Journal of Diabetes & Metabolism

ISSN - 2155-6156

+441518081309

Review Article - (2012) Volume 0, Issue 0

Role of Peroxisome Proliferator Activator Receptor γ in Diabetic Retinopathy Pathophysiology

Min K Song, Basil D Roufogalis* and Tom H.W Huang*
Herbal Medicines Group, Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia
*Corresponding Author(s): Basil D Roufogalis, Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia, Tel: +61 2 9351 2360, Fax: +61 2 9351 4391 Email:
Tom H.W Huang, Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia, Tel: +61 2 9351 3234 Email:

Abstract

Diabetic retinopathy (DR) is one of the most common complications of diabetes and one of the leading causes of blindness worldwide. DR involves an abnormal pathology of major retinal cells, including retinal pigment epithelium, vascular cells (endothelial cells and pericytes), retinal microglial cells and retinal ganglion cells. The biochemical mechanisms associated with hyperglycemic-induced DR are through multifactorial processes. Peroxisome proliferatoractivated receptor-γ ( PPAR-γ) plays an important role in the pathogenesis of DR by inhibiting diabetes-induced retinal leukostasis and leakage. Despite DR causing eventual blindness, only a few visual or ophthalmic symptoms are observed until visual loss develops. Laser photocoagulation therapy is the most common treatment. However, this therapy may cause retinal damage and scarring. Therefore, early medical interventions and prevention are the current management strategies. The recent advancements in the knowledge of the pathogenic alterations driving ocular damage and vision loss in DR strongly focus on PPAR-γ as a valuable target to control high glucose-induced inflammation and apoptosis. This review provides an analysis of potential involvement of PPAR-γ in various mechanisms and pathways associated with progression of DR.

Keywords: Diabetic retinopathy; Peroxisome proliferator-activated receptor γ; Neovascularization; Neuroretinal degeneration

Abbreviations

DR: Diabetic Retinopathy; PPAR-γ: Peroxisome Proliferator-Activated Receptor-γ; AGEs: Advanced Glycation End products; 15-dPGJ2: 15-deoxy-Δ12, 14 −Prostaglandin J2; NF-κB: Nuclear Factor-kappaB; TNF-α: Tumor Necrotic Factor; COX-2: Cyclo-Oxygenase-2; ICAM-1: Intercellular Cell adhesion Molecule-1; VCAM-1: Vascular Cell Adhesion Molecule-1; MMP-9: Matrix Metalloproteinase-9; VEGF: Vascular Endothelial Growth Factor; iNOS: Inducible Nitric Oxide Synthase; BRB: Blood Retinal Barrier; NGF: Nerve Growth Factor

Introduction

Diabetic retinopathy (DR) is one of the most prevalent diabetic eye diseases. It is a vision-threatening disease presenting neurodegenerative features associated with extensive vascular changes [1,2]. The prevalence of DR increases with the duration of diabetes, and nearly all patients with type I diabetes and more than 60% with type II diabetes have some degree of retinopathy after 20 years [3-5]. Therefore, early detection and prevention are the current management strategies [6]. Chronic hyperglycemia is believed to be the primary pathogenic factor for inducing damage to retinal cells [7-9]. However, the mechanisms that lead to DR are not fully understood [10]. DR is characterised by increased vascular permeability, due to a breakdown in the blood retinal barrier (BRB), which causes macular edema, followed later by the development of vascular microaneurysms, hemorrhages, hard exudates and intraocular pathological neovascularization [11,4]. Moreover, degenerative changes, including increased apoptosis, glial cell activation, microglial activation, and altered glutamate metabolism, occur beyond the vascular cells of the retina [12]. Laser photocoagulation therapy is the most common treatment modality for DR. However, this therapy may damage neural tissue, resulting in the deterioration of vision [13]. Therefore, development of new therapeutic strategies for the treatment of excessive retinal vasopermeability, angiogenic changes and apoptosis of neurons are the basis for further research focus [12,14].

The Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) is a ligand-activated nuclear receptor that belongs to the nuclear hormone receptor superfamily [15]. PPAR-γ plays an important role in glucose metabolism, angiogenesis, inflammation and neuroprotection [16,17]. Synthetic PPAR-γ ligands, the thiazolidinediones (TZDs), including pioglitazone and rosiglitazone improve insulin resistance in diabetic patients, and have become one of the most popular anti-diabetic drugs in developed countries [18-20]. In addition natural PPAR-γ ligands, such as 15-deoxy-Δ12, 14 −prostaglandin J2 (15-dPGJ2) have very potent anti-inflammatory effects that also modulate cellular defense against oxidative stress [21,22]. PPAR-γ agonists have been shown to inhibit endothelial dysfunction, neurotoxic inflammation and subsequently neurodegeneration, partially through the abilities of agonist bound PPAR-RXR heterodimers to antagonize the deleterious effects of advanced glycation end products and oxidative stress. This largely describes the consequences of Nuclear Factor-KappaB (NF- κB) transcription factor inhibition, modulating the composition of the cellular membrane and down-regulation of protein inflammatory genes and cytokines [23-26]. Moreover, there is accumulating data to show that PPAR-γ activators exert anti-inflammatory, anti-oxidative and anti-proliferative effects in various cells including major retinal cells [16,27-30,9].

However, very limited research has been undertaken on PPAR-γ ligands in the modulation of DR related pathophysiology. Thus this review presents a detailed discussion summerising potential involvement of PPAR-γ ligands in various mechanisms and pathways associated with modulation of DR-related pathogenesis.

Diabetic Retinopathy

Diabetes damages all the major cells of the retina, vascular cells (endothelial cells and pericytes) [31,32], pigment epithelial cells [33], retinal microglial cells and retinal ganglion cells [16,34]. Basement membrane thickening, pericyte drop out and retinal capillary nonperfusion occur prior to the damage, which changes the production pattern of a number of mediators, such as growth factors, vasoactive agents, coagulation factors and adhesion molecules. These result in increased blood flow and capillary diameter, proliferation of the extracellular matrix and thickening of basal membranes, altered cell turnover (apoptosis, proliferation, hypertrophy) and procoagulant/ proaggregant patterns, and finally angiogenesis with tissue remodeling. These pathological changes cause increased retinal vasopermeability and breakdown of the BRB, resulting in retinal hemorrhage, swelling, exudates, and retinal detachment [6,35,36]. DR has many elements that suggest chronic neurodegeneration, including neural apoptosis, loss of ganglion cell bodies, reduction in thickness of the inner retina, glial reactivity, neurofilament abnormality, slowing of optic nerve retrograde transport, changes in electrophysiological activity, and resultant deficits in perception [37]. Moreover, neuoretinal degeneration initiates and/ or activates several metabolic and signaling pathways as well as in the disruption of the BRB [38].

The underlying pathophysiological mechanisms associated with hyperglycemia-induced diabetic retinopathy are through excessive formation of advanced glycation end products (AGEs) and production of excessive oxidative stress [39,6]. Moreover, these biochemical mechanisms lead to a cascade of events, such as promotion of apoptosis, inflammation, neurodegeneration and angiogenesis, which induce damage to diabetic retina, leading to DR [39,12,6] (Figure 1).

diabetes-metabolism-progression-diabetic-retinopathy

Figure 1: Schematic representation showing the role of PPAR-γ and its receptor system in the progression of diabetic retinopathy. Black arrows indicate pathway, red arrows indicate increase or decrease in activity following PPAR-γ activation (adapted from Yamagishi et al. 2009).

AGEs in diabetic retinopathy

AGEs are associated with modification of proteins or lipids that are generated from intermediate glycation products by non-enzymatic reaction of glucose with protein side chains [40,41]. These intermediate glycation products undergo further condensation, dehydration or rearrangement, leading to eventual irreversible AGEs formation [42]. AGEs formation occurs normally over time whereas an accelerated rate of AGE formation is accompanied by hyperglycemia [43]. The accumulated AGEs products are detected in the neural retina and vascular cells of diabetic animals, responsible for mediating the pathological angiogenesis and hyper-permeability in retina [44,45]. Several bodies of evidence suggest that the interaction between AGEs and their receptor (RAGE) activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and enhances the formation of oxygen radicals, with subsequent activation and translocation of NF-κB, followed by release of pro-inflammatory cytokines and growth factors [39]. Moreover, AGEs can provide the early molecular pathogenesis mechanisms responsible for neuronal apoptosis and neuro-glial reaction [46]. In addition, AGEs enhance apoptosis in retinal pericytes, corneal endothelial cells, neuronal cells and renal mesangial cells through increased oxidative stress or via induced expression of pro-apoptotic cytokines [47-49]. Indeed, AGEs induce apoptosis, angiogenesis, breakdown of the BRB, and leukocyte adhesion in the retina. Thus, AGEs are detrimental to the retinal vasculature and contribute to the pathogenesis of DR [50,51].

Oxidative stress in diabetic retinopathy

Oxidative stress appears when there is a serious imbalance between generation of reactive oxygen species (ROS) and its clearance by antioxidant defenses [52,53]. Activation of RAGEs results in production of oxidative stress (conversely, glycation itself is promoted by oxidative stress), and subsequent activation of NF-κB transcription factor in micro-vascular endothelial cells that are considered to be linked to endothelial dysfunction [54,55]. Retina, a tissue rich in polyunsaturated fatty acid, uses more oxygen and glucose oxidation than any other tissue in the body, and is very susceptible to damage [56]. Diabetic inducedoxidative stress, followed by activation of NF-κB in the retina, is early events in the pathogenesis of DR [57-60]. Moreover, oxidative stress has been linked to the accelerated apoptosis of retinal ganglion cells, retinal capillary cells and micro-vascular abnormalities in DR [61,62].

NF-κB in Diabetic Retinopathy

NF-κB is a multi-protein complex which can activate many kinds of genes involved in cellular functions. Pathogenic stimuli allow NF-κB to enter the nucleus, and to bind to DNA recognition sites in regulatory regions of target genes [63-65]. NF-κB is required for maximal transcription of many pro-inflammatory molecules thought to be important in the generation of inflammation, including cell interaction molecules (eg intracellular adhesion molecule 1), critical enzymes (eg inducible nitric oxidase synthase, cyclooxygenase-2), and a number of cytokines (eg interleukin-1β, tumor necrosis factor-α, IL-6) [24,66]. The activation of NF-κB is considered a key signaling pathway by which high glucose induces apoptosis in endothelial cells [67]. In the retina, NF-κB is localised in sub-retinal membranes and in micro-vessels [44] and its activation is considered responsible for the accelerated loss of pericytes observed in DR [68]. Moreover, the study has shown that diabetes-induced capillary degeneration, observed in DR, is at least closely associated with NF-κB activation in both vascular and neural compartments of retina and subsequent inflammatory response [69].

Inflammation in diabetic retinopathy

In recent years inflammation has been linked to vascular leakage in DR, at least in part [70,71]. Hyperglycemia is a contributing risk factor for the development of vascular dysfunction and production of inflammatory markers [72,73]. Indeed, pro-inflammatory cytokines, chemokines and other inflammatory mediators play an important role in the pathogenesis of DR. These lead to persistent low-grade inflammation, which in turn leads to neuronal cell death, the adhesion of leukocytes to the retinal vasculature (leukostasis), breakdown of BRB and tissue ischemia [74-77]. Several inflammatory molecules are involved in the pathogenesis of DR, including tumor necrotic factor (TNF-α), fibronectin, cyclo-oxygenase-2 (COX-2), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase-9 (MMP-9) [76-79].

Angiogenesis in diabetic retinopathy

Angiogenesis is defined as the growth of new vessels from preexisting capillaries, which is a complex process comprising endothelial cell proliferation, migration, extracellular proteolysis, tube formation and vessel remodeling [80]. In retina, vascular endothelial growth factor (VEGF) is the major angiogenic factor for neovascularization and vascular leakage via the mitogen-activated protein kinase (MAPK) pathway [81-83]. Additional pro-angiogenic factors, including MMP- 9, are also required for the process of ocular neovascularization through either synergistic effects with angiogenic factor or as a stimulant for the secretion of angiogenic factors [84]. In addition, MMP-9 expression acts as a factor in increasing vascular permeability in ocular neovascularization [85]. Neurotrophic factor, such as nerve growth factor (NGF), alone or in combination with other biological active endogenous molecules, have been found to exert angiogenic activity in vitro and in vivo [86,87]. Moreover, NGF has been shown to induce neuronal-driven angiogenesis, leading to pathologic retinopathy [88].

Apoptosis in diabetic retinopathy

Apoptosis is programmed cell death and is characterised by chromatin condensation, fragmentation, and formation of apoptotic bodies that can be triggered by various signals [89-91]. Retinal microvascular cells are lost selectively via apoptosis before other histopathology is detectable in diabetes [92,93,32]. As oxidative stress is closely linked to apoptosis in diabetes, oxidative stress-induced apoptotic episodes have been demonstrated by retinal abnormalities, potential visual changes and the onset of the first neural and vascular change [75,57,94]. Moreover, apoptotic cell death in retinal regions is a probable stimulus for the increased expression of molecules that enhance the breakdown of the BRB and lead to vascular proliferation [95,96]. Several studies have shown that retinal pigment epithelial cells, Glial cells [97], retinal ganglion cells [98] and retinal pericytes [89,99] undergo high glucose induced-apoptosis. The studies have shown that diabetes causes a chronic loss of neurons from the inner retina by increasing the frequency of apoptosis [100,101]. Moreover, it has been well established that apoptosis represents a final common pathway of cell loss and hence vision loss [102]. In addition, high glucose causes activation of several proteins involved in apoptotic cell death, including members of the caspase and Bcl-2 family [61]. Therefore, apoptosis plays an important role in the progression and pathogenesis of DR [61,89].

Neurodegeneration in diabetic retinopathy

Neurodegeneration is recognised as a pivotal feature of many diseases of the central nervous system. Although much of the research effort has focused on vascular changes, it is becoming apparent that the degenerative changes occur beyond the vascular cells of the retina. These include apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism [12]. Moreover, early neuronal and glial alterations are also evident in diabetes, including decrease in components of the electroretinogram [103] and increased apoptosis of retinal neurons [104]. Indeed, current evidences has shown that neurodegeneration of the retina is a critical component of DR [12]. In addition, early in the course of DR, Müller cells markedly up-regulate their expression of glial fibrillary acidic protein (GFAP) [105]. Retinal ganglion cells are the earliest cells affected and have the highest rate of apoptosis. Moreover, neuroretinal degeneration initiates and/or activates several metabolic and signaling pathways which participate in the microangiographic process as well as the disruption of the BRB [38]. Elevated levels of glutamate, the major excitatory neurotransmitter in the retina, have been found in experimental models of diabetes [106].

Pathogenesis of microglial cells in diabetic retinopathy

Retinal glial cells, including macroglia (Müller cells and astrocytes) and microglia, are considered channels of communication between retinal blood vessels and neurons owing to their special spatial arrangement and regulatory functions. Under normal conditions, microglia are characterised by a down-regulated phenotype when compared to other macrophage populations of peripheral tissues [15]. The maintenance of microglia in the “inhibited” state is crucial for the maintaining tissue homeostasis and preventing the destructive potential of inflammatory response [107]. Moreover, microglial activation appears early in the course of DR, before the onset of overt neuronal cell death [108]. In diabetes, retinal microglial cells are activated to release inflammatory cytokines, such as IL-1β, TNF-α, NO, MMPs and VEGF, and excitatory amino acids, such as glutamate that initiate neuronal loss and BRB breakdown seen in DR [34,109]. The study has shown that in STZ-induced diabetic rats treated with minocycline, a semi-synthetic tetracycline that counteracts microglial activation, as well as decreasing the expression of pro-inflammatory cytokines, caspase-3 levels are also decreased, suggesting a potential neuroprotective anti-apoptotic effect of inhibition of microglial activation [108,15]. Moreover, in mice with alloxan-induced diabetes, changes in microglial cell morphology were the first detectable cellular modifications, apparently preceding ganglion cell apoptosis and increase in BRB permeability [110].

Pathogenesis of ganglion cells in diabetic retinopathy

Although the clinically demonstrable changes to the retinal vasculature in diabetes have led to the general assumption that the retinopathy is solely a microvascular disease, diabetes also damages non-vascular cells of the retina, resulting in loss of ganglion cells [62]. Numerous studies have suggested that exposure to AGEs, inflammation or oxidative stress might contribute to retinal ganglion cell apoptosis [62]. Moreover, the diabetes-induced degeneration of retinal ganglion has been shown to involve inhibiting the activation of the pro-inflammatory NF-κB [69]. Another potential cause of retinal ganglion cell loss is excitotoxicity due to excessive synaptic glutamate activity [111]. Immunohistochemical studies of cross-sections of human retinas demonstrated an increase in expression of Bax, caspase-3 and caspase-9 in retinal ganglion cells from diabetic patients, suggesting at least some retinal ganglion cells might die via apoptosis [112]. Moreover, activated microglial cells in hypoxic neonatal retina produce increased amounts of pro-inflammatory cytokines, including TNF-α and IL-1β that could induce retinal ganglion cell death [113].

Pathogenesis of retinal pigment epithelium in diabetic retinopathy

The retinal pigment epithelial (RPE) cells form a monolayer between the neuroretina and the choriocapillaris which are the essential components of the outer BRB that maintain physiological and structural balance within the retina [114,115]. The main characteristics of RPE cells are the presence of tight junctions at the apical side of their lateral molecules, which limit access of blood components to the retina. Moreover, RPE and photoreceptors are particularly susceptible to oxidative stress because of high oxygen consumption by photoreceptors [116]. In response to damage caused by the hyperglycemic condition, RPE cells migrate and proliferate, leading to a break-down in adhesion between the RPE and the choroidal capillaries, followed by BRB breakdown compromising blood flow within the RPE layer and leading to eventual retinal edema [117]. These cascade episodes trigger the serum components and inflammatory cells to enter the vitreous cavity and sub-retinal space, exposing the RPE cells to a variety of cytokines, pro-inflammatory mediators, extracellular matrix proteins and growth factors, causing DR [118]. Several studies have shown that the expression of angiogenic cytokines, growth factors (e.g. VEGF) and metalloproteinases (e.g. MMP-9) are produced by RPE [119]. Moreover, the combined effects from chronic sustained inflammation and ROS generation promotes the development of RPE damage [120-122].

PPAR-γ and Diabetic Retinopathy

PPAR-γ is heterogeneously expressed in the mammalian eye, prominently present in the retinal pigmented epithelium, photoreceptor outer segments, choriocapillaries, and retinal ganglion cells [16,85,123]. Recent studies have shown that retinal expression of PPAR-γ was suppressed in experimental models of diabetes and in endothelial cells treated with high glucose [73]. Moreover, PPAR-γ ligands are potent inhibitors of corneal angiogenesis and neovascularization [124,125]. Administration of 15d-PGJ2 inhibited VEGF-stimulated angiogenesis in rat cornea [125]. Similarly, choroidal neovascularization was markedly reduced by intravitreous injection of troglitazone. Laser photocoagulation-induced lesions in rat and monkey eyes showed significantly less leakage in troglitazone-treated animals [123]. In neonatal mice, intravitreous injection of rosiglitazone or troglitazone inhibited development of new retinal vessels. In the same study, TZDs have been found to inhibit retinal endothelial cell proliferation, migration, and tube formation in response to VEGF treatment [126]. In addition, rosiglitazone inhibits both the retinal leukostasis and retinal leakage observed in experimental diabetic rats, which leads to the aggravation of retinal leukostasis, and retinal leakage in diabetic mice [124]. Moreover, rosiglitazone has been shown to delay the onset of DR [127]. As inflammation plays a role in several neurodegenerative diseases, numerous research has been conducted on the role of PPAR-γ in inflammation-induced neurodegeneration [128-130]. Moreover, it has more recently become appreciated that PPAR-γ agonists act on neurons and microglia to inhibit neurotoxic inflammation and subsequently neurodegeneration, partially through the abilities of agonist bound PPAR-RXR heterodimers to antagonise NFκ-B mediated gene transcription of several inflammatory mediators such as COX-2 and iNOS in vitro and in vivo [23,131-133]. Troglitazone has been shown to prevent neuronal death induced by glutamate toxicity in vitro [134]. Similarly, retinal ganglion cells were rescued from death by troglitazone [16]. Therefore, the anti-inflammatory, anti-oxidative stress properties of PPAR-γ activation may allow the neuroprotection seen with PPAR-γ agonism [135]. These findings suggest that PPAR-γ is involved in the pathogenesis of DR (Figure 1).

PPAR-γ and AGEs

PPAR-γ ligands have a significant role in prevention of AGEsinduced micro-vascular complications, including DR [136,137]. Indeed, PPAR-γ ligands have shown to inhibit the formation of AGEs [138,139]. The inhibitory action of PPAR-γ ligands on AGE formation may be ascribed to their anti-oxidative properties [27-30]. The study has shown that rosiglitazone inhibits extracellular matrix accumulation, fibronectin and type IV collagen in AGE-injected rats, and also inhibits the AGE-induced proliferation and NO production in cardiac fibroblasts [140,141]. Moreover, activation of PPAR-γ by rosiglitazone inhibits AGE-induced inducible NO synthase expression, nitrite release, fibronectin and type IV collagen production [142,141].

PPAR-γ in NF-κB, inflammatory mediators and angiogenesis

PPAR-γ plays an important role in a variety of biological processes, including inflammation and angiogenesis, mediated through the inhibition of NF-κB [143-146]. Rosiglitazone was shown to inhibit both retinal leukostasis and retinal leakage by the inhibition of NF-κB activation, with consequent suppression of ICAM-1 expression [124]. In addition, recent evidence has shown that the suppression of PPAR-γ in diabetic retina is associated with the activation of NF-κB target gene expression [147,73]. Stimulation of a pro-inflammatory response in microglia in vitro and the resulting production of neurotoxic inflammatory mediators were found to be suppressed by administration of a number structurally distinct PPAR-γ agonists [25,133]. In addition, TZDs have been shown to attenuate lipopolysaccharideinduced neuroinflammation by PPAR-γ activation in neural cells [25]. The activation of PPAR-γ inhibits the pro-inflammatory pathways, including cytokine secretion [148,149]and iNOS expression [150,151] in a variety of cell lines. Indeed, PPAR-γ agonists have been shown to suppress cytokine evoked neuronal iNOS expression, thereby preventing NO-mediated cell death of neurons [152]. Inhibition of ICAM-1 expression and retinal vascular leakage in experimental diabetes has been shown by rosiglitazone, and the increase in the same parameters by depletion of the gene encoding PPAR-γ [124]. PPAR-γ ligands have also been shown to inhibit the expression of VEGF receptors and the subsequent activation of downstream signaling pathways [153,125]. Moreover, rosiglitazone has been shown to inhibit retinal neovascularization in OIR by a mechanism downstream from VEGF-induced angiogenesis [153]. In addition, it has been suggested that ICAM-1 is involved in VEGF-induced leukocyte-endothelial cell interactions and subsequent (BRB) breakdown in the diabetic retina [154]. Furthermore, PPAR-γ activation inhibits VEGF-mediated angiogenesis through the modulation of the stimulated COX-2 expression and activity [155].

PPAR-γ and apoptosis

Apoptosis is a complex process, involving a multitude of signaling pathways that regulate the activities of pro- and anti-apoptotic members of the Bcl-2 family of proteins which play an important role in various cell types [156-158]. Oxidative stress can induce mitochondrial dysfunction, followed by cytochrome c release and subsequent activation of caspases, a group of enzymes that execute apoptosis [159,160]. A recent study has shown that rosiglitazone protects against oxidative stress-induced apoptosis through upregulation of anti-apoptotic Bcl-2 family proteins [161]. Moreover, rosiglitazone and PPAR-γ over-expression protect against apoptosis induced by oxygen and glucose deprivation followed by re-oxygenation and up-regulation of Bcl-2 [162]. In contrast, down-regulation of NF- κB activation by PPAR-γ ligands protects the cells from destruction via the apoptotic pathways [163,164]. A screen of FDA-approved compounds identified rosiglitazone as a novel anti-apoptotic agent in retinal cells both in vivo and in vitro [102]. Troglitazone has shown cytoprotective activity in apoptotic-induced ARPE-19 cells [165]. One further study has indicated that 15d-PGJ2 helps RPE cells to maintain mitochondrial integrity by prevention of cytochrome c release and subsequent activation of the apoptosis pathway [166,167]. Moreover, rosiglitazone has been shown to protect hippocampal and dorsal root ganglion neurons against Aβ-induced mitochondrial damage and NGF deprivation-induced apoptosis [168].

PPAR-γ in retinal microglia and retinal ganglion cells

The beneficial effects of PPAR-γ ligands on the ocular system have been supported by various reports. Troglitazone and 15d-PGJ2 have been shown to protect retinal ganglion cells, RGC-5, from glutamateinduced apoptosis [16].

Microglial cells have shown to express PPAR-γ and that such basal expression is increased by its specific agonists, while it is reduced in the presence of microglial activators such as lipopolysaccharide (LPS) and interferon-γ (IFN-γ) [169]. Moreover, 15d-PGJ2 has been shown to prevent LPS-induced iNOS expression and TNF-α production in primary microglial cultures, by mechanisms involving PPAR-γ activation and reduced activation of NFκ-B, which is known to mediate LPS and IFN-γ signaling [23]. Similarly, PPAR-γ agonists have been shown to modulate LPS-induced neuronal death in mixed cortical neurons, suggesting a PPAR-γ mediated mechanism of neuroprotection [132].

PPAR-γ and RPE cells

A number of studies have shown that RPE might be the prime target for oxidative stress and PPAR-γ ligands modulate cellular defense against the oxidative stress [170]. 15-dPGJ2 protects RPE cells from oxidative stress by elevating GSH and enhancing MAPK activation through a PPAR-γ independent pathway [171]. In addition, 15-dPGJ2, independent of its PPARγ activity, protects RPE cells from oxidative injury by raising intracellular GSH levels and extending hydrogen peroxide-induced activation of Jun N-terminal kinase (JNK) and p38, suggesting the possible application of the agents in preventing ocular diseases from oxidative stress [172,171].

Conclusion

Diabetic retinopathy remains one of the major risk factors and a leading cause of preventable blindness worldwide. There is strong body of evidences on the prevalence of the variety of anti-angiogenic agents, anti-inflammatory agents, anti-oxidants, anti-fibrogenesis and neuroprotective agents present in the retinal regions for slowing down the progression of DR. Moreover, the increasing importance of understanding the specific molecular and biochemical changes in DR leads to the requirement for development of novel therapeutic interventions. Although it is an important cause of blindness, initially DR presents few visual or ophthalmic symptoms until complete visual loss occurs [4]. Current treatments of DR rarely improve visual function and are limited to surgical options in an advanced stage, with excessive side effects and significant financial burden. Hence, emerging treatments, possibly in combination with standard therapy, may provide superior efficacy and safety profile for the treatment or prevention of DR. Moreover, the new strategies move a paradigm in treating the early stages of DR. The recent advancements in the knowledge of the pathogenic alterations driving ocular damage and vision loss in DR strongly focus on PPAR-γ as a valuable target to control high glucose-induced inflammation and apoptosis. PPAR-γ functions as a transcription factor and thereby controls cellular processes at the level of gene expression, through modulation by its nuclear receptor activity of selective downstream gene expression [173]. This review confirms PPAR-γ has potential involvement in various mechanisms and pathways associated with progression of DR. Moreover, PPAR-γ is an attractive and relatively unexploited therapeutic target in DR. However, the complexity of PPAR-γ activation not only provides beneficial effects but also introduces risks from undesirable side effects, such as cardiovascular complications with long term application [174]. Therefore, future studies are warranted for extensive investigation to gather proof of efficacy in various preclinical and clinical settings.

References

  1. Fong DS, Aiello LP, Ferris FL, Klein R (2004) Diabetic retinopathy. Diabetes Care 27: 2540-2553.
  2. Silva KC, Rosales MA, Biswas SK, Lopes de Faria JB, Lopes de Faria JM (2009) Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes. Diabetes 58: 1382-1390.
  3. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, et al. (2003) Diabetic retinopathy. Diabetes Care 26: 226-229.
  4. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, et al. (2004) Retinopathy in diabetes. Diabetes Care 27: S84-S87.
  5. Williams R, Airey M, Baxter H, Forrester J, Kennedy-Martin T, et al. (2004) Epidemiology of diabetic retinopathy and macular oedema: a systematic review. Eye 18: 963-983.
  6. Ciulla TA, Amador AG, Zinman B (2003) Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care 26: 2653-2664.
  7. Hammes HP (2005) Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab Res 37: 39-43.
  8. Knudsen ST, Bek T, Poulsen PL, Hove MN, Rehling M, et al. (2002) Macular edema reflects generalized vascular hyperpermeability in type 2 diabetic patients with retinopathy. Diabetes Care 25: 2328-2334.
  9. Yanagi Y (2008) Role of Peoxisome Proliferator Activator Receptor gamma on Blood Retinal Barrier Breakdown. PPAR Res 2008: 679237.
  10. West AL, Oren GA, Moroi SE (2006) Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol 141: 157-166.
  11. Cunha-Vaz J, Faria de Abreu, Campos AJ (1975) Early breakdown of the blood-retinal barrier in diabetes. The Br J Ophthalmol 59: 649-656.
  12. Barber AJ (2003) A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry 27: 283-290.
  13. Bloomgarden ZT (2007) Screening for and managing diabetic retinopathy: current approaches. Am J Health Syst Pharm 64: S8-S14.
  14. Garcia C, Aranda J, Arnold E, Thebault S, Macotela Y, et al. (2008) Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A-dependent eNOS inactivation. J Clin Invest 118: 2291-2300.
  15. Malchiodi-Albedi F, Matteucci A, Bernardo A, Minghetti L (2008) PPAR-gamma, Microglial Cells, and Ocular Inflammation: New Venues for Potential Therapeutic Approaches. PPAR Res 2008: 295784.
  16. Aoun P, Simpkins JW, Agarwal N (2003) Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells. Invest Ophthalmol Vis Sci 44: 2999-3004.
  17. Sarafidis PA, Bakris GL (2006) Protection of the kidney by thiazolidinediones: an assessment from bench to bedside. Kidney Int 70: 1223-1233.
  18. Tilg H, Moschen AR (2008) Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14: 222-231.
  19. Tontonoz P, Spiegelman BM (2008) Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77: 289-312.
  20. Zinn A, Felson S, Fisher E, Schwartzbard A (2008) Reassessing the cardiovascular risks and benefits of thiazolidinediones. Clin Cardiol 31: 397-403.
  21. Ershov AV, Bazan NG (2000) Photoreceptor phagocytosis selectively activates PPARgamma expression in retinal pigment epithelial cells. J Neurosci Res 60: 328-337.
  22. Straus DS, Glass CK (2001) Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med Res Rev 21: 185-210.
  23. Bernardo A, Levi G, Minghetti L (2000) Role of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its natural ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) in the regulation of microglial functions. Eur J Neurosci 12: 2215-2223.
  24. Blackwell TS, Christman JW (1997) The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 17: 3-9.
  25. Luna-Medina R, Cortes-Canteli M, Alonso M, Santos A, Martinez A, et al. (2005) Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. J Biol Chem 280: 21453-21462.
  26. Marx N, Walcher D, Ivanova N, Rautzenberg K, Jung A, et al. (2004) Thiazolidinediones reduces endothelial expression of receptors for advanced glycation end products. Diabetes 53: 2662-2668.
  27. Gerry JM, Pascual G (2008) Narrowing in on cardiovascular disease: the atheroprotective role of peroxisome proliferator-activated receptor gamma. Trends Cardiovasc Med 18: 39-44.
  28. Giaginis C, Tsourouflis G, Theocharis S (2008) Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: novel pharmacological agents in the treatment of ischemia reperfusion injury. Curr Mol Med 8: 562-579.
  29. Sulistio MS, Zion A, Thukral N, Chilton R (2008) PPARgamma agonists and coronary atherosclerosis. Curr Atheroscler Rep 10: 134-141
  30. Yamagishi S, Nakamura K, Matsui T (2007) Potential utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity for the treatment of cardiometabolic disorders. Curr Mol Med 7: 463-469.
  31. Hammes HP, Strodter D, Weiss A, Bretzel RG, Federlin K, et al. (1995) Secondary intervention with aminoguanidine retards the progression of diabetic retinopathy in the rat model. Diabetologia 38: 656-660.
  32. Mizutani M, Kern TS, Lorenzi M (1996) Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 97: 2883-2890.
  33. Decanini A, Karunadharma PR, Nordgaard CL, Feng X, Olsen TW, et al. (2008) Human retinal pigment epithelium proteome changes in early diabetes. Diabetologia 51: 1051-1061.
  34. Ibrahim AS, El-Remessy AB, Matragoon S, Zhang W, Patel Y, et al. (2011) Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes. Diabetes 60: 1122-1133.
  35. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Nakamura M (2000) New insights into the pathophysiology of diabetic retinopathy: potential cell-specific therapeutic targets. Diabetes Technol Ther 2: 601-608.
  36. Yam JC, Kwok AK (2007) Update on the treatment of diabetic retinopathy. Hong Kong Med J 13: 46-60.
  37. Villarroel M, Ciudin A, Hernandez C, Simo R (2010) Neurodegeneration: An early event of diabetic retinopathy. World J Diabetes 1: 57-64.
  38. Tretiach M, Madigan MC, Wen L, Gillies MC (2005) Effect of Muller cell co-culture on in vitro permeability of bovine retinal vascular endothelium in normoxic and hypoxic conditions. Neurosci Lett 378: 160-165.
  39. Abu El-Asrar AM, Al-Mezaine HS, Ola MS (2009) Pathophysiology and management of diabetic retinopathy. Expert Review of Ophthalmology 4: 627-647.
  40. Goh SY, Cooper ME (2008) Clinical review: The role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab 93: 1143-1152.
  41. Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, et al. (1994) Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb 14: 1521-1528.
  42. Chu J, Ali Y (2008) Diabetic Retinopathy: A Review. Drug Development Research 69: 1-14.
  43. Munch G, Schinzel R, Loske C, Wong A, Durany N, et al. (1998) Alzheimer's disease--synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. J Neural Transm 105: 439-461.
  44. Hammes HP, Hoerauf H, Alt A, Schleicher E, Clausen JT, et al. (1999) N(epsilon)(carboxymethyl)lysin and the AGE receptor RAGE colocalize in age-related macular degeneration. Invest Ophthalmol Vis Sci 40: 1855-1859.
  45. Stitt AW, Li YM, Gardiner TA, Bucala R, Archer DB, et al. (1997) Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol 150: 523-531.
  46. Lecleire-Collet A, Tessier LH, Massin P, Forster V, Brasseur G, et al. (2005) Advanced glycation end products can induce glial reaction and neuronal degeneration in retinal explants. Br J Ophthalmol 89: 1631-1633.
  47. Denis U, Lecomte M, Paget C, Ruggiero D, Wiernsperger N, et al. (2002) Advanced glycation end-products induce apoptosis of bovine retinal pericytes in culture: involvement of diacylglycerol/ceramide production and oxidative stress induction. Free Radic Biol Med 33: 236-247.
  48. Kaji Y, Amano S, Usui T, Oshika T, Yamashiro K, et al. (2003) Expression and function of receptors for advanced glycation end products in bovine corneal endothelial cells. Invest Ophthalmol Vis Sci 44: 521-528.
  49. Kasper M, Roehlecke C, Witt M, Fehrenbach H, Hofer A, et al. (2000) Induction of apoptosis by glyoxal in human embryonic lung epithelial cell line L132. Am J Respir Cell Mol Biol 23: 485-491.
  50. Sato T, Iwaki M, Shimogaito N, Wu X, Yamagishi S, et al. (2006) TAGE (toxic AGEs) theory in diabetic complications. Curr Mol Med 6: 351-358.
  51. Stitt AW (2001) Advanced glycation: an important pathological event in diabetic and age related ocular disease. Br J Ophthalmol 85: 746-753.
  52. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615-1625.
  53. Ceriello A, Mercuri F, Quagliaro L, Assaloni R, Motz E, et al. (2001) Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia 44: 834-838.
  54. Moore TC, Moore JE, Kaji Y, Frizzell N, Usui T, et al. (2003) The role of advanced glycation end products in retinal microvascular leukostasis. Invest Ophthalmol Vis Sci 44: 4457-4464.
  55. Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, et al. (2007) Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 148: 548-558.
  56. Schmidt M, Giessl A, Laufs T, Hankeln T, Wolfrum U, et al. (2003) How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply in the mammalian retina. J Biol Chem 278: 1932-1935.
  57. Kowluru RA (2005) Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxid Redox Signal 7: 1581-1587.
  58. Kowluru RA, Kern TS, Engerman RL, Armstrong D (1996) Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants. Diabetes 45: 1233-1237.
  59. Kowluru RA, Tang J, Kern TS (2001) Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 50: 1938-1942.
  60. Obrosova IG, Julius UA (2005) Role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy. Curr Vasc Pharmacol 3: 267-283.
  61. Allen DA, Yaqoob MM, Harwood SM (2005) Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications. J Nutr Biochem 16: 705-713.
  62. Kern TS, Barber AJ (2008) Retinal ganglion cells in diabetes. J Physiol 586: 4401-4408.
  63. Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12: 141-179.
  64. Boileau TW, Bray TM, Bomser JA (2003) Ultraviolet radiation modulates nuclear factor kappa B activation in human lens epithelial cells. J Biochem Mol Toxicol 17: 108-113.
  65. Schreck R, Albermann K, Baeuerle PA (1992) Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 17: 221-237.
  66. Siebenlist U, Franzoso G, Brown K (1994) Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 10: 405-455.
  67. Du X, Stocklauser-Farber K, Rosen P (1999) Generation of reactive oxygen intermediates, activation of NF-kappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic Biol Med 27: 752-763.
  68. Romeo G, Liu WH, Asnaghi V, Kern TS, Lorenzi M (2002) Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. Diabetes 51: 2241-2248.
  69. Zheng L, Howell SJ, Hatala DA, Huang K, Kern TS (2007) Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes 56: 337-345.
  70. Adamis AP (2002) Is diabetic retinopathy an inflammatory disease? Br J Ophthalmol 86: 363-365.
  71. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, et al. (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 16: 438-440.
  72. Haubner F, Lehle K, Munzel D, Schmid C, Birnbaum DE, et al. (2007) Hyperglycemia increases the levels of vascular cellular adhesion molecule-1 and monocyte-chemoattractant-protein-1 in the diabetic endothelial cell. Biochem Biophys Res Commun 360: 560-565.
  73. Tawfik A, Sanders T, Kahook K, Akeel S, Elmarakby A, et al. (2009) Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Invest Ophthalmol Vis Sci 50: 878-884.
  74. Ali TK, Matragoon S, Pillai BA, Liou GI, El-Remessy AB (2008) Peroxynitrite mediates retinal neurodegeneration by inhibiting nerve growth factor survival signaling in experimental and human diabetes. Diabetes 57: 889-898.
  75. El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai NT, Caldwell RB, et al. (2006) Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am J Pathol 168: 235-244.
  76. Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, et al. (2004) A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 18: 1450-1452.
  77. Kern TS (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007: 95103.
  78. Miyamoto K, Ogura Y (1999) Pathogenetic potential of leukocytes in diabetic retinopathy. Semin Ophthalmol 14: 233-239.
  79. Yuuki T, Kanda T, Kimura Y, Kotajima N, Tamura J, et al. (2001) Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J Diabetes Complications 15: 257-259.
  80. Beck L, D'Amore PA (1997) Vascular development: cellular and molecular regulation. FASEB J 11: 365-373.
  81. De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, et al. (2008) The role of the EGFR signaling in tumor microenvironment. J Cell Physiol 214: 559-567
  82. Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81: 154-162.
  83. Miller JW, Adamis AP, Shima DT, D'Amore PA, Moulton RS, et al. (1994) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 145: 574-584.
  84. Hollborn M, Stathopoulos C, Steffen A, Wiedemann P, Kohen L, et al. (2007) Positive feedback regulation between MMP-9 and VEGF in human RPE cells. Invest Ophthalmol Vis Sci 48: 4360-4367.
  85. Herzlich AA, Tuo J, Chan CC (2008) Peroxisome proliferator-activated receptor and age-related macular degeneration. PPAR Res 2008: 389507.
  86. Calza L, Giardino L, Giuliani A, Aloe L, Levi-Montalcini R (2001) Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. Proc Natl Acad Sci U S A 98: 4160-4165.
  87. Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, et al. (2002) Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J 16: 1307-1309.
  88. Liu XL, Wang DD, Liu YZ, Luo Y, Ma W, et al. (2010) Neuronal-Driven Angiogenesis: Role of NGF in Retinal Neovascularization in an Oxygen-Induced Retinopathy Model. Inves Ophthal Vis Sci 51: 3749-3757.
  89. Leal EC, Aveleira CA, Castilho AF, Serra AM, Baptista FI, et al. (2009) High glucose and oxidative/nitrosative stress conditions induce apoptosis in retinal endothelial cells by a caspase-independent pathway. Exp Eye Res 88: 983-991.
  90. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491-501.
  91. Kern TS, Tang J, Mizutani M, Kowluru RA, Nagaraj RH, et al. (2000) Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia. Invest Ophthalmol Vis Sci 41: 3972-3978.
  92. Kowluru RA, Odenbach S (2004) Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats. Diabetes 53: 3233-3238.
  93. Lopes de Faria JM, Katsumi O, Cagliero E, Nathan D, Hirose T (2001) Neurovisual abnormalities preceding the retinopathy in patients with long-term type 1 diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 239: 643-648.
  94. Henkind P (1978) Ocular neovascularization. The Krill memorial lecture. Am J Ophthalmol 85: 287-301.
  95. Patz A (1982) Clinical and experimental studies on retinal neovascularization. XXXIX Edward Jackson Memorial Lecture. Am J Ophthalmol 94: 715-743.
  96. Zeng K, Xu H, Mi M, Zhang Q, Zhang Y, et al. (2009) Dietary taurine supplementation prevents glial alterations in retina of diabetic rats. Neurochem Res 34: 244-254.
  97. Abu El-Asrar AM, Dralands L, Missotten L, Al-Jadaan I, Geboes K (2004) Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthal Vis Sci 45: 2760-2766.
  98. Zeng K, Xu H, Mi M, Chen K, Zhu J, et al. (2010) Effects of taurine on glial cells apoptosis and taurine transporter expression in retina under diabetic conditions. Neurochem Res 35: 1566-1574.
  99. de Faria JML, Russ H, Costa VP (2002) Retinal nerve fibre layer loss in patients with type 1 diabetes mellitus without retinopathy. Br J Ophthalmol 86: 725-728.
  100. Zhang LX, Ino-ue M, Dong K, Yamamoto M (2000) Retrograde axonal transport impairment of large- and medium-sized retinal ganglion cells in diabetic rat. Curr Eye Res 20: 131-136.
  101. Doonan F, Wallace DM, O'Driscoll C, Cotter TG (2009) Rosiglitazone acts as a neuroprotectant in retinal cells via up-regulation of sestrin-1 and SOD-2. J Neurochem 109: 631-643.
  102. Sakai H, Tani Y, Shirasawa E, Shirao Y, Kawasaki K (1995) Development of electroretinographic alterations in streptozotocin-induced diabetes in rats. Ophthalmic Res 27: 57-63.
  103. Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, et al. (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 102: 783-791.
  104. Barber AJ, Antonetti DA, Gardner TW (2000) Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group. Invest Ophthalmol Vis Sci 41: 3561-3568.
  105. Pulido JE, Pulido JS, Erie JC, Arroyo J, Bertram K, et al. (2007) A role for excitatory amino acids in diabetic eye disease. Exp Diabetes Res 2007: 36150.
  106. Zeng HY, Green WR, Tso MO (2008) Microglial activation in human diabetic retinopathy. Arch Ophthalmol 126: 227-232.
  107. Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, et al. (2005) Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54: 1559-1565.
  108. Langmann T (2007) Microglia activation in retinal degeneration. J Leukoc Biol 81: 1345-1351.
  109. Gaucher D, Chiappore JA, Paques M, Simonutti M, Boitard C, et al. (2007) Microglial changes occur without neural cell death in diabetic retinopathy. Vision Res 47: 612-623.
  110. Kowluru RA, Engerman RL, Case GL, Kern TS (2001) Retinal glutamate in diabetes and effect of antioxidants. Neurochem Int 38: 385-390.
  111. Oshitari T, Yamamoto S, Hata N, Roy S (2008) Mitochondria- and caspase-dependent cell death pathway involved in neuronal degeneration in diabetic retinopathy. Br J Ophthalmol 92: 552-556.
  112. Sivakumar V, Foulds WS, Luu CD, Ling EA, Kaur C (2011) Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina. J Pathol 224: 245-260.
  113. Bok D (1993) The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl 17: 189-195.
  114. Rizzolo LJ (1997) Polarity and the development of the outer blood-retinal barrier. Histol Histopathol 12: 1057-1067.
  115. Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45: 115-134.
  116. Kennedy CJ, Rakoczy PE, Constable IJ (1995) Lipofuscin of the retinal pigment epithelium: a review. Eye (Lond) 9: 763-771.
  117. Kimoto K, Nakatsuka K, Matsuo N, Yoshioka H (2004) p38 MAPK mediates the expression of type I collagen induced by TGF-beta 2 in human retinal pigment epithelial cells ARPE-19. Invest Ophthalmol Vis Sci 45: 2431-2437.
  118. Grossniklaus HE, Ling JX, Wallace TM, Dithmar S, Lawson DH, et al. (2002) Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8: 119-126.
  119. de Jong PT (2006) Age-related macular degeneration. N Engl J Med 355: 1474-1485.
  120. SanGiovanni JP, Chew EY (2005) The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res 24: 87-138.
  121. Winkler BS, Boulton ME, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5: 32.
  122. Murata T, He S, Hangai M, Ishibashi T, Xi XP, et al. (2000) Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization. Invest Ophthalmol Vis Sci 41: 2309-2317.
  123. Muranaka K, Yanagi Y, Tamaki Y, Usui T, Kubota N, et al. (2006) Effects of peroxisome proliferator-activated receptor gamma and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model. Invest Ophthalmol Vis Sci 47: 4547-4552.
  124. Xin X, Yang S, Kowalski J, Gerritsen ME (1999) Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 274: 9116-9121.
  125. Touyz RM, Schiffrin EL (2006) Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications. Vascul Pharmacol 45: 19-28.
  126. Shen LQ, Child A, Weber GM, Folkman J, Aiello LP (2008) Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch Ophthalmol 126: 793-799.
  127. Arimoto T, Bing GY (2003) Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration. Neurobiol Dis 12: 35-45.
  128. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW (1993) Cytotoxicity of microglia. Glia 7: 111-118.
  129. Heneka MT, Klockgether T, Feinstein DL (2000) Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci 20: 6862-6867.
  130. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137: 354-366.
  131. Kim EJ, Kwon KJ, Park JY, Lee SH, Moon CH, et al. (2002) Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons: associated with iNOS and COX-2. Brain Res 941: 1-10.
  132. Storer PD, Xu JH, Chavis J, Drew PD (2005) Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: Implications for multiple sclerosis. J Neuroimmunol 161: 113-122.
  133. Uryu S, Harada J, Hisamoto M, Oda T (2002) Troglitazone inhibits both post-glutamate neurotoxicity and low-potassium-induced apoptosis in cerebellar granule neurons. Brain Res 924: 229-236.
  134. Hunter RL, Bing GY (2007) Agonism of peroxisome proliferator receptor-gamma may have therapeutic potential for neuroinflammation and Parkinson's disease. Curr Neuropharmacol 5: 35-46.
  135. Dolhofer-Bliesener R, Lechner B, Gerbitz KD (1996) Possible significance of advanced glycation end products in serum in end-stage renal disease and in late complications of diabetes. Eur J Clin Chem Clin Biochem 34: 355-361.
  136. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, et al. (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 13: 950-958.
  137. Rahbar S, Natarajan R, Yerneni K, Scott S, Gonzales N, et al. (2000) Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation. Clin Chim Acta 301: 65-77.
  138. Sobal G, Menzel EJ, Sinzinger H (2005) Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein. J Cardiovasc Pharmacol 46: 672-680.
  139. Li J, Liu NF, Wei Q (2008) Effect of rosiglitazone on cardiac fibroblast proliferation, nitric oxide production and connective tissue growth factor expression induced by advanced glycation end-products. J Int Med Res 36: 329-335.
  140. Yu X, Li C, Li X, Cai L (2007) Rosiglitazone prevents advanced glycation end products-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1. Toxicol Sci 96: 346-356.
  141. Chang PC, Chen TH, Chang CJ, Hou CC, Chan P, et al. (2004) Advanced glycosylation end products induce inducible nitric oxide synthase (iNOS) expression via a p38 MAPK-dependent pathway. Kidney Int 65: 1664-1675.
  142. Kim EK, Kwon KB, Koo BS, Han MJ, Song MY, et al. (2007) Activation of peroxisome proliferator-activated receptor-gamma protects pancreatic beta-cells from cytokine-induced cytotoxicity via NF kappaB pathway. Int J Biochem Cell Biol 39: 1260-1275.
  143. Lee KS, Kim SR, Park SJ, Park HS, Min KH, et al. (2006) Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice. J Allergy Clin Immunol 118: 120-127.
  144. Rosen ED, Spiegelman BM (2001) PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276: 37731-37734.
  145. Sung B, Park S, Yu BP, Chung HY (2006) Amelioration of age-related inflammation and oxidative stress by PPARgamma activator: suppression of NF-kappaB by 2,4-thiazolidinedione. Exp Gerontol 41: 590-599.
  146. Remels AH, Langen RC, Gosker HR, Russell AP, Spaapen F, et al. (2009) PPARgamma inhibits NF-kappaB-dependent transcriptional activation in skeletal muscle. Am J Physiol Endocrinol Metab 297: E174-183.
  147. Uchimura K, Nakamuta M, Enjoji M, Irie T, Sugimoto R, et al. (2001) Activation of retinoic X receptor and peroxisome proliferator-activated receptor-gamma inhibits nitric oxide and tumor necrosis factor-alpha production in rat Kupffer cells. Hepatology 33: 91-99.
  148. Wong A, Dukic-Stefanovic S, Gasic-Milenkovic J, Schinzel R, Wiesinger H, et al. (2001) Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. Eur J Neurosci 14: 1961-1967.
  149. Petrova TV, Akama KT, Van Eldik LJ (1999) Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2. Proc Natl Acad Sci U S A 96: 4668-4673.
  150. Reilly CM, Oates JC, Sudian J, Crosby MB, Halushka PV, et al. (2001) Prostaglandin J(2) inhibition of mesangial cell iNOS expression. Clin Immunol 98: 337-345.
  151. Heneka MT, Feinstein DL, Galea E, Gleichmann M, Wullner U, et al. (1999) Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J Neuroimmunol 100: 156-168.
  152. Murata T, Hata Y, Ishibashi T, Kim S, Hsueh WA, et al. (2001) Response of experimental retinal neovascularization to thiazolidinediones. Arch Ophthalmol 119: 709-717.
  153. Miyahara S, Kiryu J, Yamashiro K, Miyamoto K, Hirose F, et al. (2004) Simvastatin inhibits leukocyte accumulation and vascular permeability in the retinas of rats with streptozotocin-induced diabetes. Am J Pathol 164: 1697-1706.
  154. Scoditti E, Massaro M, Carluccio MA, Distante A, Storelli C, et al. (2009) PPARgamma agonists inhibit angiogenesis by suppressing PKCalpha- and CREB-mediated COX-2 expression in the human endothelium. Cardiovasc Res 86: 302-310.
  155. Bonne C (2005) [PPAR gamma: a novel pharmacological target against retinal and choroidal neovascularization]. J Fr Ophtalmol 28: 326-330.
  156. Fehlberg S, Gregel CM, Goke A, Goke R (2003) Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO. Br J Pharmacol 139: 495-500.
  157. Fuenzalida K, Quintanilla R, Ramos P, Piderit D, Fuentealba RA, et al. (2007) Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. J Biol Chem 282: 37006-37015.
  158. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116: 205-219.
  159. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787-795.
  160. Ren Y, Sun C, Sun Y, Tan H, Wu Y, et al. (2009) PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation. Vascul Pharmacol 51: 169-174.
  161. Wu JS, Lin TN, Wu KK (2009) Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J Cell Physiol 220: 58-71.
  162. Baker MS, Chen X, Cao XC, Kaufman DB (2001) Expression of a dominant negative inhibitor of NF-kappaB protects MIN6 beta-cells from cytokine-induced apoptosis. J Surg Res 97: 117-122.
  163. Grey ST, Arvelo MB, Hasenkamp W, Bach FH, Ferran C (1999) A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets. J Exp Med 190: 1135-1146.
  164. Rodrigues GA, Maurier-Mahe F, Shurland DL, McLaughlin AP, Luhrs K, et al. (2010) Differential effects of PPARgamma ligands on oxidative stress-induced death of retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 52: 890-903.
  165. Chang RC, So KF (2008) Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far? Cell Mol Neurobiol 28: 643-652.
  166. Garg TK, Chang JY (2004) 15-deoxy-delta 12, 14-Prostaglandin J2 prevents reactive oxygen species generation and mitochondrial membrane depolarization induced by oxidative stress. BMC Pharmacol 4: 6.
  167. Fuenzalida K, Quintanilla R, Ramos P, Piderit D, Fuentealba RA, et al. (2007) Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. J Biol Chem 282: 37006-37015.
  168. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, et al. (1995) 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83: 803-812.
  169. Chang JY, Bora PS, Bora NS (2008) Prevention of Oxidative Stress-Induced Retinal Pigment Epithelial Cell Death by the PPARgamma Agonists, 15-Deoxy-Delta 12, 14-Prostaglandin J(2). PPAR Res 2008: 720163.
  170. Qin S, McLaughlin AP, De Vries GW (2006) Protection of RPE cells from oxidative injury by 15-deoxy-delta12,14-prostaglandin J2 by augmenting GSH and activating MAPK. Invest Ophthalmol Vis Sci 47: 5098-5105.
  171. Garg TK, Chang JY (2003) Oxidative stress causes ERK phosphorylation and cell death in cultured retinal pigment epithelium: prevention of cell death by AG126 and 15-deoxy-delta 12, 14-PGJ2. BMC Ophthalmol 3: 5.
  172. Huang TH, Kota BP, Razmovski V, Roufogalis BD (2005) Herbal or natural medicines as modulators of peroxisome proliferator-activated receptors and related nuclear receptors for therapy of metabolic syndrome. Basic Clin Pharmacol Toxicol 96: 3-14.
  173. Roehr B (2010) FDA committee urges tight restrictions on rosiglitazone. BMJ 341: c3862.
Citation: Song MK, Roufogalis BD, Huang THW (2012) Role of Peroxisome Proliferator Activator Receptor γ in Diabetic Retinopathy Pathophysiology. J Diabetes Metab S3:005.

Copyright: © 2012 Song MK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.