- •Preface
- •Contents
- •Contributors
- •1.1 Introduction
- •1.2 Pathogenesis of AMD
- •1.2.1 Oxidative Damage
- •1.2.2 Lipofuscin Accumulation
- •1.2.4 Complement Mutations
- •1.2.5 Mitochondrial Damage
- •1.2.6 DICER 1
- •1.3 Treatment
- •1.3.1 Antioxidants
- •1.3.2 Visual Cycle Modulators
- •1.3.4 Neurotrophic Agents
- •1.3.5 Antiangiogenic Agents
- •1.3.5.1 Intracellular Angiogenic Factor Production
- •1.3.5.2 Extracellular Angiogenic Factors
- •1.3.6 Endothelial Cell Receptor Binding
- •1.3.7 Endothelial Cell Activation
- •1.3.8 Endothelial Cell Proliferation
- •1.3.9 Endothelial Cell Directional Migration
- •1.3.10 Extracellular Matrix Remodeling
- •1.3.11 Tube Formation
- •1.3.11.1 Loop Formation (Arteriovenous Differentiation)
- •1.3.11.2 Vascular Stabilization
- •1.4 Combination Therapy
- •1.5 Conclusions
- •References
- •2.1 Introduction
- •2.1.1 Complement Pathways
- •2.1.2 Oxidative Stress
- •2.3.1 The Mouse CNV Model
- •2.3.2 RPE Monolayers
- •2.3.3 Concept
- •2.5 Summary and Outlook
- •References
- •3.1 Introduction
- •3.2.1 Advanced Glycation End Products
- •3.2.2 Carboxyethylpyrrole
- •3.2.3 Oxidation Products of Lipofuscin
- •3.3 Summary and Conclusions
- •References
- •4.1 Introduction
- •4.2 Oxidative Stress and AMD
- •4.2.1 Basic Concepts on Oxidative Stress
- •4.2.2 Oxidative Stress in AMD
- •4.3 Malondialdehyde in AMD
- •4.3.1 Lipid Peroxidation and Malondialdehyde
- •4.3.2 Materials and Methods
- •4.3.2.1 RPE Cell Culture
- •4.3.2.2 Patients
- •4.3.2.3 MDA Assay
- •4.3.3 MDA Levels in Cultured RPE Cells and in Patients with AMD
- •4.4 Summary and Conclusions
- •References
- •5.1 Introduction
- •5.2 The Origin and Housing of RPE Lipofuscin
- •5.3 Bisretinoid Constituents of RPE Lipofuscin
- •5.3.1 A2E, Isomers and Precursors
- •5.3.4 Photooxidized Forms of Bisretinoid Pigments
- •5.4 Photoreactivity of RPE Lipofuscin
- •5.5 Photooxidation of RPE Bisretinoids
- •5.6 Bisretinoid Photodegradation
- •5.7 Potential for Cell and Tissue Damage
- •5.9 A Role for Antioxidants
- •5.10 Conclusions
- •References
- •6.1 Introduction
- •6.1.1 RPE Lipofuscin Accumulation with Age and Relation to AMD
- •6.1.2 Known Chromophores Found in RPE Lipofuscin and the Mechanism of Damage
- •6.1.3 Formation of Higher Molecular Weight Material
- •6.1.4 Current Studies and Possible Structures of Higher Molecular Weight Products
- •6.1.4.1 Lipofuscin Extracts
- •6.1.4.3 Esters and Aldehydes
- •6.2 Conclusions
- •References
- •7.2 DHA in Photoreceptor Cells
- •7.3 Neuroprotectin D1 Synthesis is an Early Response to Oxidative Stress in RPE Cells
- •7.5 Neurotrophins Trigger the Synthesis and Polarized Secretion of Neuroprotectin D1 from Human RPE Cells
- •7.6 Photoreceptor Outer Segment Phagocytosis Induces RPE Cell Survival Signaling with Associated Synthesis of NPD1 During Oxidative Stress
- •References
- •8.1 Introduction
- •8.2.1 Subcellular Localization
- •8.2.2 Expression Levels in the Retina
- •8.4.3 Regulation of RDH12 Expression and Activity During Chronic and Acute Stress
- •8.5 RDH12 and Leber Congenital Amaurosis
- •8.5.1 Inactivating Mutations of RDH12
- •8.5.2 Loss of Which RDH12 Function Induces LCA?
- •8.6 Summary and Conclusions
- •References
- •9.1 Introduction
- •9.2 GSH Metabolism: General Principles
- •9.2.2 Role of Mitochondrial GSH in Protection
- •9.2.3 GSH as a ROS Scavenger
- •9.2.4 GSH Distribution in the Retina and RPE in Health and Disease
- •9.5 Future Perspectives
- •References
- •10.1 Introduction
- •10.2 Mitochondria
- •10.2.1 Mitochondrial Biogenesis and Maintenance
- •10.2.2 Mitochondrial Removal and Degradation
- •10.3 Mitochondria and Reactive Oxygen Species
- •10.3.1 Reactive Oxygen and Nitrogen Species (ROS and RNS)
- •10.3.2 Mitochondria are a Major Source of Intracellular ROS
- •10.3.3 Other Sources of ROS in the Retina
- •10.4 The Mitochondrial Genome
- •10.4.1 Susceptibility of Mitochondrial DNA to Oxidative Stress
- •10.4.2 Mitochondrial DNA Damage
- •10.4.3 Mitochondrial DNA Repair Pathways
- •10.4.4 The Mitochondrial Base Excision Repair (mtBER) Pathway
- •10.4.6 Other Mitochondrial DNA Repair Pathways
- •10.4.6.2 Mismatch Repair (MMR)
- •10.4.6.3 Translesion Synthesis (TLS) and Damage Tolerance
- •10.4.6.4 Nucleotide Excision Repair (NER)
- •10.4.7 Intramitochondrial Localization of DNA Repair Proteins
- •10.4.8 mtDNA Damage Sensing and Signaling
- •10.4.9 Import of Nuclear Encoded DNA Repair Enzymes into the Mitochondria
- •10.5 Mitochondrial DNA Damage/Repair in the Retina and RPE
- •10.5.1 Mitochondrial DNA Damage/Repair in the RPE
- •10.5.2 DNA Repair and the Adaptive Response in the RPE
- •10.6 Pathologies Associated with Mitochondrial Dysfunction and Oxidative Stress in the Retina
- •10.6.2 Diabetic Retinopathy
- •10.6.3 Glaucoma
- •10.6.4 Uveitis
- •10.7 Pathologies Associated with Inherited Mitochondrial Disorders
- •10.8 Potential Therapeutic Options for Targeting Mitochondrial DNA Damage
- •10.8.1 Mitochondrial Biogenesis
- •10.8.2 Enhancing mtDNA Repair
- •10.8.3 Antioxidants
- •10.8.4 Autophagy
- •10.9 Conclusion
- •References
- •11.1 Introduction
- •11.2 ER Function in Normal Physiology
- •11.2.1 Major Roles of Rough ER (RER) and Smooth ER (SER)
- •11.2.2 ER and Oxidative Protein Folding
- •11.2.3 ER Resident Proteins
- •11.2.4 Potential Threat to ER Function in RPE
- •11.3 ER Response to Oxidative Stress in RPE
- •11.3.2 Initiation of UPR to Alleviate ER Burden
- •11.4 Chronic ER Stress and Oxidative Stress in the Vicious Cycle of Apoptosis Induction
- •11.5 Future Perspectives
- •References
- •12.1 Introduction
- •12.2 Iron Homeostasis
- •12.2.1 General Iron Homeostasis
- •12.2.2 Iron Import into the Retina
- •12.2.2.1 Transferrin Mediated Transport
- •12.2.2.3 Dexras
- •12.2.3 Iron Storage
- •12.2.3.1 Ferritin
- •12.2.3.2 Mitochondrial Ferritin
- •12.2.4 Iron Export
- •12.2.4.1 Ceruloplasmin
- •12.2.4.2 Hephaestin
- •12.2.4.3 Ferroportin and Hepcidin
- •12.3 Disruption of Iron Homeostasis and Oxidative Damage
- •12.4 Retinal Disorders Resulting from Abnormal Retinal Iron Metabolism
- •12.4.2 Aceruloplasminemia
- •12.4.3 Hemochromatosis
- •12.4.4 Friedreich’s Ataxia
- •12.4.6 Siderosis
- •12.4.7 Subretinal Hemorrhage
- •12.5 Potential Therapeutics
- •References
- •13.1 Vascular Endothelial Growth Factor and Its Functions in the Retina
- •13.1.1 VEGF Isoforms
- •13.1.2 VEGF Functions
- •13.1.3 Cells Secreting VEGF in the Retina
- •13.1.3.1 Retinal Pigment Epithelium
- •13.1.3.2 Müller Cells
- •13.1.3.3 Astrocytes
- •13.1.3.4 Pericytes
- •13.1.4 VEGF Receptors and VEGF Induced Signal Transduction
- •13.1.4.1 VEGF Receptors
- •VEGFR-1
- •VEGFR-2
- •Neuropilin
- •Heparan Sulfate Proteoglycan
- •13.2 Regulation of VEGF Expression
- •13.2.1 Transcriptional Regulation
- •13.2.2 Translational Regulation
- •13.2.3 Hypoxia Induced VEGF Regulation
- •13.2.4 Posttranslational Regulation
- •13.2.5 Autocrine VEGF Regulation
- •13.2.6 Pathological VEGF Production
- •13.2.6.1 Hyperglycemia
- •13.2.6.2 Oxidative Stress
- •13.2.6.3 Cytokines
- •13.2.6.4 Endoplasmic Reticulum
- •13.2.6.5 Additional Factors
- •13.3.1 Pegaptanib
- •13.3.2 Bevacizumab and Ranibizumab
- •13.3.4 siRNA
- •13.3.5 Small Molecule Tryrosine Kinase Inhibitors
- •13.3.6 Other Inhibitors
- •13.4.2 Interaction of VEGF Antagonists with Antiangiogenic VEGFxxxb
- •13.5 Conclusion
- •References
- •14.1 Introduction
- •14.2 NADPH Oxidase and Redox Signaling
- •14.3 Expression of NADPH Oxidase Subunit p22phox in the Retina
- •14.4 NADPH Oxidase and Choroidal Neovascularization
- •14.5 Implication and Therapeutic Potential of NADPH Oxidase in Development of CNV
- •14.6 Summary and Future Perspective
- •References
- •15.1 Introduction
- •15.2 Aging
- •15.3 Deposition and Formation of Oxidized LDL
- •15.6 Treatments for AMD
- •15.7 Conclusions
- •References
- •16.1 Introduction
- •16.2 HGF and Its Receptor (MET)
- •16.2.1 Production and Secretion of HGF
- •16.2.2 MET and Biological Effects of HGF
- •16.2.3 Signaling Pathways of HGF
- •16.2.4 HGF and MET in Disease States
- •16.4 HGF Protects RPE Cells from Oxidative Stress
- •16.4.1 HGF and RPE Cells
- •16.4.2 HGF Promotes Cell Survival
- •16.4.3 HGF Protects Cells from Oxidative Stress
- •16.4.4 HGF Protects RPE Cells from Hydrogen Peroxide
- •16.4.5 HGF Protects RPE Cells Against Ceramide Damage
- •16.4.6 HGF Protects RPE Cells from Glutathione Depletion
- •References
- •17.1 Introduction
- •17.2.1 Fundoscopy
- •17.2.2 Histology
- •17.2.3 Ultrastructure
- •17.3.1 Lipofuscin (A2E)
- •17.3.3 HtrA2/Omi
- •References
- •18.1 Introduction
- •18.2 Systemic Markers of Oxidative Stress
- •18.2.1 Redox Status
- •18.2.2 DNA Damage
- •18.2.4 Lipid Peroxidation
- •18.3 Defenses Against Oxidative Stress
- •18.3.1 Antioxidants
- •18.3.2 Antioxidant Enzymes
- •18.4 Oxidative Stress and Genetics
- •18.4.1 Antioxidant Enzyme Polymorphisms
- •18.5 Environmental Exposures and Oxidative Stress
- •18.5.1 Smoking
- •18.5.2 Light Exposure
- •18.6 AMD Treatments and Oxidative Stress
- •18.8 Summary and Conclusions
- •References
- •19.1 Characteristics of Cerium Oxide Nanoparticles
- •19.3 Mechanism of Nanoceria Uptake, Internalization, and Localization in the Cell
- •19.4 Biological Effect, Functional Mechanism, and Applications
- •19.4.1 Bacteria
- •19.4.2 Plants
- •19.4.3 Medical Usage
- •19.4.3.1 Radioprotectants
- •19.4.3.2 Burn Treatment
- •19.4.4 Medical Imaging
- •19.5 Stability of Nanoceria Under storage Conditions and Its Longevity in the Cell In Vivo
- •19.6 Oxidative Damage Results in Neurodegeneration
- •19.7.1 Prolong Cellular Life Span
- •19.7.2 Cardioprotection
- •19.8 Treatment of Ocular Disorders
- •19.8.1 Methodology
- •19.8.2 Prevention of Light Damage and Rescue of Retinal Function
- •19.8.3 Treatment of Degenerative Ocular Diseases
- •19.8.4 Treatment of Ocular Neovascular Diseases
- •19.9 Toxicity and Environmental Impacts
- •19.10 Conclusion and Future Directions
- •References
- •20.1 Introduction
- •20.2 Retinal Progenitor Cells (RPCs) Are Multipotential
- •20.4 Therapeutic Strategies for Repair and Regeneration of Retinal Cells: Repair of the RPE
- •20.5 Challenges for RPE Stem Cell Therapy
- •20.6 Characterization of RPE-Like Cells Derived from BMDCs
- •20.7 BMDCs Differentiate into Retinal Cells
- •20.8 Summary and Future of Cell Therapy for Dysfunctional RPE
- •References
- •21.1 Introduction
- •21.2 Carotenoids in Retinal Diseases
- •21.4 Polyphenols or Phenolic Esters in Retinopathies
- •21.4.1 Caffeic Acid Phenethyl Ester
- •21.4.2 Catechin
- •21.4.3 Curcumin
- •21.4.4 Proanthocyanidin
- •21.4.5 Resveratrol
- •21.5.2 Sulforaphane
- •21.6 Vitamins in Retinopathies
- •21.6.1 Vitamin A
- •21.7 Perspectives
- •References
- •22.1 Introduction
- •22.1.1 Neuroprotection as a Strategy for Retinal Degenerative Disease
- •22.2.2 Putative Mechanisms of CNS Neuroprotection
- •22.3.9 Conclusion
- •22.4 Mechanisms of Retinal Protection
- •22.4.1 Insights from In Vitro Models
- •22.5.1 Background to the Disease and the Associated Preclinical Data
- •22.5.2 Overview of the Clinical Development Program
- •References
- •23.1 Introduction
- •23.2 Pathogenesis
- •23.4 Pegaptanib
- •23.5 Bevacizumab
- •23.6 Ranibizumab
- •23.7.1 Ranibizumab
- •23.7.2 Bevacizumab
- •23.8 Comparison of AMD Treatment Trials (CATT)
- •23.9 Management of Nonresponders
- •23.11 Conclusion
- •References
- •24.1 Introduction
- •24.2 Rationale for Combination Therapy
- •24.3 Supporting Evidence for Combination Therapy
- •24.4 Currently Applied Combination Therapies
- •24.5 Challenges for Combination Therapy
- •References
- •25.1 Human Endothelial Progenitor Cells
- •25.3 Function of EPCs
- •25.3.1 EPCs in Vascular Repair and Neovascularization
- •25.4 EPCs in Diabetes
- •25.4.1 EPC as a Biomarker in Diabetes
- •25.4.1.1 EPC Dysfunction in Diabetes
- •25.4.1.2 Oxidative Stress and EPC Dysfunction in Diabetes
- •25.4.1.3 Therapeutic Angiogenesis by EPCs in Diabetic Retinopathy
- •25.5 Conclusion
- •References
- •26.1 Introduction
- •26.1.1 Nitric Oxide
- •26.1.2 Nitric Oxide Regulation
- •26.1.3 Nitric Oxide in Normal and Pathophysiological Conditions
- •26.2 Retinal Vascular Diseases: The Role of iNOS
- •26.2.1 Nitric Oxide in Diabetic Retinopathy
- •26.2.2 iNOS in Diabetic Retinopathy
- •26.2.2.2 iNOS and Leukocyte Adhesion to Retinal Vessels
- •26.2.2.3 iNOS and Retinal Cell Death
- •26.2.3 Proliferative Retinal Diseases
- •26.2.3.1 iNOS and Proliferative Retinal Diseases
- •26.2.3.2 iNOS and Ocular Neovascularization in Retinal Vascular Diseases
- •26.3 Conclusions
- •References
- •27.1 Introduction
- •27.2 Animal Model
- •27.2.1 LHP Preparation and Injection Procedure
- •27.2.2 Acridine Orange Digital Fluorography
- •27.3 Experimental Results
- •27.3.1 Leukocyte Rolling
- •27.3.2 Accumulated Leukocytes in the Retinal Microcirculation
- •27.3.3 Diameter of Major Retinal Vessels
- •27.3.4 SOD Treatment
- •27.4 Discussion
- •27.5 Conclusions
- •References
- •28.1 Introduction
- •28.1.2 Metabolism and Balance in Generation and Quenching of ROS
- •28.2 Role of Oxygen Concentration on Generation of ROS in the Developing Retina
- •28.3.1 Perinatal Considerations
- •28.3.2 Neonatal Considerations
- •28.3.2.1 Polyunsaturated Fatty Acids in Retina and Brain
- •28.3.2.2 Increased Oxidation
- •28.3.2.3 Reduced Antioxidant Enzyme Systems
- •28.3.3 Environmental Stimuli
- •28.3.3.1 Light
- •28.3.3.2 Oxygen Changes in Development and Prematurity
- •28.3.3.3 Nutrition
- •28.3.3.4 Effect of Blood Transfusions on Oxidative Stress in Prematurity
- •28.4 Evidence from Animal Models
- •28.4.1 Background
- •28.4.2 Effects of Hypoxia on Bioenergetic Oxygen Sensor Mechanisms and Related to ROP
- •28.4.2.2 NADPH Oxidase
- •28.4.2.3 Cytochrome p450 Monooxygenases (CYP)
- •28.4.2.4 eNOS
- •28.4.2.5 Heme Oxygenase
- •28.4.2.6 Metabolic Effects of Hypoxia
- •28.4.3 Laboratory Evidence of Antioxidants on Animal Models of ROP
- •28.5 Clinical Studies of Antioxidants on ROP
- •28.6 Genetics
- •28.7 Summary
- •References
- •29.1 Introduction
- •29.1.1 Oxidative Stress in Glaucoma
- •29.1.2 Oxidative Stress in Diabetic Retinopathy
- •29.1.3 Oxidative Stress in Age Related Macular Degeneration
- •29.1.4 Vascular Endothelial Growth Factor
- •29.1.5 VEGF Mediated Neuroprotection
- •29.1.6 Mechanisms of VEGF Protection Against Oxidative Stress
- •References
- •30.1 Introduction
- •30.1.1 Oxidation and Oxidative Stress
- •30.1.2 Reactive Oxygen Intermediates
- •30.1.3 ROIs and Cellular Retinal Damage
- •30.1.4 Light, Cellular Retinal Damage and AMD
- •30.1.5 Carotenoids
- •30.1.6 Chemistry of Carotenoids: Basic Structural Components
- •30.2 Building Blocks
- •30.3 The Polyene Backbone
- •30.5 Terminal Groups
- •30.5.1 Source of Macular Carotenoids
- •30.5.2 Macular Carotenoids: The Origins of Macular Pigment
- •30.5.3 The Functions of the Macular Carotenoids as Macular Pigment for AMD
- •30.6 Antioxidant Properties
- •30.6.1 The Functions of the Macular Carotenoids as Macular Pigment for Visual Performance
- •References
- •31.1 Introduction
- •31.2 Composition and Distribution
- •31.3 Selective Uptake and Deposition Process of MP
- •31.4 Measurements
- •31.4.1 Heterochromatic Flicker Photometry
- •31.4.4 Resonance Raman Spectroscopy
- •31.5 Antioxidant Mechanism of MP and Its Relation to Retinal Health and Disease
- •31.5.1 Oxidative Stress in Human Retina and the Antioxidant Mechanism of MP
- •31.5.2 MP in Human Eye Health and Disease
- •31.5.2.2 MacTel
- •31.5.2.3 Acuity
- •31.6 Ocular Carotenoid Supplementation Studies
- •31.7 Conclusion
- •References
- •Index
- •About the Authors
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Pretreatment with recombinant human HGF at levels from 1 to 100 ng/mL inhibits H2O2-induced apoptosis at a dose-dependent manner. Viability of RPE cells pretreated with 10, 30, and 100 ng/mL HGF was significantly higher than that of cells treated with H2O2 alone. However, RPE viability when treated with HGF plus H2O2 was lower than that of the cells without H2O2. These results suggest that HGF significantly decreased but did not completely abolish the in vitro cytotoxic effects of H2O2 on RPE cells.
16.4.5HGF Protects RPE Cells Against Ceramide Damage
Ceramide is a membrane sphingolipid which is a second messenger involved in the induction of apoptosis. Ceramide is both a signaling product of oxidative stress and a mediator of the production of ROS in the mitochondria [2, 60]. Human cultured RPE treated with C2 ceramide (N-acetylsphingosine) undergo apoptosis in a dosedependent manner. This process is accompanied by accumulation of ROS in mitochondria, an increase of mitochondrial membrane permeability transition, activation of caspase-3, and a decrease of catalase activity [60]. Kannan et al. [60] reported that HGF inhibited ceramide-induced apoptosis of cultured human RPE cells.
Pretreatment with HGF significantly inhibited ceramide-induced apoptosis and reduced the accumulation of ROS in the mitochondria. This effect was accompanied by preservation of catalase activity, inhibition of ceramide-induced mitochondrial membrane permeability transition, and activation of caspase-3 [60].
Kannan et al. [60] then suggested that the major effects of HGF protection against ceramide damage resulted from attenuation of mitochondrial ROS accumulation. In contrast, another study had showed that HGF induced growth suppression of a sarcoma cell line and that this effect was mediated through an increase of ROS with activation of caspase-3 [88]. Kannan et al. hypothesized that this conflicting result might be due to dysregulation of growth signaling in the transformed cells. This sarcoma cell line shows constitutive activation of the MET, with only a modest increase in receptor phosphorylation with HGF treatment. To the contrary, cultured RPE cells demonstrated regulated MET activation with large and rapid induction of MET phosphorylation after exposure to HGF [60].
16.4.6HGF Protects RPE Cells from Glutathione Depletion
It has been reported that glutathione and its precursor protects retina and RPE cells from oxidative injury [14, 89]. Jin et al. [61] reported that HGF protects RPE cells against glutathione depletion induced by DL-buthionine-(S,R)-sulfoximine (BSO), a glutathione depletory [61]. BSO treatment caused a significant decrease of intracellular glutathione levels and induced apoptosis of RPE cells. Pretreatment with HGF led to a significant increase of intracellular glutathione levels, particularly for
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mitochondrial glutathione. HGF also partially inhibited BSO-induced apoptosis of RPE cells. HGF did not influence intracellular glutathione levels in RPE cells not treated with BSO [61].
BSO treatment also caused a dramatic increase of ROS levels in the mitochondria and an increase of lipid peroxidation, and pretreatment with HGF significantly decreased both of these effects, reducing mitochondrial ROS and lipid peroxide levels to those of the cells not treated with BSO [61].
The mitochondrial apoptosis signaling pathway is activated in RPE cells by treatment of BSO, since upon treatment, expression of Bcl-2 was significantly decreased, cytochrome c was released into the cytoplasm, and caspase-3 was activated. Again, pretreatment with HGF increased expression of Bcl-2 and partially decreased the release of cytochrome c and activation of caspase-3 [61].
NF-E2-related factor (Nrf2) is a nuclear transcription factor which stimulates antioxidant response elements resulting in the induction of various antioxidant genes (i.e., superoxide dismutases, glutathione peroxidases, glutathione-S-transferase, g-glutamylcysteine synthetase, etc.). BSO also led to activation of NrF2, an increase of expression of glutathione-S-transferase and g-glutamylcysteine synthetase, whereas glutathione peroxidase expression remained unchanged. Pretreatment with HGF caused a further increase of glutathione-S-transferase and upregulation of glutathione peroxidase, whereas g-glutamylcysteine synthetase was not affected. Treatment of RPE cells with HGF alone increased the expression of glutathione peroxidase, but not glutathione-S-transferase and g-glutamylcysteine synthetase [61].
In summary, Jin et al. concluded that HGF protects RPE cells from apoptosis induced by glutathione depletion and this protective effect may be attributed in part to the elevation of mitochondrial glutathione [61].
16.5Significance and Summary
Studies of the protective effects of HGF on oxidative stress-induced RPE damage in three different in vitro models, including H2O2, ceramide, and glutathione depletion, demonstrates that HGF provides a partial protection for RPE cells against oxidative stress-induced damage [59–61]. HGF decreases the loss of cell viability induced by oxidative stress via the upregulation of Bcl-2 and inhibition of the mitochondrial apoptosis pathway. Furthermore, the accumulation of ROS in the mitochondria caused by oxidative stress is also reduced by HGF, mainly through the increased expression of various antioxidative enzymes and glutathione [59–61].
Studies of the signaling pathways involved in the HGF protection from H2O2- induced damage in various cells demonstrated that the binding of HGF to MET leads to an activation of MET and a cascade of events which activates various signal pathways, including the PI3k/Akt pathway, the ERK pathway and the NF-kB pathway, with PI3k/Akt probably the main pathway [44, 45, 50]. A complete understanding of how these pathways are involved in the protective effects of HGF on RPE cells requires further studies.
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HGF is produced by RPE cells constitutively [51]. Studies of HGF protective effects indicate that HGF is one of the natural substances that protect the cells and tissues from oxidative stress-induced damage. In vitro studies demonstrated that H2O2 stimulates the expression of HGF. Hence, it seems that HGF plays an autocrine role in the protection of RPE cells from oxidative stress-induced damage [59–61].
That HGF protects RPE cells from oxidative stress-induced damage suggests that application of exogenous HGF may have therapeutic effects in certain clinical circumstances in which loss of RPE cell viability is due to the oxidative stress. However, HGF can induce angiogenesis and may activate cell malignant changes [37–41]. Therefore, the clinical application of HGF needs to be carefully evaluated and to find a balance between therapeutic efficiency and potential untoward sideeffects.
The HGF/MET system is unusually complicated. Interactions between HGF and MET can lead to a variety of responses through many different signaling pathways. Much interest has centered upon delineating which interactions between the various docking molecules are required and/or involved in the diverse biologic pathways altered by the HGF/NET system. For example, experiments using transgenic mice with specific mutations introduced into the MET docking site found that tyrosines 1349 and 1356 are essential for normal development. Functional loss of these two tyrosines results in the loss of binding to Gab1, Gab2, Src, and PI3K. When these multifunctional docking sites were mutated to reproduce optimal binding motifs for PI3K, Src, or Grb2, the data showed that both PI3K and Src are necessary for hepatocyte survival and myoblast migration. Src binding alone was sufficient for both placental and myoblast proliferation and PI3K alone was sufficient for axon outgrowth and branching [40].
As we understand more about the HGF and MET, strategies aimed at using modern genetic technologies to modify HGF and its receptors in favor of combating disorders where HGF is involved may be possible.
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