Phosphate Metabolism: From Physiology to Toxicity (Advances in Experimental Medicine and Biology, 1362)

This contributed volume discusses the most important physiological aspects of phosphate metabolism, and how its pathological dysregulation can induce organ damage, which includes but is not limited to blood vessels, kidney, bone and tumor. The editor has selected a varied group of world renowned experts to provide a basic understanding of normal phosphate regulation, to then move on to explain the complex molecular mechanisms of abnormal phosphate regulation, also shedding some light on the downstream clinical consequences owing to phosphate toxicity. Each chapter clearly presents the biochemically important problems related to phosphate dysregulation with the necessary illustrations. Readers will be able to use the proposed book as a quick reference for updated information on phosphate metabolism, ranging from cellular system to physiology, from pathology to toxicity, also including the associated clinical consequences, without much prior acquaintance with the field. Preface 6 Contents 7 1: Phosphate Metabolism: From Physiology to Toxicity 9 1.1 Phosphate Homeostasis 9 1.2 Book Chapters 10 1.3 Conclusion 12 References 12 2: Phosphate Burden and Inflammation 15 2.1 Phosphate in the Human Body 15 2.2 Inflammation Associated with Phosphate Toxicity 16 2.3 Mechanisms of Phosphate-Induced Inflammation 17 2.4 Phosphate Toxicity and Cardiovascular Disease 17 2.5 Phosphate Toxicity and Tumorigenesis 18 2.6 Conclusions 19 References 20 3: Extracellular Phosphate, Inflammation and Cytotoxicity 22 3.1 Introduction 22 3.2 FGF23-αKlotho System and Phosphate Metabolism 23 3.3 Phosphate and Morbidity and Mortality 24 3.4 Phosphate and Pathological Calcification 25 3.5 Phosphate and Inflammation 25 3.6 Phosphate-Induced Signaling and Cytotoxicity 26 3.7 Phosphate and Oxidative Stress 27 3.8 Effects of Phosphate on Tumorigenesis 28 3.9 Conclusions 28 References 28 4: Phosphate-Sensing 33 4.1 General 34 4.2 Fibroblast Growth Factor 23: FGF23 34 4.2.1 The Structure of FGF23 Protein 34 4.2.2 The Posttranslational Modification of FGF23 Protein Via a Phosphate Responsive Gene: GALNT3 35 4.3 Phosphate-Sensing 36 4.3.1 Intracellular Signaling Induced by Phosphate: MEK/ERK Pathway 36 4.3.2 A Potential Candidate Molecule for Phosphate-Sensing in the Bone: FGFR1c 36 4.3.2.1 The Significance of FGFR1c as a Phosphate-Sensing Molecule In Vivo 37 4.3.2.2 The Specific FGFR1c Signal Transduction Mediated by Phosphate 37 4.3.2.3 The Activation Model of Unliganded FGFR1c by Phosphate 38 4.3.3 The Involvement of Type III Sodium-Phosphate Cotransporters: PiT1 and PiT2 38 4.3.4 A Molecule for Phosphate-Sensing in the Parathyroid Glands: Calcium-Sensing Receptor 39 4.4 Perspectives 39 References 40 5: Vitamin D and Phosphate Interactions in Health and Disease 42 5.1 Introduction 42 5.2 Physiological Regulation of Phosphate Homeostasis 43 5.2.1 Parathyroid Hormone (PTH) 45 5.2.2 Vitamin D (Calcitriol) 45 5.2.3 Fibroblast Growth Factor 23 (FGF23) 46 5.3 Hyperphosphatemia 47 5.4 Hypophosphatemia 47 5.5 Genetic Disorders Associated with Hypophosphatemia 48 5.6 Conclusions 48 References 48 6: Fibroblast Growth Factor 23 as Regulator of Vitamin D Metabolism 52 6.1 Physiology of FGF23 53 6.2 Direct and Indirect Effects of FGF23 on Various Factors 53 6.3 Significance of Inhibition of Vitamin D Activation by FGF23 in Non-CKD Individuals 55 6.4 Potential Role of FGF23 in Regulation of Vitamin D Metabolism in Non-CKD Individuals 55 6.5 Potential Role of FGF23 in Regulation of Phosphate Metabolism in Non-CKD Individuals 56 6.6 Vitamin D Metabolism and FGF23-Klotho Axis in Non-CKD Individuals 56 6.7 Future Prospects 56 6.8 Conclusion 57 References 57 7: Phosphate and Cellular Senescence 60 7.1 Introduction 60 7.2 Cellular Senescence 62 7.2.1 Cellular Senescence and Its Signaling Pathways 62 7.2.2 Senescence-Associated Secretory Phenotype 62 7.2.3 Cellular Senescence Effect on Aging 63 7.2.4 Cellular Senescence in Human Disease 63 7.2.4.1 Tumorigenesis 63 7.2.4.2 Chronic Non-neoplastic Diseases 63 7.3 Phosphotoxicity in Aging and Age-Associated Disease 63 7.3.1 Phosphate Effect on Aging and Klotho 63 7.3.2 Phosphotoxicity and Human Disease 64 7.3.2.1 Cancer 65 7.3.2.2 Cardiovascular Disease 65 7.3.2.3 Kidney Disease 65 7.3.2.4 Metabolism 65 7.3.2.5 Other Diseases 65 7.4 Stimulation of Cellular Senescence by Phosphate 66 7.4.1 Direct Stimulation of Cellular Senescence 66 7.4.2 Indirect Stimulation of Cellular Senescence 67 7.4.2.1 Downregulation of Klotho 67 7.4.2.2 Upregulation of Plasminogen Activator Inhibitor Type-1 67 7.4.2.3 Activation of SASP 67 7.5 Cellular Senescence: A Novel Downstream Target for the Treatment of Phosphotoxicity 67 7.5.1 Control of Dietary Phosphate Intake and Reduction of Serum Phosphate 68 7.5.2 Augmentation of Phosphate Excretion from the Kidney 68 7.5.3 Restoration of Plasma Klotho 69 7.5.3.1 Delivery of Klotho cDNA 69 7.5.3.2 Administration of Recombinant Klotho Protein 69 7.5.3.3 Disinhibition of Endogenous Klotho Production 69 7.5.4 Direct Suppression of Senescence Signaling Pathway and Removal of Senescent Cells to Ameliorate Phosphotoxicity 70 7.5.4.1 Removal of Senescence Stimuli 70 7.5.4.2 Removal of Senescent Cells 70 7.5.4.3 Interruption of SASP 70 7.6 Conclusion 71 References 71 8: Phosphate Toxicity and Epithelial to Mesenchymal Transition 78 8.1 Phosphate Toxicity 78 8.2 EMT Overview 79 8.2.1 TGFβ-Induced EMT 80 8.2.1.1 Smad-Dependent EMT 80 8.2.1.2 Smad-Independent EMT 81 8.2.2 Non-TGFβ-Induced EMT Pathways 82 8.2.3 EMT and Diseases 82 8.2.3.1 Cancer Metastasis 82 8.2.3.2 Fibrosis 83 8.2.3.3 Therapeutics by Targeting EMT 83 8.3 Lethal EMT 83 8.4 High Pi-Mediated EMT 84 8.5 Open Questions and Future Directions 85 8.6 Concluding Remarks 85 References 86 9: Phosphate and Endothelial Function: How Sensing of Elevated Inorganic Phosphate Concentration Generates Signals in Endothel... 90 9.1 Introduction 90 9.2 Pi and Endothelial Function - What Pi Does to Endothelium In Vitro and In Vivo 92 9.2.1 Effects on Vasodilation 92 9.2.2 Oxidative Stress and Cell Survival 93 9.2.3 Microvesicles 93 9.2.4 Angiogenesis 94 9.2.5 Endothelial-Mesenchymal Transition 94 9.3 How Pi Concentration Is Regulated in Mammalian Cells 95 9.4 How Changes in Pi Concentration Are Sensed in Mammalian Cells 96 9.5 Amplification of Pi Signals in Endothelial Cells 97 9.6 How Pi Signals Trigger Functional Effects in Endothelial Cells 97 9.7 Directions for Future Work 98 9.8 Conclusions 99 References 99 10: Common Dietary Sources of Natural and Artificial Phosphate in Food 104 10.1 Introduction 104 10.2 Recommended Dietary Allowance (RDA) in USA 105 10.3 Adequate Intake (AI) in Japan 105 10.4 Common Phosphate-Containing Food 105 10.5 Inorganic Phosphate Additives 106 10.6 Phosphate Intake and Bioaccessibility 107 10.7 Food Additives and Health 107 10.8 Conclusion and Perspective 108 References 109 11: Phosphate Is a Cardiovascular Toxin 111 11.1 Physiology of Phosphate Homeostasis 111 11.1.1 FGF23 112 11.1.2 PTH 112 11.1.3 Phosphate 113 11.2 Phosphate-Related Cardiovascular Disease 114 11.2.1 Mechanisms of Phosphate-Induced Vascular Calcification 114 11.2.1.1 Phosphate-Dependent Osteochondrogenic Transdifferentiation of VSMCs 115 11.2.1.2 ECM Remodeling During Hyperphosphatemia 115 11.2.1.3 Phosphate-Induced Apoptosis, Senescence and Autophagy 117 11.2.1.4 Regulation of Endogenous Calcification Inhibitors by Phosphate 117 11.2.1.5 Hyperphosphatemia-Associated Inflammatory Pathways 118 11.2.1.6 The Role of Calciprotein Particles in Vascular Calcification 119 11.2.2 Hyperphosphatemia-Associated Left Ventricular Hypertrophy 119 11.2.3 The Role of Hyperphosphatemia in Hypertension 121 11.3 Hypophosphatemia and CVD Risk 122 11.4 Therapeutics Interventions to Prevent Phosphate-Dependent CVDs 124 11.4.1 Treatment of Hypophosphatemia 124 11.4.2 Treatment of Hyperphosphatemia 125 11.4.2.1 Phosphate Restricted Diet 125 11.4.2.2 Phosphate Binders Targeting Intestinal Phosphate Absorption 125 11.4.2.3 Drugs Targeting the Phosphate Transporters in the Intestine 126 11.4.2.4 Drugs Targeting the Renal Phosphate Transporters 126 11.4.2.5 Magnesium 127 11.5 Conclusions 128 References 128 12: Coordination of Phosphate and Magnesium Metabolism in Bacteria 139 12.1 Phosphorus Acquisition in Bacteria 139 12.2 Sensing and Responding to Pi Starvation 141 12.3 Phosphate Cytotoxicity via Pst 143 12.4 The Role of Mg2+ on the Utilization of Assimilated Pi 144 12.5 Sensing and Responding to Mg2+ Starvation 145 12.6 Coordination of Pi and Mg2+ Homeostasis in Bacteria 147 12.7 Concluding Remarks 147 References 149 Chapter 13: Phosphate Dysregulation and Neurocognitive Sequelae 155 13.1 Introduction 155 13.2 Hyperphosphatemia and Neuronal Dysfunction 156 13.3 Hyperphosphatemia-Induced Neurovascular Complications 157 13.4 Hypophosphatemia and Neuronal Dysfunction 158 13.5 Hypophosphatemia-Induced Neurovascular Complications 159 13.6 FGF23-Klotho Axis and Neuronal Functions 159 13.7 FGF23 and Neuronal Functions 160 13.8 Klotho and Neuronal Functions 161 13.9 Summary 161 References 162 Index 165