Studies on Renal Disorders (eBook)

Studies on Renal Disorders 3
Preface 5
Contents 7
Contributors 11
Part I: Oxidative Stress 19
Chapter 1: Oxidative Stress Injury in Glomerular Mesangium 20
1 Introduction 22
2 Sources of Oxidative and Nitrosative Stress in Mesangial Cells 22
3 Actions of Oxidative and Nitrosative Stress in Mesangial Cells 25
3.1 Oxidative and Nitrosative Stress and Apoptosis 25
3.2 Effects of ROS and NO on the Phosphoproteome 26
3.3 Effects of Oxidative and Nitrosative Stress on the Transcription Pattern of Mesangial Cells 28
4 Therapeutic Opportunities 31
5 Conclusion 34
References 34
Chapter 2: Transition Metals and Other Forms of Oxidative Protein Damage in Renal Disease 41
1 Introduction 41
2 Chemical Pathways of Protein Damage by Oxidation 42
2.1 HOCl Mediated Pathways 43
2.2 Free Radicals Oxidation 44
2.3 Metal-Catalyzed Oxidation (MCO) 45
2.4 Oxidation by Peroxynitrite (ONOO-/HONOO) 46
3 Protein Carbonyls (PCs) and Advanced Oxidation Products (AOPPs) in Renal Disorders 48
3.1 Clinical Studies 49
3.1.1 Oxidation Markers in End Stage Renal Failure and Earlier Stages of Renal Disease 49
3.1.2 Relationship Between Oxidation and Complications in ESRD 52
3.1.3 Interventions That Decrease Plasma Oxidation Products in Humans 53
Dialysis Therapy 53
Antioxidants and Other Drugs 55
Transplantation 56
4 Metal Catalyzed Oxidant (MCO) Stress in End Stage Renal Disease and the Impact of Iron Supplementation 56
5 Conclusions and Therapeutic Implications 58
References 59
Chapter 3: Cyclooxygenase in the Kidney and Oxidative Stress 67
1 Introduction 67
2 Cyclooxygenase Distribution in the Kidney 69
3 Potential Roles of Cyclooxygenases in Kidney Injury 71
4 Glomerular Inflammatory Injury 72
5 Glomerular Noninflammatory Injury 74
6 COX-2 in Hypertension 76
7 Acute Kidney Injury (AKI) 76
8 Urinary Tract Obstruction 77
9 Diabetes Mellitus 77
10 Role of Reactive Oxygen Species as Mediators of COX-2 Actions 78
11 Nonenzymatic Metabolism of Arachidonic Acid 79
12 Conclusion 79
References 79
Chapter 4: Renin-Angiotensin System in the Kidney and Oxidative Stress: Local Renin-Angiotensin-Aldosterone System and NADPH Oxidase-DependentOxidative Stress in the Kidney 86
1 Introduction 87
2 Regulation of Circulating RAAS and Its Role 88
3 Intrarenal RAAS 89
3.1 Regulation of Intrarenal AngII and Aldosterone Levels 89
3.2 AngII Receptors and MR in the Kidney 90
4 NADPH Oxidase-Dependent ROS Production in Renal Injury 92
5 Renal ROS Production Associated with Activation of the RAAS 95
5.1 AngII 95
5.2 Aldosterone 96
6 ROS-Dependent RAAS Activation in the Kidney 96
7 Conclusion 98
References 98
Chapter 5: Thiamine in Diabetic Renal Disease: Dietary Insufficiency, Renal Washout, Antistress Gene Response, Therapeutic Supplements, RiskPredictor, and Link to Genetic Susceptibility 107
1 Introduction: Role of Thiamine in Metabolism and Nutritional Sufficiency in Renal Disease 108
2 Thiamine Transporters and Impaired Renal Handling of Thiamine in Diabetic Nephropathy and Renal Failure 109
3 Transketolase: Countering Oxidative and Metabolic Stress and the Antistress Gene Response in Diabetic Nephropathy 111
4 Thiamine in Early Stage Diabetic Nephropathy: Therapeutic Supplements, Risk Predictor, and Link to Genetic Susceptibility 113
5 Future Prospects 114
References 115
Chapter 6: Novel Members of the Globin Family and Their Function Against Oxidative Stress 119
1 Introduction 119
2 Globins, Hypoxia, and Oxidative Stress 119
3 Hemoglobin 120
4 Myoglobin 122
5 Neuroglobin 123
6 Cytoglobin 125
7 Conclusion 127
References 127
Part II: Clinical Aspects of Oxidative Stress in the Kidney 132
Chapter 7: Hypertension 133
1 Introduction 133
2 Association Between Oxidative Stress and Hypertension: Experimental and Clinical Evidence 134
3 Mechanisms Involved in the Relationship Between Oxidative Stress and Hypertension 137
3.1 Intravascular Pressure, Shear Stress, and Oscillatory Stress 137
3.2 Reduction of NO Availability and Endothelial Dysfunction 137
3.3 Reactive Oxygen Species, Vascular Tone, and Arteriolar Remodeling 138
4 Oxidative Stress in the Kidney, Inflammation, Angiotensin Activity, and Salt Retention 140
4.1 Salt and Oxidative Stress 140
4.2 Oxidative Stress and Renal Medullary Blood Flow 140
4.3 Oxidative Stress, Renal Angiotensin Activity, and Inflammation 141
4.4 Autoimmune Reactivity as a Potential Cause of Oxidative Stress in Hypertension 144
References 145
Chapter 8: Uric Acid and Oxidative Stress 155
1 Uric Acid the Antioxidant 157
1.1 Antioxidant Chemistry of Uric Acid 157
1.1.1 Reaction with Superoxide and Hydroxyl Radical 157
1.1.2 Reaction with Peroxynitrite 158
1.1.3 Reaction with Nitric Oxide 158
1.1.4 Other Antioxidant Reactions 159
1.2 Evidence for Antioxidant Actions of Uric Acid 159
1.2.1 Preservation of Endothelial Function 159
1.2.2 Protection of the Central Nervous System 160
1.2.3 Other Possible Antioxidant Functions 160
1.3 Summary 160
2 Uric Acid the Pro-Oxidant 161
2.1 Intracellular Effects of Uric Acid 161
2.2 Animal Studies 162
3 Xanthine Oxidoreductase and Uric Acid 162
4 Uric Acid and Its Role in Hypertension, Metabolic Syndrome, and Renal Disease 163
4.1 Uric Acid and Hypertension 163
4.2 Uric Acid and Metabolic Syndrome 163
4.3 Uric Acid and Renal Disease 164
5 Conclusion 165
References 167
Chapter 9: Reactive Oxygen and Nitrogen Species, Oxidative and Nitrosative Stress, and Their Role in the Pathogenesis of Acute Kidney Injury 172
1 Definitions 172
2 Redox Signaling Functions 173
3 Mitochondrial ROS: Generation and Defenses 174
3.1 Generation of Mitochondrial ROS 175
3.2 Defense Against Mitochondrial Oxidative Stress 176
4 The Concept of Stress-Induced Hormesis and ROS- and RNS-Induced Toxicity 177
4.1 Hormesis 177
4.2 Oxidative Stress-Induces Programmed Cell Death, Types I and II 177
5 Mitochondrial Biogenesis 178
6 Mitochondrial Oxidative Stress in Acute Kidney Injury 179
7 Therapeutic Implications 181
References 186
Chapter 10: Oxidative Stress in the Kidney: Proximal Tubule Disorders 189
1 Introduction 190
1.1 Redox Status Determines Cell Function 190
1.2 Oxidative Stress 191
1.3 Antioxidant Defense 194
1.4 Redox-Sensitive Signaling 195
1.4.1 NFkappaB and AP-1 196
1.4.2 Protein 53 (p53) 197
1.4.3 HIF and Nrf2 197
2 The Proximal Tubule as a ROS Target 198
2.1 ROS and Renal Disease: A Focus on the Proximal Tubule 199
2.1.1 Diabetic Nephropathy 199
2.1.2 Toxic-Induced Nephropathies 200
2.1.3 Genetic Disorders of the Proximal Tubule 201
2.2 CAIII: A Novel Player in the Antioxidant Defense in the Proximal Tubule 202
3 Protein Reabsorption in the Proximal Tubule: Crucial or Deleterious? 204
3.1 Antioxidant Properties of Albumin 204
3.2 Oxidative Capacity of Albumin 206
3.3 Future Directions 207
4 Conclusion 207
References 208
Chapter 11: Iron Metabolism and Oxidative Stress 214
1 Iron Absorption and Distribution 214
2 Hepcidin, Ferroportin, and Systemic Iron Homeostasis 218
3 Iron: Friend and Foe 219
4 Iron Overload and Pathological Conditions 222
4.1 Cardiovascular System 223
4.2 Iron and Chronic Kidney Disease 225
4.3 Iron and the Nervous System 227
5 Iron: A Potential Risk Factor for Diabetes 229
6 Iron and Carcinogenesis 229
7 Concluding Remarks 230
References 231
Chapter 12: Hypoxia, Oxidative Stress, and the Pathophysiology of Contrast-Media-Induced Nephropathy 238
1 Introduction 238
2 Radiocontrast Agents Hamper Renal Oxygenation 240
3 Radiocontrast-Mediated Changes in Renal Blood Supply 242
4 Mechanisms Involved in Radiocontrast-Induced Altered Renal Microcirculation 243
5 Changes in Renal Oxygen Consumption 245
6 Radiocontrast Agents and Direct Tubular Cell Toxicity 245
7 Risk Factors Predisposing to CIN: A Role for Renal Oxygenation Imbalance 246
8 Risk Factors, Renal Hypoxia, and CIN: Lessons from Animal Models 249
9 Evidence for Enhanced ROS Production in CIN 251
10 ROS and the Pathophysiology of CIN 253
11 Clinical Trials: The ROS Perspective 254
12 Conclusion 257
References 257
Chapter 13: Cardiovascular Complications in Renal Failure: Implications of Advanced Glycation End Products and Their Receptor RAGE 266
1 Introduction 267
2 AGEs in Patients with CKD 268
2.1 Pathways of AGE Generation in Patients with ESRD 269
2.2 AGE Accumulation and Cardiovascular Complications in Patients with ESRD 271
3 Receptor for Advanced Glycation End Products 273
3.1 RAGE and Atherosclerosis 276
3.2 RAGE and Impaired Angiogenic Response 277
3.3 RAGE and Neointimal Expansion Following Arterial Injury 279
3.4 RAGE Modifies Functions of Inflammatory Cells 280
4 C-Terminally Truncated form of RAGE (Soluble RAGE) 280
4.1 sRAGE and esRAGE as Biomarkers for Cardiovascular and Metabolic Diseases 281
4.2 Soluble RAGE, CKD, and Cardiovascular Disease 284
4.3 sRAGE vs. esRAGE: Any Differences? 286
4.4 Soluble RAGE as a Therapeutic Target? 287
References 290
Chapter 14: Infection and the Kidney 302
1 Introduction 302
2 Host-Pathogen Interaction and Oxidative Stress 303
3 Infection and ER Stress 303
4 Oxidative Stress in Urinary Tract Infection 304
4.1 Urinary Tract Infection 304
4.1.1 Lipid Peroxidation and Urinary Tract Infection 305
4.1.2 Inducible NOS in Urinary Tract Infection 305
4.1.3 Urinary Tract Infection, Oxidative Stress, and Carcinogenesis 305
4.1.4 Antioxidant for Urinary Tract Infection 305
4.2 Pyelonephritis 306
5 Oxidative Stress in Sepsis Kidney 306
6 Toll-Like Receptor and Oxidative Stress 308
6.1 Recognition of Exogenous and Endogenous Ligands by Toll-Like Receptors 308
6.2 ROS and Toll-Like Receptor Activation 309
7 Conclusion 311
References 311
Chapter 15: Oxidative/Carbonyl Stress in the Renal Circulation and Cardiovascular Renal Injury 314
1 Introduction 315
2 Physiological Role of Oxidative/Carbonyl Stress in the Regulation of Renal Function and Blood Pressure 315
3 Role of Oxidative/Carbonyl Stress in CKD: Clinical Point of View 321
4 Role of Renal Perfusion Pressure and Oxidative Stress on the Progression of Hypertensive Renal Injury 322
5 Strain Vessel Hypothesis Could Explain the Pathophysiological Connections Between CKD and CVD 324
6 Paradigm Shift of Antiaging Between Ancient and Modern Times 324
7 Conclusion 326
References 326
Part III:Current Therapy Targeting Oxidative tress 330
Chapter 16: The Renin Angiotensin System 331
1 Interruption of the Renin Angiotensin System 331
2 Angiotensinogen 333
3 Renin 334
4 Angiotensin-Converting Enzyme 336
5 Angiotensins 337
6 Angiotensin II Receptors 337
7 Conclusion 339
References 339
Chapter 17: Oxidative Stress in Kidney Injury: Peroxisome Proliferator-Activated Receptor-.Agonists Are in Control 344
1 Experimental Studies 344
1.1 Peroxisome Proliferator-Activated Receptor-.Agonists in Chronic Kidney Disease Animal Models 344
1.2 Peroxisome Proliferator-Activated Receptor-. and Transforming Growth Factor-ß 347
1.3 Peroxisome Proliferator-Activated Receptor-.and the Renin-Angiotensin System 348
1.4 Peroxisome Proliferator-Activated Receptor-.and Aging 348
1.5 Peroxisome Proliferator-Activated Receptor-. Agonist and Oxidative Stress 349
1.6 Peroxisome Proliferator-Activated Receptor-. Agonists and Macrophages 350
2 Human Studies 351
2.1 Peroxisome Proliferator-Activated Receptor-. and Human Chronic Kidney Disease 351
3 Conclusion 352
References 352
Chapter 18: Current Therapy Targeting Oxidative Stress: Statin 358
1 Introduction 358
2 Dyslipidemia of CKD 359
3 Oxidative Stress in the Kidney 362
4 Statins Modulate Oxidative Stress 363
5 Statins and the Kidneys 365
6 Clinical Trials with Statins in CKD Patients 366
7 Conclusion 369
References 370
Chapter 19: N-Acetylcysteine in Kidney Disease 374
1 Introduction 374
2 Contrast-Induced Nephropathy 375
2.1 N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy 378
3 Acute Kidney Injury After Cardiac Surgery 383
3.1 N-Acetylcysteine for Prevention of Acute Kidney Injury After Cardiac Surgery 385
4 Unresolved Issues 388
5 Conclusion and Future Directions 389
References 389
Chapter 20: Advanced Glycation End Products Inhibitor 396
1 Introduction 397
2 Advanced Glycation End Products and Their Receptors 398
2.1 Advanced Glycation End Products 398
2.2 Receptors for AGEs 399
2.3 Soluble RAGE 399
3 Inhibitors of the AGE-RAGE System 399
3.1 AGE Inhibitor 400
3.2 Angiotensin Receptor Blocker 404
3.3 AGE Breaker 406
3.4 RAGE Antagonist 406
3.5 AGE Binder 407
3.6 HIF Activator 408
4 Conclusion 408
References 409
Part IV: Hypoxia 414
Chapter 21: Involvement of Hypoxia-Inducible Factor 1 in Physiological and Pathological Responses to Continuous and Intermittent Hypoxia: Roleof Reactive Oxygen Species 415
1 Introduction: Defining Hypoxia 415
2 Molecular Mechanisms of Oxygen Sensing: The PHD-VHL-HIF-1 Pathway 416
3 Cellular Oxygen Homeostasis: Regulation of Glucose and Energy Metabolism 417
4 Systemic Oxygen Homeostasis: Regulation of Erythropoiesis 419
5 Pathological Effects of Intermittent Hypoxia 420
References 421
Chapter 22: Regulation of Oxygen Homeostasis by Prolyl Hydroxylase Domains 425
1 Introduction 425
2 Milestones in the Field of Hypoxia Research 426
3 Regulation of PHD Enzymatic Properties 427
3.1 Oxygen 427
3.2 2-OG, Iron, Ascorbate, and Reactive Oxygen Species 428
4 Regulation of PHD Abundance and Functions 429
5 PHD Isoforms 431
6 Novel PHD Targets Other than HIF-a 432
7 PHDs as Potential Therapeutic Targets for Human Diseases 433
7.1 Ischemic Disorders 434
7.2 Anemia 434
7.3 Cancer 435
7.4 Inflammation 435
8 Conclusion 436
References 436
Chapter 23: Oxygen-Dependent Regulation of Erythropoiesis 443
1 Introduction 443
2 EPO Regulation as a Paradigm of Systemic Hypoxia Responses 444
3 Regulation of EPO Synthesis by Molecular Oxygen 446
4 Tissue Sources of EPO 448
5 Nonrenal Oxygen Sensing in EPO Homeostasis: Indirect Mechanisms 451
6 HIF-1 Vs HIF-2 in EPO Synthesis 452
7 Oxygen-Dependent Regulation of Iron Homeostasis 455
8 Oxygen and the Bone Marrow 458
9 Erythrocytosis Associated with Genetic Alterations in the HIF Oxygen-Sensing Pathway 458
10 The VHL/HIF/PHD Axis as a Therapeutic Target 460
References 462
Chapter 24: Intricate Link between Hypoxia and Oxidative Stress in Chronic Kidney Disease 470
1 Introduction 471
2 Tubulointerstitial Hypoxia in the Kidney 471
3 Hypoxia-Inducible Factors and Their Role in Renal Disorders 473
4 Reactive Oxygen Species in Hypoxia 474
5 A Role of Mitochondrial ROS in Hypoxia 476
6 Regulation of HIF-a by PHDs 476
7 Mitochondria as an Oxygen Sensor 477
8 Conclusion 479
References 479
Chapter 25: RNA Interference and the Regulation of Renal Gene Expression in Hypoxia 483
1 Clinical Perspective: Hypoxia and Renal Disease 483
2 RNA Interference 486
3 The Biology of Micro RNA 486
4 Hypoxia and miRNAs 488
5 Inflammation and miRNAs in the Immune System 488
6 MicroRNA Expression and Regulation in the Kidney 489
7 siRNAs and shRNAs 490
8 siRNA-Mediated RNAi as an In Vitro Tool 491
9 siRNA as an In Vivo and Clinical Tool 492
10 Side Effects and Problems with siRNA- or shRNA-Mediated RNAi 493
11 Conclusion 494
References 494
Part V: Hypoxia Pathology in Renal Disorders 501
Chapter 26: Cardio-Renal Connection: The Role of Hypoxia and Oxidative Stress 502
1 Introduction: The Concept of the Cardiorenal Connection 502
1.1 The Association of Cardiovascular Disease in Chronic Kidney Disease Patients 502
1.2 The Acute or Severe Cardiorenal Syndrome 503
1.3 The New Proposed Classification for CRS 503
2 Pathophysiological Paradigms in CRS 505
2.1 RAAS Activation 505
2.2 Sympathetic Nervous System 506
2.3 Uremic Calcification and Coronary Heart Disease 507
2.4 Inflammation 508
3 Hypoxia and Its Role in CRS 509
3.1 The Kidney and Hypoxia 509
3.2 Hypoxia and Hypoxic Gene Regulation in the Kidney and the Heart 511
3.3 Acute Kidney Injury and the Concept of Distant Organ Damage 513
3.4 Chronic Hypoxia and Kidney Fibrosis 513
3.5 Anemia and Left Ventricular Hypertrophy 514
4 Oxidative Stress and Its Role in CRS 517
4.1 CRP and Oxidative Stress 517
4.2 Angiotensin II and Oxidative Stress 518
4.3 Nitric Oxide Synthase and Oxidative Stress 518
4.4 The Sympathetic Nervous System and Oxidative Stress 519
5 Perspectives: Therapeutic Options 521
References 522
Chapter 27: Hypoxia-Inducible Factors in Acute Kidney Injury: From Pathophysiology to a Novel Approach of Organ Protection 537
1 Introduction 537
2 Renal Oxygenation in Acute Kidney Injury 538
3 The Kidney Has a Widespread Capacity to Induce HIF 538
4 HIF Is Upregulated in Different Forms of Acute Kidney Injury 539
4.1 Partial Deficiency of HIF Worsens Renal Injury 540
4.2 HIF Induction Protects Against Acute Renal Injury 541
5 The Perspective of HIF as a Therapeutic Target 543
References 543
Chapter 28: Hypoxia in Chronic Kidney Disease: The Final Common Pathway to End Stage Renal Disease 547
1 Introduction 548
2 Anatomical Basis of Hypoxia in the Kidney 548
3 Mechanisms of Hypoxia in Chronic Kidney Disease 549
4 Animal Models of Chronic Hypoxia in the Kidney 550
5 Chronic Hypoxia in the Aging Kidney 551
6 Molecular Pathophysiology of Chronic Hypoxia in the Kidney 552
7 Consequences of Chronic Hypoxia 553
8 Hypoxia and Glomerular Injury 553
9 Therapeutic Approaches Targeting Hypoxia in Chronic Kidney Disease 554
10 Findings in Humans 555
11 Conclusion 556
References 556
Chapter 29: Oxidative Stress and Hypoxia in the Pathogenesis of Diabetic Nephropathy 560
1 Introduction 560
2 The Role of Hypoxia and Oxidative Stress 562
2.1 Diabetes-Induced Decreases in Kidney Oxygen Tension 562
2.2 Diabetes Induces Increases in Kidney Oxygen Consumption 563
2.2.1 Activation of the Polyol Pathway and Pseudohypoxia 563
2.3 Alterations in the Nitric Oxide System 564
2.3.1 Dimethyl Arginines 567
2.4 Proinsulin C-Peptide 568
2.5 Adenosine 568
3 Sources and Molecular Effects of Oxidative Stress 569
3.1 Reactive Oxygen Species: The Unifying Mechanism 569
3.1.1 Activation of Protein Kinase C 570
3.1.2 Advanced Glycation End Products 570
3.1.3 The Hexosamine Pathway 571
3.2 Hypoxia and Oxidative Stress in Mitochondria 571
3.3 NADPH and the Pentose Phosphate Shunt 572
3.4 NADPH Oxidase 572
3.5 Angiotensin II 573
4 Conclusion 575
References 575
Chapter 30: Estimation of Kidney Oxygenation by Blood Oxygenation Level Dependent Magnetic Resonance Imaging 588
1 Introduction 589
1.1 Renal Medullary Hypoxia 590
1.2 Renal Oxygenation Measurements 590
1.2.1 Magnetic Resonance Imaging Technique 591
1.2.2 BOLD MRI Principle 591
1.2.3 R2* as a BOLD MRI Index 592
1.2.4 Practical Logistical Issues When Using BOLD MRI 593
1.2.5 Effect of Field Strength 595
2 Experimental Studies 595
2.1 Renal BOLD MRI Validation Studies 595
2.1.1 Reproducibility Study 596
2.2 Renal BOLD MRI Applications 596
2.2.1 Physiological/Pharmacological Induced Changes in Intra-Renal Oxygenation 596
2.2.2 Renal BOLD MRI in Disease 599
Diabetes Mellitus 599
Hypertension 600
Renal Artery Stenosis (RAS) 600
Unilateral Ureteral Obstruction 602
Renal Transplants 602
3 Renal BOLD MRI: Limitations 605
4 Conclusion 605
References 606
Chapter 31: Anemia and Progression of Chronic Kidney Disease 611
1 The Progressive Nature of Chronic Kidney Disease 612
2 Renal Tissue Hypoxia and CKD Progression 613
2.1 Methods to Assess Oxygenation of Renal Tissue 613
2.2 Response to Renal Tissue Hypoxia 613
2.3 Renal Tissue Hypoxia in CKD 614
2.4 Other Clinical Conditions Resulting in Significant Renal Tissue Hypoxia 615
3 Anemia and CKD Progression 616
4 Renal Anemia, EPO, and rHuEPO 616
4.1 Tissue Expression of EPO and the Erythropoietin Receptor 616
4.2 Molecular Actions of EPO 618
5 Treatment of Renal Anemia and CKD Progression 618
6 Other Actions of rHuEPO and Its Derivates to Prevent Renal Tissue Injury 621
6.1 Tissue Protection by Nonhematologic Effects of rHuEPO 621
7 Renoprotection by Nonhematologic Effects of rHuEPO 622
8 Conclusion 624
References 624
Part VI: Novel therapeutic approaches against oxidative stress and hypoxia 631
Chapter 32: Novel Therapeutic Approaches Against Oxidative Stress and Hypoxia, Targeting Intracellular Sensor Molecules for Oxygen and Oxidative Stress 632
1 Introduction 633
2 Abnormal Oxygen Metabolism 634
2.1 Hypoxia 634
2.2 Oxidative Stress 635
2.3 Broad Derangement of Oxygen Metabolism 636
3 Implications in Current Therapies 638
3.1 Inhibitor of the Renin-Angiotensin System: Blood Pressure Lowering Agent 638
3.2 Glucose Lowering Agent 639
3.3 Correction of Obesity 639
4 Novel Therapeutic Target 640
4.1 Hypoxia-Inducible Factor 640
4.2 Oxygen Sensor (PHD) 641
4.3 Specific Inhibitor for Oxygen Sensor 642
4.4 Nrf2 646
4.5 Oxidative Stress Sensor (KEAP1) 647
4.6 Nrf2 Inducer and Inhibitor of Oxidative Stress Sensor 648
5 Conclusion 648
References 649
Chapter 33: Endoplasmic Reticulum Stress as a Target of Therapy Against Oxidative Stress and Hypoxia 656
1 Endoplasmic Reticulum Stress and Its Cellular Response 657
2 Pathophysiological States of ER Stress: A Link to Oxidative Stress and Hypoxia 657
2.1 ER Stress and Hypoxia 657
2.2 ER Stress and Oxidative Stress 659
3 Contribution of ER Stress in Kidney Disease 661
3.1 ER Stress in Glomerular Injury 662
3.2 ER Stress in Tubulointerstitial Injury 662
3.3 ER Stress in Aged Kidney 664
4 Therapeutic Approaches Targeting ER Stress 664
5 Conclusion 667
References 667
Chapter 34: Stem Cell Therapy Against Oxidative Stress and Hypoxia 672
1 Introduction 672
2 Stem Cell Sources for Therapy Against Oxidative Stress 673
2.1 Endothelial Progenitor Cells 673
2.2 Hematopoietic Stem Cells 674
2.3 Mesenchymal Stem Cells 674
2.4 Embryonic Stem Cells 675
2.5 Induced Pluripotent Stem Cells 676
3 DDS against Oxidative Stress Using Stem Cells 677
4 Supplementing Stem Cells by Mobilization and Transplantation 678
5 De Novo Establishment of EPO Producers from Stem Cells 680
6 Conclusion 681
References 682
Name Index 687
Subject Index 776