sugars and the free amino group of proteins, lipids or DNA (reviewed in).  AGEs act through their receptor (RAGEs) to activate mitogen-activated protein kinase and NFkB pathways leading to increased expression of proinflmmatory cytokines such as TNF-α and IL-1β. ,, Accumulation of AGEs is accelerated in diabetes and is implicated in DR. ,,, In addition to the effect of benfotiamine on HBP pathway; the drug also inhibits AGE formation to prevent the development of DR.  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. ,,
| 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 FDA-approved 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.
| References|| |
American Diabetes Association, editor. American Diabetes Association: All About Diabetes. ADA; 2014. [Last accessed on 2014 Oct 10].
American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013;36:1033-46.
Ey C. Pathophysiology of diabetic retinopathy. In: LeRoith D, Breen TL, Olefsky JM, editors. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, PA: Lippincott Williams and Wilkins; 2004,
Frank RN. Diabetic retinopathy. N Engl J Med 2004;350:48-58.
Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013;93:137-88.
Frank RN. Treating diabetic retinopathy by inhibiting growth factor pathways. Curr Opin Investig Drugs 2009;10:327-35.
Deschler EK, Sun JK, Silva PS. Side-effects and complications of laser treatment in diabetic retinal disease. Semin Ophthalmol 2014;29:290-300.
de Gooyer TE, Stevenson KA, Humphries P, Simpson DA, Gardiner TA, Stitt AW. Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Invest Ophthalmol Vis Sci 2006;47:5561-8.
Du Y, Veenstra A, Palczewski K, Kern TS. Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci U S A 2013;110:16586-91.
Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev 2014;10:CD007419.
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al.
Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801.
Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al.
Long-term outcomes of ranibizumab therapy for diabetic macular edema: The 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120:2013-22.
Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology 2014;121:1783-9.
Bressler NM, Varma R, Suñer IJ, Dolan CM, Ward J, Ehrlich JS, et al.
Vision-related function after ranibizumab treatment for diabetic macular edema: Results from RIDE and RISE. Ophthalmology 2014;121:2461-72.
Ferraz DA, Vasquez LM, Preti RC, Motta A, Sophie R, Bittencourt MG, et al
. A randomized controlled trial of panretinal photocoagulation with and without intravitreal ranibizumab in treatment-naive eyes with non-high-risk proliferative diabetic retinopathy. Retina 2015;35:280-7.
Izzedine H. Anti-VEGF cancer therapy in nephrology practice. Int J Nephrol 2014;2014:143426.
Zhu M, Chew JK, Broadhead GK, Luo K, Joachim N, Hong T, et al.
Intravitreal Ranibizumab for neovascular Age-related macular degeneration in clinical practice: Five-year treatment outcomes. Graefes Arch Clin Exp Ophthalmol 2014. [Epub ahead of print].
Montezano AC, Touyz RM. Oxidative stress, Noxs, and hypertension: Experimental evidence and clinical controversies. Ann Med 2012;44:S2-16.
Radak D, Resanovic I, Isenovic ER. Link between oxidative stress and acute brain ischemia. Angiology 2014;65:667-76.
Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol 2013;2013:343560.
Zhang W, Liu H, Al-Shabrawey M, Caldwell RW, Caldwell RB. Inflammation and diabetic retinal microvascular complications. J Cardiovasc Dis Res 2011;2:96-103.
Wilkinson-Berka JL, Rana I, Armani R, Agrotis A. Reactive oxygen species, Nox and angiotensin II in angiogenesis: Implications for retinopathy. Clin Sci (Lond) 2013;124:597-615.
Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, et al.
Vascular endothelial growth factor and diabetic retinopathy: Role of oxidative stress. Curr Drug Targets 2005;6:511-24.
Ali TK, El-Remessy AB. Diabetic retinopathy: Current management and experimental therapeutic targets. Pharmacotherapy 2009;29:182-92.
Mann JF, Lonn EM, Yi Q, Gerstein HC, Hoogwerf BJ, Pogue J, et al.
Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: Results of the HOPE study. Kidney Int 2004;65:1375-80.
Williams M, Hogg RE, Chakravarthy U. Antioxidants and diabetic retinopathy. Curr Diab Rep 2013;13:481-7.
Dikalov S. Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 2011;51:1289-301.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107:1058-70.
Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 2013;19:1110-20.
Wingler K, Hermans JJ, Schiffers P, Moens A, Paul M, Schmidt HH. NOX1, 2, 4, 5: Counting out oxidative stress. Br J Pharmacol 2011;164:866-83.
Sedeek M, Montezano AC, Hebert RL, Gray SP, Di Marco E, Jha JC, et al.
Oxidative stress, Nox isoforms and complications of diabetes - Potential targets for novel therapies. J Cardiovasc Transl Res 2012;5:509-18.
Chen P, Guo AM, Edwards PA, Trick G, Scicli AG. Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. Am J Physiol Regul Integr Comp Physiol 2007;293:R1619-29.
Al-Shabrawey M, Rojas M, Sanders T, Behzadian A, El-Remessy A, Bartoli M, et al
. Role of NADPH oxidase in retinal vascular inflammation. Invest Ophthalmol Vis Sci 2008;49:3239-44.
Tawfik A, Sanders T, Kahook K, Akeel S, Elmarakby A, Al-Shabrawey M. Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen-induced retinopathy: Role of NADPH oxidase. Invest Ophthalmol Vis Sci 2009;50:878-84.
Kowluru RA, Kowluru A, Veluthakal R, Mohammad G, Syed I, Santos JM, et al.
TIAM1-RAC1 signalling axis-mediated activation of NADPH oxidase-2 initiates mitochondrial damage in the development of diabetic retinopathy. Diabetologia 2014;57:1047-56.
Al-Shabrawey M, Bartoli M, El-Remessy AB, Ma G, Matragoon S, Lemtalsi T, et al
. Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Invest Ophthalmol Vis Sci 2008;49:3231-8.
Al-Shabrawey M, Bartoli M, El-Remessy AB, Platt DH, Matragoon S, Behzadian MA, et al.
Inhibition of NAD(P) H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am J Pathol 2005;167:599-607.
Jarajapu YP, Caballero S, Verma A, Nakagawa T, Lo MC, Li Q, et al.
Blockade of NADPH oxidase restores vasoreparative function in diabetic CD34 cells. Invest Ophthalmol Vis Sci 2011;52:5093-104.
Wang H, Yang Z, Jiang Y, Hartnett ME. Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity. Mol Vis 2014;20:231-41.
Li J, Wang JJ, Yu Q, Chen K, Mahadev K, Zhang SX. Inhibition of reactive oxygen species by Lovastatin downregulates vascular endothelial growth factor expression and ameliorates blood-retinal barrier breakdown in db/db mice: Role of NADPH oxidase 4. Diabetes 2010;59:1528-38.
Bhatt L, Groeger G, McDermott K, Cotter TG. Rod and cone photoreceptor cells produce ROS in response to stress in a live retinal explant system. Mol Vis 2010;16:283-93.
Dvoriantchikova G, Grant J, Santos AR, Hernandez E, Ivanov D. Neuronal NAD(P) H oxidases contribute to ROS production and mediate RGC death after ischemia. Invest Ophthalmol Vis Sci 2012;53:2823-30.
Wilkinson-Berka JL, Deliyanti D, Rana I, Miller AG, Agrotis A, Armani R, et al
. NADPH oxidase, NOX1, mediates vascular injury in ischemic retinopathy. Antioxid Redox Signal 2014;20:2726-40.
Ellis EA, Guberski DL, Hutson B, Grant MB. Time course of NADH oxidase, inducible nitric oxide synthase and peroxynitrite in diabetic retinopathy in the BBZ/WOR rat. Nitric Oxide 2002;6:295-304.
Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 2003;52:818-23.
El-Remessy AB, Behzadian MA, Abou-Mohamed G, Franklin T, Caldwell RW, Caldwell RB. Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor. Am J Pathol 2003;162:1995-2004.
Pacher P, Obrosova IG, Mabley JG, Szabó C. Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem 2005;12:267-75.
Du Y, Smith MA, Miller CM, Kern TS. Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine. J Neurochem 2002;80:771-9.
Ali TK, Matragoon S, Pillai BA, Liou GI, El-Remessy AB. Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes. Diabetes 2008;57:889-98.
Liu Q, Li J, Cheng R, Chen Y, Lee K, Hu Y, et al.
Nitrosative stress plays an important role in Wnt pathway activation in diabetic retinopathy. Antioxid Redox Signal 2013;18:1141-53.
El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai NT, Caldwell RB, Liou GI. Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am J Pathol 2006;168:235-44.
Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001;50:1938-42.
Aldebasi YH, Aly SM, Rahmani AH. Therapeutic implications of curcumin in the prevention of diabetic retinopathy via modulation of anti-oxidant activity and genetic pathways. Int J Physiol Pathophysiol Pharmacol 2013;5:194-202.
Kowluru RA, Zhong Q. Beyond AREDS: Is there a place for antioxidant therapy in the prevention/treatment of eye disease? Invest Ophthalmol Vis Sci 2011;52:8665-71.
Abdelsaid MA, Pillai BA, Matragoon S, Prakash R, Al-Shabrawey M, El-Remessy AB. Early intervention of tyrosine nitration prevents vaso-obliteration and neovascularization in ischemic retinopathy. J Pharmacol Exp Ther 2010;332:125-34.
el-Remessy AB, Bartoli M, Platt DH, Fulton D, Caldwell RB. Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration. J Cell Sci 2005;118:243-52.
Ali TK, Al-Gayyar MM, Matragoon S, Pillai BA, Abdelsaid MA, Nussbaum JJ, et al.
Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury. Diabetologia 2011;54:657-68.
Al-Gayyar MM, Matragoon S, Pillai BA, Ali TK, Abdelsaid MA, El-Remessy AB. Epicatechin blocks pro-nerve growth factor (proNGF)-mediated retinal neurodegeneration via inhibition of p75 neurotrophin receptor expression in a rat model of diabetes corrected. Diabetologia 2011;54:669-80.
Zou MH, Li H, He C, Lin M, Lyons TJ, Xie Z. Tyrosine nitration of prostacyclin synthase is associated with enhanced retinal cell apoptosis in diabetes. Am J Pathol 2011;179:2835-44.
El-Remessy AB, Franklin T, Ghaley N, Yang J, Brands MW, Caldwell RB, et al.
Diabetes-induced superoxide anion and breakdown of the blood-retinal barrier: Role of the VEGF/uPAR pathway. PLoS One 2013;8:e71868.
Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol 2008;30:65-84.
Mohamed IN, Ishrat T, Fagan SC, El-Remessy AB. Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit. Antioxid Redox Signal 2014. [Epub ahead of print].
Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med 2014;66:75-87.
Price SA, Gardiner NJ, Duran-Jimenez B, Zeef LA, Obrosova IG, Tomlinson DR. Thioredoxin interacting protein is increased in sensory neurons in experimental diabetes. Brain Res 2006;1116:206-14.
Cheng DW, Jiang Y, Shalev A, Kowluru R, Crook ED, Singh LP. An analysis of high glucose and glucosamine-induced gene expression and oxidative stress in renal mesangial cells. Arch Physiol Biochem 2006;112:189-218.
Perrone L, Devi TS, Hosoya KI, Terasaki T, Singh LP. Inhibition of TXNIP expression in vivo
blocks early pathologies of diabetic retinopathy. Cell Death Dis 2010;1:e65.
Devi TS, Hosoya K, Terasaki T, Singh LP. Critical role of TXNIP in oxidative stress, DNA damage and retinal pericyte apoptosis under high glucose: Implications for diabetic retinopathy. Exp Cell Res 2013;319:1001-12.
Devi TS, Lee I, Hüttemann M, Kumar A, Nantwi KD, Singh LP. TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: Implications for diabetic retinopathy. Exp Diabetes Res 2012;2012:438238.
Al-Gayyar MM, Abdelsaid MA, Matragoon S, Pillai BA, El-Remessy AB. Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity. Br J Pharmacol 2011;164:170-80.
El-Azab MF, Baldowski BR, Mysona BA, Shanab AY, Mohamed IN, Abdelsaid MA, et al.
Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury. Br J Pharmacol 2014;171:1299-313.
Mohamed IN, Hafez SS, Fairaq A, Ergul A, Imig JD, El-Remessy AB. Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia 2014;57:413-23.
Abdelsaid MA, Matragoon S, El-Remessy AB. Thioredoxin-interacting protein expression is required for VEGF-mediated angiogenic signal in endothelial cells. Antioxid Redox Signal 2013;19:2199-212.
Abdelsaid MA, Matragoon S, Ergul A, El-Remessy AB. Deletion of thioredoxin interacting protein (TXNIP) augments hyperoxia-induced vaso-obliteration in a mouse model of oxygen induced-retinopathy. PLoS One 2014;9:e110388.
Park KS, Kim SS, Kim JC, Kim HC, Im YS, Ahn CW, et al.
Serum and tear levels of nerve growth factor in diabetic retinopathy patients. Am J Ophthalmol 2008;145:432-7.
Kim HC, Cho YJ, Ahn CW, Park KS, Kim JC, Nam JS, et al.
Nerve growth factor and expression of its receptors in patients with diabetic neuropathy. Diabet Med 2009;26:1228-34.
Aloe L, Rossi S, Manni L. Altered expression of nerve growth factor and its receptors in the kidneys of diabetic rats. J Nephrol 2011;24:798-805.
Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science 2001;294:1945-8.
Teng KK, Felice S, Kim T, Hempstead BL. Understanding proneurotrophin actions: Recent advances and challenges. Dev Neurobiol 2010;70:350-9.
Mysona BA, Shanab AY, Elshaer SL, El-Remessy AB. Nerve growth factor in diabetic retinopathy: Beyond neurons. Expert Rev Ophthalmol 2014;9:99-107.
Mysona BA, Al-Gayyar MM, Matragoon S, Abdelsaid MA, El-Azab MF, Saragovi HU, et al.
Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. Diabetologia 2013;56:2329-39.
Al-Gayyar MM, Mysona BA, Matragoon S, Abdelsaid MA, El-Azab MF, Shanab AY, et al.
Diabetes and overexpression of proNGF cause retinal neurodegeneration via activation of RhoA pathway. PLoS One 2013;8:e54692.
Lebrun-Julien F, Bertrand MJ, De Backer O, Stellwagen D, Morales CR, Di Polo A, et al.
ProNGF induces TNF alpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. Proc Natl Acad Sci U S A 2010;107:3817-22.
Duan L, Chen BY, Sun XL, Luo ZJ, Rao ZR, Wang JJ, et al.
LPS-induced proNGF synthesis and release in the N9 and BV2 microglial cells: A new pathway underling microglial toxicity in neuroinflammation. PLoS One 2013;8:e73768.
Mantelli F, Lambiase A, Colafrancesco V, Rocco ML, Macchi I, Aloe L. NGF and VEGF effects on retinal ganglion cell fate: New evidence from an animal model of diabetes. Eur J Ophthalmol 2014;24:247-53.
Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV. Role of endoplasmic reticulum stress in atherosclerosis and diabetic macrovascular complications. Biomed Res Int 2014;2014:610140.
Dunys J, Duplan E, Checler F. The transcription factor X-box binding protein-1 in neurodegenerative diseases. Mol Neurodegener 2014;9:35.
Zhang SX, Sanders E, Fliesler SJ, Wang JJ. Endoplasmic reticulum stress and the unfolded protein responses in retinal degeneration. Exp Eye Res 2014;125:30-40.
Maurel M, Chevet E. Endoplasmic reticulum stress signaling: The microRNA connection. Am J Physiol Cell Physiol 2013;304:C1117-26.
Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol 2011;490:71-92.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519-29.
Jing G, Wang JJ, Zhang SX. ER stress and apoptosis: A new mechanism for retinal cell death. Exp Diabetes Res 2012;2012:589589.
Zhong Y, Li J, Chen Y, Wang JJ, Ratan R, Zhang SX. Activation of endoplasmic reticulum stress by hyperglycemia is essential for Müller cell-derived inflammatory cytokine production in diabetes. Diabetes 2012;61:492-504.
Li J, Wang JJ, Yu Q, Wang M, Zhang SX. Endoplasmic reticulum stress is implicated in retinal inflammation and diabetic retinopathy. FEBS Lett 2009;583:1521-7.
Yang L, Wu L, Wang D, Li Y, Dou H, Tso MO, et al.
Role of endoplasmic reticulum stress in the loss of retinal ganglion cells in diabetic retinopathy. Neural Regen Res 2013;8:3148-58.
Adachi T, Yasuda H, Nakamura S, Kamiya T, Hara H, Hara H, et al.
Endoplasmic reticulum stress induces retinal endothelial permeability of extracellular-superoxide dismutase. Free Radic Res 2011;45:1083-92.
Nakamura S, Takizawa H, Shimazawa M, Hashimoto Y, Sugitani S, Tsuruma K, et al.
Mild endoplasmic reticulum stress promotes retinal neovascularization via induction of BiP/GRP78. PLoS One 2013;8:e60517.
Zhong Y, Wang JJ, Zhang SX. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. Adv Exp Med Biol 2012;723:285-92.
Pathak D, Gupta A, Kamble B, Kuppusamy G, Suresh B. Oral targeting of protein kinase C receptor: Promising route for diabetic retinopathy? Curr Drug Deliv 2012;9:405-13.
Bezy O, Tran TT, Pihlajamäki J, Suzuki R, Emanuelli B, Winnay J, et al.
PKCd regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J Clin Invest 2011;121:2504-17.
Das Evcimen N, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res 2007;55:498-510.
Frank RN. Potential new medical therapies for diabetic retinopathy: Protein kinase C inhibitors. Am J Ophthalmol 2002;133:693-8.
Aiello LP, Vignati L, Sheetz MJ, Zhi X, Girach A, Davis MD, et al.
Oral protein kinase c ß inhibition using ruboxistaurin: Efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study 2. Retina 2011;31:2084-94.
Semba RD, Huang H, Lutty GA, Van Eyk JE, Hart GW. The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy. Proteomics Clin Appl 2014;8:218-31.
Buse MG. Hexosamines, insulin resistance, and the complications of diabetes: Current status. Am J Physiol Endocrinol Metab 2006;290:E1-8.
Schleicher ED, Weigert C. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int Suppl 2000;77:S13-8.
Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic vascular complications. J Diabetes Investig 2010;1:77-89.
Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, et al.
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003;9:294-9.
Gurel Z, Sieg KM, Shallow KD, Sorenson CM, Sheibani N. Retinal O-linked N-acetylglucosamine protein modifications: Implications for postnatal retinal vascularization and the pathogenesis of diabetic retinopathy. Mol Vis 2013;19:1047-59.
Gurel Z, Zaro BW, Pratt MR, Sheibani N. Identification of O-GlcNAc modification targets in mouse retinal pericytes: Implication of p53 in pathogenesis of diabetic retinopathy. PLoS One 2014;9:e95561.
Xu C, Liu G, Liu X, Wang F. O-GlcNAcylation under hypoxic conditions and its effects on the blood-retinal barrier in diabetic retinopathy. Int J Mol Med 2014;33:624-32.
Oates PJ. Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol 2002;50:325-92.
Gabbay KH. The sorbitol pathway and the complications of diabetes. N Engl J Med 1973;288:831-6.
Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int 2014;2014:801269.
Drel VR, Pacher P, Ali TK, Shin J, Julius U, El-Remessy AB, et al.
Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. Int J Mol Med 2008;21:667-76.
Obrosova IG, Maksimchyk Y, Pacher P, Agardh E, Smith ML, El-Remessy AB, et al.
Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina. Int J Mol Med 2010;26:135-42.
Obrosova IG, Mabley JG, Zsengellér Z, Charniauskaya T, Abatan OI, Groves JT, et al.
Role for nitrosative stress in diabetic neuropathy: Evidence from studies with a peroxynitrite decomposition catalyst. FASEB J 2005;19:401-3.
El-Remessy AB, Abou-Mohamed G, Caldwell RW, Caldwell RB. High glucose-induced tyrosine nitration in endothelial cells: Role of eNOS uncoupling and aldose reductase activation. Invest Ophthalmol Vis Sci 2003;44:3135-43.
Tang J, Du Y, Petrash JM, Sheibani N, Kern TS. Deletion of aldose reductase from mice inhibits diabetes-induced retinal capillary degeneration and superoxide generation. PLoS One 2013;8:e62081.
Lee CA, Li G, Patel MD, Petrash JM, Benetz BA, Veenstra A, et al.
Diabetes-induced impairment in visual function in mice: Contributions of p38 MAPK, rage, leukocytes, and aldose reductase. Invest Ophthalmol Vis Sci 2014;55:2904-10.
Vedantham S, Thiagarajan D, Ananthakrishnan R, Wang L, Rosario R, Zou YS, et al.
Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals. Diabetes 2014;63:761-74.
Chen M, Curtis TM, Stitt AW. Advanced glycation end products and diabetic retinopathy. Curr Med Chem 2013;20:3234-40.
Zong H, Ward M, Madden A, Yong PH, Limb GA, Curtis TM, et al.
Hyperglycaemia-induced pro-inflammatory responses by retinal Müller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia 2010;53:2656-66.
Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, et al.
A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 2004;18:1450-2.
Ibrahim AS, El-Remessy AB, Matragoon S, Zhang W, Patel Y, Khan S, et al.
Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes. Diabetes 2011;60:1122-33.
Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci 2005;1043:567-81.
Stitt AW, Li YM, Gardiner TA, Bucala R, Archer DB, Vlassara H. Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol 1997;150:523-31.
Hammes HP, Alt A, Niwa T, Clausen JT, Bretzel RG, Brownlee M, et al.
Differential accumulation of advanced glycation end products in the course of diabetic retinopathy. Diabetologia 1999;42:728-36.
Fosmark DS, Torjesen PA, Kilhovd BK, Berg TJ, Sandvik L, Hanssen KF, et al.
Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus. Metabolism 2006;55:232-6.
Tarallo S, Beltramo E, Berrone E, Dentelli P, Porta M. Effects of high glucose and thiamine on the balance between matrix metalloproteinases and their tissue inhibitors in vascular cells. Acta Diabetol 2010;47:105-11.
Beltramo E, Berrone E, Tarallo S, Porta M. Different apoptotic responses of human and bovine pericytes to fluctuating glucose levels and protective role of thiamine. Diabetes Metab Res Rev 2009;25:566-76.
Berrone E, Beltramo E, Solimine C, Ape AU, Porta M. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem 2006;281:9307-13.