Antiangiogenic cytokines as potential new therapeutic targets for resveratrol in diabetic retinopathy

Figures & data

Table 1 Classification of DR severity

International clinical DR disease severity scale
Mild NPDR	Moderate NPDR	Severe NPDR	PDR
Microaneurysms only	More than just microaneurysms Less than severe NPDR	>20 intraretinal hemorrhages in each of 4 quadrants OR Definite venous bleeding in 2+ quadrants OR Prominent IRMA in 1+ quadrant and no PDR	One or more: Neovascularization Vitreous/preretinal hemorrhage

Notes: Adapted from: The Royal College of Ophthalmologists. Diabetic retinopathy guidelines; December 2012. Available from: https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-301-FINAL-DR-GUIDELINES-DEC-2012-updated-July-2013.pdf. © The Royal College of Ophthalmologists 2012. All rights reserved.²⁴

Abbreviations: DR, diabetic retinopathy; IRMA, intraretinal microvascular abnormalities; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy.

Figure 1 The main mechanisms of hyperglycemia-induced damage considered responsible for the occurrence of diabetic retinopathy: increased polyol pathway flux, increased AGEs formation, increased hexosamine pathway flux, and activation of PKC.

Notes: Adapted from Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mecha nisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int. 2014;2014:801269. Copyright © 2014 Sher Zaman Safi et al.³¹
Abbreviations: AGEs, advanced glycation end-products; PKC, protein kinase C; ROS, reactive oxygen species.

Figure 2 Schematic presentation of stages of polyol pathway: (I) glucose reduction to sorbitol by AR (using NADPH as a cofactor) followed by (II) sorbitol oxidation to fructose by SDH (using NAD⁺ as a cofactor).

Notes: Adapted from Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mecha nisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int. 2014;2014:801269. Copyright © 2014 Sher Zaman Safi et al.³¹
Abbreviations: AR, aldose reductase; NAD⁺, nicotinamide adenine dinucleotide – oxidized; NADH, nicotinamide adenine dinucleotide – reduced; NADP⁺, nicotinamide adenine dinucleotide phosphate – oxidized; NADPH, nicotinamide adenine dinucleotide phosphate – reduced; SDH, sorbitol dehydrogenase.

Figure 3 Polyol pathway changes induced in NADH (NADPH)/NAD⁺ (NADP⁺) ratios with the decrease of GR, leading to ROS accumulation and tissue impairments.

Notes: Adapted from Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mecha nisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int. 2014;2014:801269. Copyright © 2014 Sher Zaman Safi et al.³¹
Abbreviations: GR, glutathione reductase; NAD⁺, nicotinamide adenine dinucleotide – oxidized; NADH, nicotinamide adenine dinucleotide – reduced; NADP⁺, nicotinamide adenine dinucleotide phosphate – oxidized; NADPH, nicotin-amide adenine dinucleotide phosphate – reduced; ROS, reactive oxygen species.

Figure 4 Schematic presentation of AGEs formation and the pathways through which AGEs target cells: altered function of intracellular proteins; abnormal interaction between matrix components and protein receptors (integrins); increased production of ROS due to abnormal interaction between plasma proteins and specific AGE receptors.

Notes: *Intracellular actions; **extracellular actions. Original figure; adapted from data from Brownlee.³⁰
Abbreviations: AGEs, advanced glycation end-products; ROS, reactive oxygen species.

Figure 5 Schematic presentation of the contribution of increased hexosamine pathway flux in pathogenesis of DR.

Note: Original figure; adapted from data from Giacco and Brownlee.⁴¹
Abbreviations: DR, diabetic retinopathy; F-6-P, fructose-6-phosphate; G-6-P, glucose-6-phosphate; GFAT, glutamine–fructose-6-phosphate aminotransferase; GlcN-6P, N-acetylglucosamine-6-phosphate; PAI-1, plasminogen activator inhibitor-1; TGF-α, transforming growth factor-alpha; TGF-β1, transforming growth factor-beta 1.

Figure 6 Schematic presentation of the contribution of PKC activation to the development of diabetic retinopathy.

Note: Original figure; adapted from data from Geraldes and King.⁴³
Abbreviations: DAG, diacylglycerol; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PKC, protein kinase C; VEGF, vascular endothelial growth factors.

Table 2 Proteins secreted from RPE cells

Cytokines secreted by RPE	Functions	Role in DR
VEGF	Proinflammatory and angiogenic molecule	Regulates neovascularization
Transforming growth factor-β	Controls proliferation and cellular differentiation	Alters growth factor’s balance
Insulin-like growth factor-I	Promotes cellular growth and insulin-like metabolic effects	Autocrine/paracrine regulation of proliferation
Platelet-derived growth factor	Regulates cell growth and division and pericyte viability	Promotes neovascularization and traction of epiretinal membranes
Lens epithelium-derived growth factor	Growth and survival factor	Enhances survival in RPE cells when challenged by oxidative stress
TIMP (TIMP-1 and TIMP-3)	Involved in extracellular matrix degradation	Plays a role in preneovascularization
Pigment epithelium-derived factor	Antiangiogenic, anti-tumorigenic, and neurotrophic protein	Fails to inhibit cell proliferation and maintain the retinal structure
Ciliary neurotrophic factor	Interferes with MAPK, PI3K, and NF-κB signaling pathways	Increases RPE cell survival
Fibroblast growing factor	Induces VEGF expression in retinal vascular cells	May represent a source of neural regeneration

Note: Data adapted from Weight et al.⁵⁸

Abbreviations: DR, diabetic retinopathy; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; RPE, retinal pigment epithelium; TIMP, tissue inhibitor of matrix metalloproteinase; VEGF, vascular endothelial growth factors.

Figure 7 Schematic presentation of a possible mechanism of action for resveratrol in the development of diabetic retinopathy.

Abbreviations: AGEs, advanced glycation end-products; BRB, blood–retinal barrier; MMPs, matrix metalloproteinases; NF-κB, nuclear factor-κB; PEDF, pigment epithelium-derived factor; TSP-1, thrombospondin-1.

The Royal College of OphthalmologistsDiabetic retinopathy guidelines Available from: https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-301-FINAL-DR-GUIDELINES-DEC-2012-updated-July-2013.pdfAccessed May 13, 2017

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