Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic retinopathy and neuropathy

in Journal of Endocrinology

Pigment epithelium-derived factor (PEDF) is a pluripotent glycoprotein belonging to the serpin family. PEDF can stimulate several physiological processes such as angiogenesis, cell proliferation, and survival. Oxidative stress plays an important role in the occurrence of diabetic retinopathy (DR), which is the major cause of blindness in young diabetic adults. PEDF plays a protective role in DR and there is accumulating evidence of the neuroprotective effect of PEDF. In this paper, we review the role of PEDF and the mechanisms involved in its antioxidative, anti-inflammatory, and neuroprotective properties.

Abstract

Pigment epithelium-derived factor (PEDF) is a pluripotent glycoprotein belonging to the serpin family. PEDF can stimulate several physiological processes such as angiogenesis, cell proliferation, and survival. Oxidative stress plays an important role in the occurrence of diabetic retinopathy (DR), which is the major cause of blindness in young diabetic adults. PEDF plays a protective role in DR and there is accumulating evidence of the neuroprotective effect of PEDF. In this paper, we review the role of PEDF and the mechanisms involved in its antioxidative, anti-inflammatory, and neuroprotective properties.

Introduction

Nontransmissible chronic diseases are increasing all over the world, resulting in financial and logistical challenges for all health care systems in the 21st century. Contributing to this scenario, diabetic retinopathy (DR), one of the most devastating acquired vascular complications of diabetes mellitus, is responsible for affecting overall life quality worldwide. It has been estimated that the number of Americans suffering from DR will be 16 million by 2050 (Milne & Brownstein 2013).

In DR disease, premature death of pericytes occurs via apoptosis, and may result in a dramatic reduction in retinal function, due to the formation of pericyte ghosts in the basement membrane, subsequently leading to nonproliferative DR (Amano et al. 2005, Hammes 2005, Ejaz 2008). Pericytes are one of the main cell types of retinal microvessels, playing an important role in retinal capillary homeostasis via control of proliferation of endothelial cells (ECs). Furthermore, experimental evidence shows that pericytes are responsible for protection of ECs against lipid peroxide-induced injuries, preserving their capacity to produce prostacyclins (Yamagishi et al. 1993a,b). Therefore, in DR, major structural change occurs, including thickening of the basement membrane, hyperpermeability, and the formation of microaneurysms. These changes ultimately predispose the capillaries to neovascularization, angiogenesis, ECs injuries, and the proliferative form of DR, which mostly results in vision loss due to macular edema (Yamagishi & Matsui 2011).

Metabolic and signaling disturbances in diabetes can initiate apoptosis in retinal capillaries and may culminate in pericyte apoptosis and depletion (Ejaz 2008, Yamagishi & Matsui 2011). These disturbances include formation of advanced glycation end products (AGEs), upregulation of protein kinase C, the polyol pathway, focal leukostasis, and oxidative stress. In DR, promoted by an islet-based inability to secrete or failure of target tissues to optimally respond to insulin, hyperglycemic events are common and these, per se, promote the aberrant production of reactive oxygen species (ROS) and an overwhelmed detoxification system in insulin-responsive cells, which leads to oxidative stress (Yamagishi et al. 2002a, Newsholme et al. 2012). In this context, pigment epithelium-derived factor (PEDF, a glycoprotein (50 kDa, 418 amino acids) widely expressed in most body tissues) exerts anti-inflammatory functions, attenuating the expression of chemical mediators, such as vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα), and intercellular adhesion molecule 1 (ICAM1) in retinal vascular ECs (Zhang et al. 2008, 2011).

Recent advances in molecular and cell biology have provided the basis for the discovery of inhibitory activity of PEDF against cancers, such as osteosarcoma (Dass et al. 2007, Ek et al. 2007a,b,c, Ta et al. 2009), breast and prostate cancers (Filiz & Dass 2012), and chondrosarcoma (Tan et al. 2010). It also protects against oxidative stress, which includes diabetic damage in the eye and angiogenic-related disease (Yamagishi et al. 2003), vascular injuries (Yoshida et al. 2006, Nakamura et al. 2007), and neurotoxicity (Araki et al. 1998, Yabe et al. 2005a). However, recent work has provided evidence that in uncontrolled diabetes, PEDF levels in the retina and vitreous fluids are low, which may contribute to proliferative DR (Boehm et al. 2003, Yokoi et al. 2007). Considering the epidemic challenge of diabetes and its complications, a better understanding of DR, its mechanisms, and targets will be essential to future new strategies and treatments. In the following sections, first the mechanisms and pathways that are involved in the development of DR and pericyte loss is discussed and next the inhibitory and protective role of PEDF will be presented.

Role of oxidative stress and inflammation in the development of DR

The Maillard process, a nonenzymatic reaction between a reducing sugar and free amino groups in proteins (the carbonyl group of the sugar reacts with the amino group producing N-substituted glycosylamine and water), is important for the development of DR. The glycosylamine undergoes Amadori rearrangement to form various ketosamines that undergo further rearrangement, important for the creation of glycation products which can undergo further complex reactions such as dehydration, condensation, and rearrangement, and become permanently cross-linked to form AGEs (Sato et al. 2006, Yamagishi et al. 2007a, Yamagishi & Matsui 2011). During the progression of diabetes, the formation and accumulation of AGEs increase. Retinal pericytes are associated with higher levels of AGEs, which then contribute to retinal vascular hyperpermeability and DR (Yamagishi et al. 2002a, 2007a, Sato et al. 2006). AGEs, and signaling stimulated by their receptors (RAGEs), can induce the generation of intracellular ROS and provoke oxidative stress, initiating vascular inflammation and complications in diabetes (Fukami et al. 2004). Furthermore, AGE–RAGE interaction can also cause apoptosis in retinal pericytes and become embroiled in the early phase of DR (Hammes et al. 1999, Yamagishi et al. 2002a,b).

Free radical (containing an unpaired electron) and nonradical ROS can be produced through different mechanisms including the plasma or organelle membrane-bound NADPH oxidase (NOX) family of enzymes, ischemia/reperfusion, inflammatory response, transition metal ions, and inefficient electron transport chain reactivity in organelles such as mitochondria. Some ROS such as superoxide anion (O2) or hydroxyl radicals (OH•) are extremely unstable, whereas others such as hydrogen peroxide (H2O2) are freely diffusible and relatively long-lived, from nanoseconds to milliseconds (Newsholme et al. 2012). In general, ROS are considered highly reactive molecules as they tend to capture electrons from other molecules (oxidation) and produce other ROS, such as peroxynitrite (ONOO), thiol-based radicals (RS•), and others (Brownlee 2001). Moreover, these unstable molecules can promote DNA damage by reacting with nucleotides, proteins, and especially structural components in the cell such as neutral lipids and phospholipids of the membranes via a process known as lipid peroxidation (propagation step of ROS; Finkel & Holbrook 2000). Lipid peroxidation changes the fluidity of cell membranes, reduces the capacity to maintain defined ion gradients (e.g. Na+ and K+), and also increases membrane permeability. Consequently, lipid peroxidation leads to a loss of intracellular proteins, reduces Ca2+ transport across the cell and endoplasmic reticulum membranes, altering mitochondrial voltage channels, and cell function (Dias & Griffiths 2014).

It has been well-documented that high glucose, fatty acids, and AGEs can increase intracellular ROS generation and induce apoptosis in retinal pericytes (Amano et al. 2002, Yamagishi et al. 2002a,b,c). High glucose and fatty acid levels may overstimulate electron transport activity in the mitochondria, leading to excessive generation of superoxide (Newsholme et al. 2007).

Characterized by increased levels of ROS due to excessive production and slow removal by the anti-oxidant systems, the phenomenon of oxidative stress has attracted attention in the last decades. The rationale for this scientific interest arises from the fact that oxidative stress, and consequently the change in the intracellular redox state, occurs in several disease mechanisms (Krause & de Bittencourt 2008, Cruzat et al. 2014), including the complications of diabetes (Newsholme et al. 2007) and aging (Ristow et al. 2009). The detrimental effects of AGEs on pericyte survival and function are mediated via increased ROS generation, which then leads to apoptosis. It has been shown that AGE-modified BSA (AGE–BSA) has the potential to stimulate glucose transport into retinal pericytes followed by an elevation in ROS production therefore provoking cell death. The activation of AGE-sensitive cell surface receptors, such as RAGE, or nonreceptor-dependent pathways may be involved in increasing ROS generation (Schmidt et al. 2001; Fig. 1).

Figure 1
Figure 1

A brief overview of the protective mechanisms mediated by PEDF in conditions of oxidative stress caused by advanced glycation end products (AGEs), NADPH oxidase activation and glycated LDL in pericytes and endothelial cells (EC). (A) In LDL-exposed pericytes, PEDF can suppress the binding of nuclear factor kappa B (NFκB) to DNA and, as a result, inhibit the monocyte chemoattractant protein 1 (MCP1) (Zhang et al. 2008). (B) In AGE-exposed pericytes, PEDF is able to attenuate caspase 3 activity by improving the ratio of BCL2/BAX (Yamagishi et al. 2002a,c). (C) In AGE-exposed EC, PEDF can reduce reactive oxygen species (ROS) generation by downregulating p22PHOX and gp91PHOX thus suppressing NADPH oxidase activity (Yoshida et al. 2009, Yamagishi et al. 2006a). A full colour version of this figure is available at http://dx.doi.org/10.1530/JOE-14-0065.

Citation: Journal of Endocrinology 222, 3; 10.1530/JOE-14-0065

The BCL2 family of proteins are key players in the regulation of apoptosis. The anti-apoptotic members of this family, such as BCL2, inhibit apoptosis by blocking the release of cytochrome c from mitochondria. However, the pro-apoptotic members of this family, including BAX, enhance the release of cytochrome c, which subsequently leads to activation of different caspase molecules (such as caspases 3 and 9) that cleave various downstream pro-caspases within the cell to induce full-blown apoptosis (Cory & Adams 2002, Broadhead et al. 2009). Furthermore, inflammatory reactions and apoptosis are initiated as a result of activation of MAP kinase/RAS, nuclear factor kappa B (NFκB), AKT, and p38 in addition to key molecules in apoptotic pathways, for example forkhead transcription factors (FOXO) and c-JUN (Min et al. 1999, Alikhani et al. 2007). During pericyte apoptosis, caspase 3, a key enzyme required for the execution of apoptosis, increases in concentration due to a decreased ratio of BCL2/BAX.

Oxidative stress can result in direct, free radical-based DNA damage, but can also trigger redox pathways required for transcriptional activation. NFκB in retinal pericytes is extremely sensitive to the redox status of the cells, and normally remains in an inactive form, as it is bound with an inhibitory IκB protein. Several inflammatory stimuli, such as TNFα, and also elevated levels oxidative stress can promote specific signal transducing pathways to enable phosphorylation of the IκB and subsequent degradation by the 26S proteosome (Sethi et al. 2008). The phosphorylation of IκB releases NFκB from IκB protein and permits NFκB to translocate to the nucleus (Heck et al. 2011). The subunit composition of NFκB can vary, although NFκB p65 (Rel A) and NFκB p50 (NFκB1) are the classical NFκB pathway components studied in inflammation (Sethi et al. 2008). Many target genes related to pro-inflammatory response (e.g. NFκBIA, NFκB1, COX2, MYD88, and IRAK1) are cyclically activated by NFκB. The imbalance between NFκB and IκB has several consequences, such as hyper-inflammation and loss of cell repair and function, which lead to apoptosis and DR disease evolution (Duarte et al. 2013).

Summary of the key roles of PEDF and potential mechanisms of protection in oxidative stress conditions

Apoptosis and PEDF: balance of BCL2 and BAX

PEDF has neurotrophic and neuroprotective effects on dopaminergic neurons (Falk et al. 2009), as well as protective effect on pericytes. A dose-dependent effect of PEDF on BCL2 was observed in cultured cortical neurons where PEDF upregulated the expression of BCL2 and promoted neuronal survival against oxidative stress (Sanchez et al. 2012). In photoreceptor cells, the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria intermembrane space during apoptosis results in chromatin condensation and DNA fragmentation. The upregulation of BCL2 by PEDF leads to inhibition of the nuclear translocation of AIF, resulting in prevention of the apoptosis in both in vitro and in vivo (Murakami et al. 2008). PEDF significantly prevents the arrest of DNA synthesis in cultured AGE-exposed pericytes by reversing the reduction in expression of BCL2, as well as inactivating BAX expression in retinal pericytes and thus aids pericyte survival (Fig. 1; Yamagishi et al. 2002a,c).

PEDF and inflammatory signal transduction

The protective effect of PEDF on retinal pericytes exposed to high-glucose or H2O2 is via stimulation of antioxidative mechanisms, such as inhibition of ROS production, and normalizing or enhancing the level of antioxidant enzymes such as phospholipid hydroperoxide/glutathione peroxidase (GSH-Px). PEDF is able to induce and increase the mRNA expression level of GSH-Px (Yamagishi et al. 2002a,c, Amano et al. 2005). However, the role of PEDF in regulating the levels and activity of the other major antioxidant enzymes – catalase and Cu/Zn superoxide dismutase (SOD) – has yet to be elucidated. Similarly, JAK2/STAT3 and ERKs (ERK1/2) are activated in bovine retinal capillary ECs (BRECs) (Zheng et al. 2010) and human retinal pigment epithelial cells (ARPE-19) respectively (Tsao et al. 2006). PEDF decreased the level of mitochondria-generated ROS, suppressed JAK2/STAT3 activation, leading to lower VEGF mRNA expression (Zheng et al. 2010). On the contrary, PEDF can induce ERK1/2 phosphorylation and activation and protect ARPE-19 cells against H2O2-mediated oxidative stress (Tsao et al. 2006). Similar pathways are involved in PEDF-mediated protection in cerebellum granule cells (Taniwaki et al. 1995, 1997), hippocampal neurons (DeCoster et al. 1999), and spinal motor neurons (Bilak et al. 1999) against glutamate toxicity. PEDF can induce ERK1/2 phosphorylation followed by phosphorylation and activation of cAMP-responsive element-binding protein (CREB) – the two key molecules in the cell survival signal transduction pathway – therefore providing protective properties in cultured rat cerebellar granule cells (CGCs) (Yabe et al. 2005b). Interestingly, the protective effect of PEDF has been observed in immature CGCs rather than mature cells (Taniwaki et al. 1995, Araki et al. 1998). The suggested mechanism underlying glutamate neurotoxicity is the elevation of intracellular Ca2+ as a result of opening N-methyl-d-aspartate (NMDA) channels. The high free intracellular Ca2+ leads to activation of Ca2+-dependent enzymes – nucleases, proteases, protein kinases, and protein phosphatases – and may also lead to the generation of free radicals. It has been postulated that PEDF can block the initial signal transduction, which leads to the opening of NMDA channels as well as maintain Ca2+ homeostasis through removal of excess Ca2+, thus helping cell survival (Taniwaki et al. 1997).

As mentioned before NFκB is one of the transcription factors activated during oxidative stress. PEDF inhibition of this particular pathway results in protection for AGE-exposed mesangial cells. In this situation, the coupling of RAGE and AGE can initiate downstream signaling and stimulate ROS-generated inflammatory and thrombogenic reactions via redox-sensitive transcriptional factor NFκB. PEDF can inhibit ROS generation, attenuating NFκB activation and subsequently inhibiting the expression of inflammatory and thrombogenic genes such as monocyte chemoattractant protein 1 (MCP1), vascular cell adhesion molecule 1 (VCAM1), and plasminogen activator inhibitor 1 (PAI1) (Ide et al. 2010). Furthermore, there is a correlation between MCP1 protein abundance in vitreous fluids and progression of proliferative DR (Mitamura et al. 2001). However, PEDF can inhibit AGE-induced overexpression of MCP1 in ECs by suppressing the generation of intracellular ROSs (Inagaki et al. 2003). This may be similar to the situation in retinal pericytes when exposed to glycated LDL. This oxidizing factor could activate the NFκB pathway and lead to overexpression of MCP1. PEDF has an inhibitory effect on MCP1 expression, which consequently results in decreased cell permeability and leakage and ultimately neovascularization in DR (Fig. 1). It also has been shown that PEDF can suppress the binding of NFκB to DNA and its transcription activation in a cell-type-specific manner (Yabe et al. 2001, Zhang et al. 2008). Production of pro-inflammatory cytokines can be inhibited by the activation of NFκB or CREB in cultured microglia (Sanagi et al. 2005), neonatal astrocytes (Yabe et al. 2005a), and rat culture CGCs (Yabe et al. 2005b). PEDF regulates the level of these transcription factors and therefore acts as a neuroimmune modulator in the CNS (Sanagi et al. 2005).

In relation to AGE-induced apoptosis in podocytes (epithelial cells around glomerular capillaries), restoration of transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) is the proposed pathway for PEDF protection, although it did not affect the AGE-induced reduction in PPARγ protein expression (Ishibashi et al. 2013). The antagonist effect of PEDF/RAGE also contributes to activation of PPARγ therefore inhibiting generation of ROS. PPARγ activation by PEDF can inhibit platelet-derived growth factor (PDGF)-induced migration and proliferation of smooth muscle cell (SMC) as well as suppress macrophage-mediated inflammatory reactions (Yang et al. 2010, Wang et al. 2012) which ultimately would lead to atherosclerosis as a result of ROS-induced signal transduction involving angiotensin II mediated EC activation and SMC proliferation (Nishikawa et al. 2000, Sorescu et al. 2002).

PEDF and NADPH

NOX-mediated ROS production and initiation of the redox-dependent signaling cascade as a result of Ang II expression and stimulation is an important event in vascular injury and inflammation (Yamagishi et al. 2005). PEDF can inhibit NOX ROS generation and in the case of MOLT-3 T cells, an immortalized T cell line, it leads to blocking and suppressing Ang II-induced VEGF expression (Yamagishi et al. 2006a). The protective effect of PEDF via its antioxidative effect has also been observed in Ang II-exposed human umbilical vein ECs (HUVECs). The activation of redox-sensitive transcription factor NFκB, and as a result, overexpression of MCP1 in HUVECs, is induced by activation of Ang II. PEDF can protect HUVECs via downregulation of the mRNA level of p22PHOX associated with NOX4 and gp91PHOX associated with NOX2. These subunits are membrane-bound components of NOX. A reduction in the level of these proteins can inhibit Ang II-induced ROS production (Yamagishi et al. 2005).

Studies on vascular hyperpermeability and oxidative stress in retinal ECs also include examination of the role of NOX and its various membrane components. NOX will be critical to superoxide and subsequently H2O2 generation (via SOD) in PEDF-stimulated ECs (Fig. 1). Some findings suggest that PEDF has an inhibitory effect on AGE-mediated VEGF-induced vascular hyperpermeability via suppression of VEGF expression (Yamagishi et al. 2006b, Yoshida et al. 2009). The latter authors have also shown that NOX activity has an important role in elevating ROS generation and ultimately in apoptosis and increased cell permeability. PEDF can downregulate p22PHOX and gp91PHOX mRNA levels and subsequently suppress NOX protein levels and activity (Yamagishi et al. 2006b, 2007b, Yoshida et al. 2009). Reduced NOX activity inhibits NFκB-dependent VEGF expression in ECs, affecting EC's vascular lining permeability and inhibiting ROS generation (Fig. 1). Furthermore, PEDF also has a protective effect in H2O2-induced retinal pigment epithelium (RPE) permeability. It has been shown that in H2O2-induced oxidative stress, PEDF is able to suppress the stress-activated p38/MAPK signaling pathway by inhibiting the phosphorylation and activation of a key substrate (HSP27; Ho et al. 2006). In a leptin-induced ROS generation model, PEDF inhibited VEGF expression, thus potentially eliminating the angiogenic effect of leptin and protecting ECs through its antioxidant properties (Yamagishi et al. 2003).

Adhesion of leukocytes and inflammatory cells to the capillary endothelium (leukostasis) is one of the possible mechanisms of DR, which can be related to ICAM1 levels. In AGE-induced oxidative stress conditions, ICAM1 overexpression may result in retinal leukostasis. PEDF can inhibit the overexpression of ICAM1 in ECs via its antioxidative properties (Yamagishi et al. 2006c).

Table 1 summarizes the suggested mechanisms of PEDF action in various cell types and PEDF-mediated survival in oxidative stress conditions.

Table 1

Summary of PEDF protective mechanisms in oxidative stress condition

Regulatory molecules/pathwaysConditionCell lineEffectsReferences
BCL2/BAXAGE exposurePericytesInhibition of apoptosisYamagishi et al. (2002a), Murakami et al. (2008), Falk et al. (2009) and Sanchez et al. (2012)
Oxidative stressCultured cortical neurons
Antioxidative molecule (GSH-Px)High glucosePericytesInhibition of ROS generationYamagishi et al. (2002a,c) and Amano et al. (2005)
H2O2 exposureNormalization of the level of anti-oxidant enzymes
PPARγAGE exposurePodocytesBlocking of RAGE expression and ROS generationNishikawa et al. (2000), Sorescu et al. (2002), Yang et al. (2010) and Ishibashi et al. (2013)
RAGEAGE exposureProximal tubular cellsInhibition of ROS generationNishikawa et al. (2000), Sorescu et al. (2002) and Yang et al. (2010)
Blocking of the inflammatory and fibrogenic gene expression
ERK1/2H2O2 exposureARPE-19Activation of CREBTaniwaki et al. (1995, 1997), Araki et al. (1998), Bilak et al. (1999), DeCoster et al. (1999), Tsao et al. (2006) and Zheng et al. (2010)
Cerebellar granule cells
JAK2/STAT3High glucoseBRECsInhibition of ROS generationTaniwaki et al. (1995, 1997), Araki et al. (1998), Bilak et al. (1999), DeCoster et al. (1999), Tsao et al. (2006) and Zheng et al. (2010)
Downregulation of VEGF
NFκBAGE exposureMesangial cells and ECsInhibition of ROS generationYabe et al. (2001, 2005a,b), Sanagi et al. (2005), Yamagishi et al. (2005) and Zhang et al. (2008)
LDL exposurePericytesBlocking of the expression of inflammatory and fibrogenic genes such as MCP1, VCAM1, and PAI1
HUVECInhibition of cell permeability and neovascularization
Ang II exposureCultured microgliaInhibition of NADPH-mediated and Ang II-induced ROS generation
Glutamate toxicityCultured rat cerebellar cellsDownregulation of membrane component of NADPH oxidase
Neonatal astrocytes
ICAM1AGE exposureECsSuppression of ICAM1 overexpressionYamagishi et al. (2006c)
P38/MAPK signalingH2O2 exposureRPEInhibition of substrate activation via suppression of phosphorylationYamagishi et al. (2003) and Ho et al. (2006)
VEGFH2O2 exposureMOLT-3 T cellsSuppression of the Ang II-induced VEGF expressionYamagishi et al. (2002b, 2006a,b) and Yoshida et al. (2009)
Leptin exposureECsBlocking of receptor–Ang II interaction
Inhibition of VEGF mRNA overexpression

Pericyte–EC communication and PEDF

The communication system between pericytes and ECs during angiogenesis and maturation of the vasculature system consists of several complex paracrine signaling pathways such as PDGFβ, activated transforming growth factor beta, VEGF, angiopoietin 1 (Ang I), and its antagonist angiopoietin 2 (Ang II) (Milne & Brownstein 2013). The regulatory effect of PEDF on paracrine signaling and its role in the maintenance of homeostasis between pericytes and ECs are also dependent on the antioxidative function of PEDF. Platelet activation and aggregation is a common cause of vascular complications in diabetic patients and oxidative stress via the action of AGEs (Yamagishi et al. 2001). The antioxidative activity of PEDF can reduce the production of NOX-driven superoxide, and can inhibit platelet activation and aggregation as well as have a detrimental effect on AGEs in diabetic rat models (Yamagishi et al. 2009).

Moreover, both in vivo and in vitro hyperglycemic conditions can result in activation of NFκB in retinal pericytes which can upregulate BAX and TNFα (Romeo et al. 2002). Ang I has a protective effect on pericytes in such conditions; however, Ang II accelerates TNFα- and hyperglycemia-induced apoptosis as well as pericyte migration from retinal capillaries, which lead to pericyte loss and EC proliferation (Cai et al. 2008, Pfister et al. 2008). In a high-glucose ROS-induced condition, the mRNA ratio of Ang II to Ang I increases and consequently elevates the VEGF mRNA level in pericytes (Amano et al. 2005). This may disrupt pericyte–EC interactions and induce angiogenesis-related gene expression. Through its antioxidative properties, PEDF can inhibit pericyte apoptosis, modifying VEGF-mediated gene expression and ultimately delaying or even halting the progression of DR (Amano et al. 2005).

Clinical implications and possible future studies

In the normal adult eye (especially in macular region), the concentration of PEDF is tenfold higher than VEGF, which may suggest that PEDF is the main factor responsible for the low number of blood vessels associated with macular avascularity (Kociok & Joussen 2007, Kozulin et al. 2010). However, the level of PEDF in the vitreous of the eye in patients suffering from proliferative diseases such as PDR is significantly lower than in the normal eye, which may be a biomarker of oxidative stress in the eye, and the pharmacological upregulation or administration of PEDF may be a therapeutic strategy to address PDR (Yokoi et al. 2007). The imbalanced ratio of VEGF and PEDF bring the concept of anti-angiogenic therapy into perspective. Anti-VEGF antibodies have been used clinically and showed significant positive results, but the efficacy is limited by short half-life (10 days). Therefore, to maintain the therapeutic effect, regular dosing is required, although repetitive injections carry substantial risks for the patient, such as retinal detachment, endophthalmitis, cataract formation, ocular hypertension, and submacular hemorrhage. In this approach, using PEDF (a potent anti-angiogenic molecule) seems a promising strategy. However, the short half-life is still an issue. In this regard, some new delivery systems have been tested in order to increase the efficiency of delivery and half-life of the PEDF gene therapy method. The examples include adeno-associated virus vector-mediated PEDF delivery, which has been recently described (Streck et al. 2005, Park et al. 2011, He et al. 2012). However, because of its potential carcinogenic properties, immunogenicity, uncertain quantitative expression, and lower production rate, this application is limited for therapy. Other studies have also used poly(d,l-lactide-coglycolide acid) nanoparticles for efficient PEDF gene delivery, but processing and formulation lead to loss of activity of PEDF (Pai et al. 2009). Polyethylene glycol is a polyether with many applications in medicine and has recently been used to improve the pharmacokinetic and pharmacodynamic properties of administered PEDF. This strategy provided promising results for long-term therapy of PDR as well as other retinal angiogenic diseases (Bai et al. 2012).

Conclusion

Pericytes and ECs respond in different ways to oxidative stress. AGE-induced ROS inhibits the growth of pericytes. Oxidative stress commonly occurs in chronic diseases such as diabetes mellitus, thus PEDF could protect retinal pericytes exposed to such stress through its antioxidative properties as well as through inhibition of EC activation. PEDF may act directly on ECs to prevent inflammation-mediated pro-proliferative responses, therefore playing a protective role against angiogenesis. Furthermore, PEDF could affect or upregulate anti-apoptotic gene expression in neural cells that can improve neuronal survival. Taken together, PEDF is emerging as a novel and suitable candidate for new therapeutic approaches in neurodegenerative disorders and vascular complications in diseases such as diabetes mellitus.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

M E is supported by an IPR Scholarship from Victoria University and CRD by a Curtin Academic50 scheme. V F C is supported by Brazilian National Council for Scientific and Technological Development (CNPq)/Science without borders Programme (process 245562/2012-5). P N is supported by the School of Biomedical Sciences and Faculty of Health Sciences with respect to diabetes and metabolism research at Curtin University.

Author contribution statement

M E and C D designed the outline of the review, and M E was responsible for writing the first draft of this review. S B-H, V F C, P N, and C D were responsible for subsequent revisions to the manuscript. All authors approved the final version of the manuscript.

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    A brief overview of the protective mechanisms mediated by PEDF in conditions of oxidative stress caused by advanced glycation end products (AGEs), NADPH oxidase activation and glycated LDL in pericytes and endothelial cells (EC). (A) In LDL-exposed pericytes, PEDF can suppress the binding of nuclear factor kappa B (NFκB) to DNA and, as a result, inhibit the monocyte chemoattractant protein 1 (MCP1) (Zhang et al. 2008). (B) In AGE-exposed pericytes, PEDF is able to attenuate caspase 3 activity by improving the ratio of BCL2/BAX (Yamagishi et al. 2002a,c). (C) In AGE-exposed EC, PEDF can reduce reactive oxygen species (ROS) generation by downregulating p22PHOX and gp91PHOX thus suppressing NADPH oxidase activity (Yoshida et al. 2009, Yamagishi et al. 2006a). A full colour version of this figure is available at http://dx.doi.org/10.1530/JOE-14-0065.

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