کلیه، ویرایش پنجم: فیزیولوژی و پاتوفیزیولوژی

Front Cover......Page 1 Seldin and Giebisch’s the Kidney......Page 4 Copyright Page......Page 5 Dedication......Page 6 Contents......Page 8 Foreword......Page 14 Preface......Page 16 List of Contributors......Page 18 I: Epithelial and Nonepithelial Transport and Regulation......Page 22 The Nature and Physiologic Implications of Epithelial Polarity......Page 24 The Junctional Complex......Page 25 Biogenesis of Epithelial Polarity......Page 34 In Vitro Systems......Page 35 Sorting Pathways......Page 42 Epithelial Cell Polarity and Renal Disease......Page 53 References......Page 55 The Cell Interior and Extracellular Fluid Have Different Ionic Compositions......Page 66 The Plasma Membrane: Structure Related to Function......Page 67 The Plasma Membrane is Selectively Permeable......Page 68 Active and Passive Transport Processes can be Evaluated by Considering Direction of Electrochemical Potential Difference (D.........Page 69 Pathways and Mechanisms of Passive Transport......Page 70 Pathways and Mechanisms of Active Transport......Page 74 Ion Transport PROTEINS......Page 75 Channels......Page 76 Carriers......Page 79 Pumps......Page 81 References......Page 84 Structure and Function of Ca2+-ATPases (SERCA and PMCA)......Page 88 Structure of Na,K-ATPase and H,K-ATPase......Page 89 β-Subunit......Page 90 FXYD Proteins......Page 91 Ion Transport......Page 92 Pharmacology......Page 93 Substrates......Page 94 Na,K-ATPase in the Kidney......Page 96 Regulation of Na,K-ATPase in Proximal Tubule......Page 97 Regulation of Na,K-ATPase in Thick Ascending Limb of Henle’s Loop......Page 98 Control of Na,K-ATPase in Collecting Duct......Page 99 Induction of Na,K-ATPase is Associated with Sodium Retention in Nephrotic Syndrome and Liver Cirrhosis......Page 100 Gastric H,K-ATPase......Page 101 Structure and Mechanism of Action of V-ATPases......Page 103 Multiple Functions of the V-ATPASE in the Kidney......Page 104 References......Page 107 Osmotic Equilibrium is a Balance of Osmotic and Hydrostatic Forces......Page 116 Osmotic Water Flows Across Lipid and Porous Membranes have Different Properties......Page 117 Comparison of Diffusion and Osmotic Permeability Coefficients Reveals Whether Water Permeates Lipid Bilayer or Pores......Page 119 Unstirred Layers are a Major Source of Artifacts in Water Permeability Measurements......Page 120 Solute Reflection Coefficients Denote Effective Osmolality of a Solution vis-à-vis a Membrane......Page 122 Intracellular Water Behaves Similar to Water in Free Solution......Page 123 Net Water Transport Across Membranes of Animal Cells is Osmotic......Page 124 Water Permeability of the Plasma Membrane Varies Considerably Among Cell Types......Page 125 Pathways for Water Transport Across Cell Membranes......Page 126 Epithelia Have Very Different Water Permeabilities......Page 131 Two Types of Transepithelial Water Transport......Page 132 Solute–Solvent Coupling......Page 133 Pathways for Transepithelial Water Transport are also Controversial......Page 136 References......Page 137 Cell Volume Regulatory Mechanisms......Page 142 Ions in Cell Volume Maintenance......Page 143 Ion Uptake upon Cell Shrinkage......Page 144 Metabolic Pathways Sensitive to Cell Volume......Page 145 Signaling of Cell Volume Regulation......Page 146 Alterations of Extracellular Fluid Osmolarity and Composition......Page 148 Functional States Affecting Cell Volume Control......Page 149 References......Page 153 Na Transport and Energy Consumption in the Kidney......Page 164 Energy Cost of Primary Active Transport......Page 165 Energy Production Pathway in the Kidney......Page 170 Preference of Metabolic Substrates in Nephron Segments......Page 175 The Effect of Active Transport on Metabolism......Page 179 The Effect of Metabolism on Active Transport......Page 180 Structure and Regulation of AMPK......Page 182 NA+,K+-ATPase......Page 183 The Epithelial Na+ Channel (ENaC)......Page 184 Other Factors Linking Transport and Cellular Metabolism......Page 185 Renal Ischemia......Page 186 References......Page 188 Introduction......Page 198 Measurement of Transepithelial Resistance in Open Circuited Renal Tubules......Page 200 Measurement of Transepithelial Resistance in Voltage Clamped Renal Tubules......Page 202 Contribution of Active Transport to Vte......Page 203 Contribution of Circulating Current to Vte......Page 204 Short-Circuit Current......Page 205 Estimation of Membrane Parameters from Transepithelial Measurements......Page 207 Cell Membrane Potentials in Epithelia......Page 209 Evaluation of Individual Membrane Resistances from an Equivalent Circuit Analysis......Page 210 Evaluation of Individual Membrane Resistances Using Multiple Intracellular Recordings......Page 212 Estimation of Renal Na-K Pump Current and Electrogenic Potential......Page 216 Patch-Clamp and Single-Channel Analysis......Page 218 Single-Channel Current......Page 219 Channel Selectivity......Page 220 Open Probability......Page 221 Number of Channels......Page 222 Open and Closed Times......Page 223 Channel Pharmacology......Page 224 Apical Membranes......Page 225 Isolated Cells......Page 226 Noise Analysis......Page 227 Molecular Identification of Channels......Page 228 Appendix 1 The basic equations for the general equivalent circuit......Page 229 Appendix 3 Equations for partial ionic conductance......Page 231 Appendix 4 Contribution of the electrogenic Na-K pump to the membrane potential......Page 232 References......Page 233 8 Renal Ion Channels, Electrophysiology of Transport, and Channelopathies......Page 238 The Tubule is a Barrier......Page 239 Routes of Transport across the Tubule......Page 241 Types of Transport and Transporters......Page 242 Urine Flows down the Tubule......Page 243 Recording Ion Channel Activity with Patch-Clamp Electrophysiology......Page 244 Adaptation of Ohm’s Law to Biological Systems: Explaining Current Carried by Ion Channels......Page 245 The Goldman–Hodgkin–Katz Voltage Equation......Page 246 What do Ohm’s Law, the Nernst Equation, and the GHK Equation Tell us About Transport?......Page 247 Channels are Selective......Page 248 Ions Permeate Through Channels......Page 249 Channels Gate......Page 250 Types of Gates......Page 251 The Consequences of Regulation of Gating......Page 252 Modeling Channel Gating......Page 253 Pore Block......Page 254 CLC (CLCN) Channels and Barttin (BSND)......Page 255 KCNJ (Kir) Channels......Page 256 TRP Channels......Page 257 Ion Channel Structure......Page 259 The Architecture of ClC Channels......Page 260 The Architecture of K+ Channels and TRP Channels: ROMK as a Representative......Page 266 Molecular Basis of ROMK Gating......Page 268 ClC-Kb: Barrter Syndrome Type III......Page 269 Barttin: Bartter Syndrome Type IV......Page 271 ENaC......Page 272 ROMK: Bartter Syndrome Type II......Page 275 TRPM6: Hypomagnesemia with Secondary Hypocalcemia......Page 277 References......Page 278 Introduction......Page 284 Microvascular Ultrastructure......Page 285 Passive Transport and Permeability Coefficients of Porous Membranes......Page 286 Ultrastructural Basis of Permeability......Page 293 Coupling of Fluid and Solute Transport during Ultrafiltration......Page 296 Fluid Movements through Microvascular Walls......Page 297 Interstitial Hydrostatic Pressure......Page 300 Starling Pressures and Local Lymph Flow......Page 303 Microvascular Blood Flow and Solute Transport......Page 304 Increased Microvascular Permeability......Page 306 Measuring Increases in Vascular Permeability......Page 307 References......Page 308 Is the Capacity of any System Always Limited?......Page 312 Speed of Balance Restoration......Page 314 Mechanism of Balance Restoration......Page 315 Model B......Page 316 Model C......Page 317 Infinite Gain Control Mechanism......Page 318 Common Misconceptions and New Insights......Page 319 There is no Set Point for Renal Salt Excretion......Page 320 Renal Salt Output Does Not Exceed Salt Intake in Salt Losing Nephropathy......Page 321 Sodium Intake and Sodium Balance are Poor Predictors of Effective Vascular Volume......Page 322 Does Overflow Mechanism Explain Ascites Formation?......Page 323 Determinants of Sodium Delivery to the Cortical Collecting Duct and Renal K Excretion......Page 324 Enigma of Pendred Syndrome......Page 325 Mechanism of Volume Depletion in Chronic Hypernatremia......Page 327 Measurement of Net Acid Excretion......Page 328 Sulfuric Acid......Page 329 Phosphoric Acid......Page 330 Conversion of Creatine-P to ATP......Page 331 Organic Acids in Meat......Page 332 Ingestion of a Poorly- or Non-Absorbable Cation Accompanied by an Absorbable Anion......Page 333 Calculation of Net Alkali in a Complex System......Page 334 Bone Buffering in Acute Metabolic Acidosis......Page 336 References......Page 337 Introduction......Page 340 Ciliary Axoneme......Page 343 Transition Fibers......Page 344 Intraflagellar Transport (IFT) and IFT Motors......Page 345 Mechanisms of Cilia Protein Entry......Page 346 Ciliary Targeting and the BBSome......Page 347 Cilia Extension......Page 348 Cilia Signaling in the Nephron......Page 349 Renal Cilia and Jak/STAT Signaling......Page 350 Renal Cilia and Non-Canonical Wnt/Planar Cell Polarity (PCP) Signaling......Page 351 Renal Cilia and Canonical Wnt Signaling......Page 352 Renal Cilia and mTOR......Page 353 Renal Cilia and Vasopressin Signaling......Page 354 Renal Cilia and Hedgehog Signaling......Page 355 Caenorhabditis elegans......Page 356 Danio rerio......Page 357 The Human Renal Ciliopathies......Page 358 Nephronophthisis (NPHP)......Page 359 Meckel–Gruber Syndrome (MKS)......Page 360 Jeune Asphyxiating Thoracic Dystrophy (ATD)......Page 361 References......Page 362 Structure......Page 368 Biochemical Composition......Page 369 Physiology of the Tight Junction in Different Nephron Segments......Page 372 Tight Junction Dysfunction in Ischemic Acute Kidney Injury......Page 376 Structure and Biochemical Composition......Page 377 Renal Localization......Page 378 Physiological Function in the Kidney......Page 379 Roles in Renal Pathology......Page 381 Structure and Localization of Desmosomes......Page 382 References......Page 383 Cell Surface Receptors......Page 390 G-Protein Coupled Receptors......Page 391 TGFβ Signaling in the Kidney......Page 397 Receptors Activated by Proteolytic Cleavage......Page 398 Receptors that Signal Cell Location......Page 401 The Cilia as a Signaling Structure......Page 403 Intracellular Signaling Pathways......Page 404 The Phospholipase C Pathway Regulates Intracellular Calcium Release and Activates PKC Signaling......Page 405 The Mitogen Activated Protein Kinase (MAPK) Pathway Regulates Cell Survival, Proliferation, and Morphology......Page 407 The Phosphoinositide 3-Kinase Pathway Regulates Diverse Events Including Glucose Metabolism, Cell Migration, Cell Survival,.........Page 410 Examples of Signaling Effectors in the kidney......Page 411 Regulation of Ion Transport Channels......Page 412 References......Page 416 Structural Basis for PDZ Interaction......Page 426 Regulation of PDZ Binding......Page 427 MAGUKs, the Archetypal PDZ Scaffolds......Page 428 Apical Membrane PDZ Protein Complexes......Page 429 NHERF in Epithelial Transport......Page 430 The Lin-7/CASK/PSD-97 System......Page 435 Dystrophin-Associated Protein Complex......Page 437 Common Properties of AKAP Proteins......Page 438 Function of AKAPS in Kidney Transport Processes......Page 439 References......Page 440 Renin......Page 448 Angiotensinogen......Page 449 Angiotensin Receptors......Page 450 Aldosterone......Page 452 Sources of Renin......Page 453 Baroreceptor Regulation of Renin Release......Page 455 Regulation of Cellular Release of Renin......Page 457 Control of Renal Hemodynamics by the RAS......Page 458 Renal Epithelial Actions of the RAS......Page 459 Tubular Effects of Angiotensin II......Page 460 References......Page 461 Extrinsic Innervation......Page 472 Intrinsic Innervation......Page 473 Pharmacology......Page 474 Autocrine and Paracrine Influences on Neurotransmission......Page 475 Renal Denervation......Page 477 Renal Denervation......Page 478 Renin Containing Cells......Page 479 Activation of the Renal Nerves......Page 480 Recruitment of Functionalities......Page 481 Patterns of Electrical Stimulation of the Renal Nerves......Page 482 Reflex Regulation of the Renal Nerves......Page 484 Central Nervous System......Page 487 Neuroanatomy......Page 489 Selective Afferent Renal Denervation: Dorsal Rhizotomy......Page 490 Activation of Renal Mechanosensory Nerves: Physiological Conditions......Page 491 Activation of Renal Mechanosensory Nerves: Pathohysiological Conditions......Page 498 References......Page 500 Phospholipase-Mediated Arachidonic Acid Release......Page 508 Cyclooxygenase Derived Prostanoids......Page 509 Prostaglandin E2......Page 511 E-Prostanoid Receptors......Page 512 EP3 Receptor......Page 513 Prostaglandin F Synthesis......Page 514 D-Prostanoid Receptors......Page 515 Prostaglandin Transport......Page 516 Prostaglandins and Progression of Kidney Disease......Page 517 Lipoxygenase Derived Eicosanoids: 5-, 12-, and 15-HETEs and Leukotrienes......Page 518 Role of Renal CYP450-Derived Arachidonate Metabolites in Renal Damage......Page 519 References......Page 520 P2Y Receptors......Page 532 Synthetic Agonists and Antagonists of P2 Receptors......Page 533 The Renal Vasculature......Page 535 Renal Autoregulation......Page 537 Glomerular and Medullary Microcirculation......Page 538 Secretion of Nucleotides......Page 544 Mechanism of Nucleotide Release......Page 546 Ectonucleotidases......Page 547 Role of P2 Receptors in Renal Pathophysiology......Page 549 Acknowledgments......Page 552 References......Page 553 Historical Perspective......Page 560 Sources of L-DOPA......Page 561 Aromatic Amino Acid Decarboxylase (AADC) Activity......Page 562 Dietary Influence Including Salt Intake......Page 563 Dopamine Receptor Signaling......Page 565 Protein Kinase C......Page 566 Adenylyl Cyclase......Page 567 DARPP-32......Page 568 Regulation of Dopamine Receptor Function......Page 569 Renal Distribution of Dopamine Receptors......Page 571 Receptors in Juxtaglomerular Apparatus......Page 572 D2-Like Receptors......Page 573 Glomerular Filtration......Page 574 Renin, Angiotensinogen, and Aldosterone Secretion......Page 575 Ion Transport......Page 578 Loop of Henle......Page 579 Medullary Collecting Duct......Page 580 Basolateral Membrane......Page 581 Hypovolemia......Page 582 Dopamine Receptor Subtype Mutant Mice......Page 583 Interaction among the Dopamine Receptors and with Other GPCRs in the Regulation of Renal Function and Blood Pressure......Page 584 Angiotensin II and Angiotensin Receptors......Page 585 AT2R and Dopamine Receptors......Page 586 Insulin and Insulin Receptors......Page 587 Regulation of Reactive Oxygen Species (ROS)......Page 588 Dopamine and Essential Hypertension......Page 589 Dopamine and Blood Pressure Regulation: Peripheral versus Central Nervous System......Page 590 Conclusion......Page 591 References......Page 592 II: Structural and Functional Organization of the Kidney......Page 614 Renal Vasculature......Page 616 Wall Structure of Intrarenal Vessels......Page 620 Nephrons and Collecting Duct System......Page 621 Interstitial Fibroblasts......Page 623 Cortical Interstitial Fibroblasts......Page 626 Medullary Interstitial Fibroblasts......Page 627 Dendritic Cells......Page 628 Periarterial Connective Tissue and Lymphatics......Page 629 Cortex......Page 631 Medulla......Page 633 Architecture of the Glomerulus......Page 637 The Glomerular Basement Membrane (GBM)......Page 639 The Cells of the Glomerular Tuft......Page 641 Filtration Barrier......Page 646 Parietal Epithelium of Bowman’s Capsule......Page 647 General Overview of Renal Epithelial Organization......Page 648 Primary Single Cilia......Page 652 Morphology of Proximal Tubular Epithelium......Page 653 Functional Aspects......Page 654 Thin Limbs of Henle’s Loop (Intermediate Tubule)......Page 656 Thick Ascending Limb of Henle’s Loop......Page 661 Role in Bicarbonate Reabsorption......Page 662 Role in Mg2+ and Ca2+ Recovery......Page 663 Segments Downstream of the Tal: Distal Convoluted Tubule, Connecting Tubule, and Collecting Duct......Page 664 Distal Convoluted Tubule (DCT)......Page 665 Connecting Tubule (CNT)......Page 669 Functional Aspects......Page 670 Collecting Ducts......Page 671 Intercalated Cells (IC Cells)......Page 674 Juxtaglomerular Apparatus......Page 679 Macula Densa......Page 680 The Renal Medulla......Page 684 The Outer Stripe of the Outer Medulla......Page 686 Countercurrent Exchange of Solutes and Water......Page 689 Urea Recycling......Page 690 References......Page 691 Introduction......Page 714 Glomerular Hemodynamics and Micropuncture......Page 716 Ultrafiltration Coefficient, LpA, and Filtration Pressure Equilibrium......Page 718 Hydrostatic Pressure, PGC, and ΔP......Page 720 Interactions Among the Determinants of SNGFR......Page 721 The Filtration Barrier and Filtration of Macromolecules......Page 722 Pore Theory......Page 723 Intravital Microscopy and Albumin Sieving......Page 728 Charge Selectivity of the Filtration Barrier......Page 729 Serial Membrane Models......Page 732 Structure-Based Models of the Glomerular Capillary......Page 733 References......Page 736 Structure and Function of the Glomerulus (Renal Corpuscle)......Page 742 Functional Maintenance of Glomerular Endothelial Cells: Insights from Studies of Angiogenic Factors......Page 743 Mesangial Cells Produce and Maintain Mesangial Matrix......Page 749 Signaling Molecules Involved in Mesangial Cell Biology......Page 750 Description......Page 751 Podocyte Morphology......Page 753 Podocyte Development, Transcription Factors, and Notch......Page 754 Podocyte Slit Diaphragm Assembly......Page 757 Podocyte–GBM Interaction......Page 760 Podocytes and Metabolism......Page 762 Podocyte Progenitors......Page 764 Size Barrier......Page 765 References......Page 767 Macula Densa Cells......Page 778 Extraglomerular Mesangial (EGM) Cells......Page 780 Granular Cells......Page 781 The Tubuloglomerular Feedback Loop......Page 782 The Tubular Signal and the Sensing Mechanism......Page 784 The Vascular Effector Mechanism......Page 786 Integrated Function of the TGF Mechanism......Page 791 Evidence for Macula Densa Control of Renin Secretion......Page 799 Sensing Mechanism for Macula Densa-Mediated Renin Secretion......Page 800 The Stimulus–Response Coupling Mechanism......Page 801 References......Page 806 Cortical Microcirculation......Page 824 Medullary Microcirculation......Page 825 The Renal Cortex and Capillary Uptake of Tubular Reabsorbate......Page 830 Transport of Small Solutes and Water by Vasa Recta and Red Blood Cells......Page 831 Transport of Macromolecules in the Cortex and Medulla......Page 837 Intrarenal Hematocrit......Page 838 Videomicroscopy......Page 839 Laser-Doppler......Page 840 The Split Hydronephrotic Kidney......Page 841 Voltage-Gated Ca2+ Channels......Page 842 Chloride Channels......Page 843 Potassium Channels......Page 844 Connexins......Page 845 Regulation of Blood flow and Microvessel Contraction......Page 846 Autoregulation and Pressure Natriuresis......Page 847 Vasopressin and Excretion of Water......Page 848 Angiotensins......Page 849 Adrenomedullin......Page 850 Nitric Oxide......Page 851 Reactive Oxygen Species......Page 852 Adenosine and P1 Purinoceptors......Page 853 Extracellular ATP and Renal P2 Purinoceptors......Page 854 Arachidonic Acid Metabolites......Page 855 Natriuretic Peptides......Page 858 References......Page 859 Overview......Page 880 Development of the Metanephros......Page 881 Organ Culture......Page 882 Isolated Ureteric Bud Culture......Page 883 Isolated Metanephric Mesenchyme Culture: Recombination with Isolated Ureteric Bud......Page 885 Molecular Approaches to Kidney Development......Page 888 Transcription Factors in Metanephrogenesis......Page 889 Transcription Factors Regulating Glial Cell Line-Derived Neurotrophic Growth Factor......Page 890 Transcription Factors Regulating Ureteric Bud Formation (or Early Kidney Development)......Page 891 Transcription Factors Regulating Stroma Development......Page 892 Restriction of GDNF Expressed Region by Slit-Robo......Page 893 Ureteric Bud Branching Morphogenesis......Page 894 Fibroblast Growth Factors and Receptors......Page 895 Gremlin......Page 896 Extracellular Matrix......Page 897 Proteoglycans......Page 898 Tubulogenesis after Induction of the Metanephric Mesenchyme......Page 899 Prevention of Apoptosis......Page 900 Molecules Involved in Metanephric Mesenchyme Induction and Nephron Tubule Formation......Page 901 Vascular and Glomerular Development......Page 902 References......Page 903 Vascular Clefts of Comma- and S-Shaped Stage......Page 912 Maturing Glomeruli......Page 913 Intrarenal Origins......Page 914 VEGF Signaling......Page 915 Renal HIF Expression......Page 916 Development of the Mesangium......Page 917 Pod1/Tcf21......Page 918 Slit Diaphragm Components......Page 919 Signaling at the Slit Diaphragm......Page 921 Laminin......Page 922 Collagen Type IV......Page 923 Sulfated Proteoglycans......Page 924 Receptors and receptor-Associated Proteins Mediating Glomerular cell Interactions with The GBM......Page 925 References......Page 926 Glomerular Filtration Rate......Page 932 Glomerulotubular Balance......Page 933 Na+/K+-ATPase Activity......Page 934 Developmental Changes in the Paracellular Transport......Page 935 Distal Tubule NaCl Transport......Page 936 Renin–Angiotensin–Aldosterone......Page 937 Proximal Tubules......Page 938 Titratable Acid and Ammonia Excretion......Page 940 Induction of Nephron Maturation......Page 941 Phosphate Transport......Page 942 Potassium Transport......Page 944 Urinary Concentrating and Diluting Ability......Page 945 References......Page 946 Introduction......Page 954 Cell Cycle......Page 955 Cyclins and Cyclin-Dependent Kinases: Positive Regulators of the Cell Cycle......Page 956 Stopping the Cell Cycle: Cdk Inhibitors Act as Negative Regulators......Page 957 Glomerular Hyperplasia......Page 958 Cdk Inhibitors and Mesangial Cell Proliferation......Page 959 Glomerular Hypertrophy......Page 966 Cell Cycle-Dependent Tubular Cell Hypertrophy......Page 968 Cell Cycle-Independent Tubular Cell Hypertrophy......Page 969 References......Page 972 Epithelial Cells......Page 980 Normal Conditions......Page 981 Organ Repair from Injury......Page 982 Cellular Markers......Page 984 In Vivo Growth Behavior......Page 985 Cellular Function......Page 986 Podocyte Precursors......Page 988 Renal Mesenchymal Stem Cells and/or Pericytes......Page 989 Highly Proliferative Regions......Page 990 Stem Cell “Niches”......Page 991 Renal Progenitors in Invertebrates......Page 992 Renal Fibroblast and Myofibroblasts......Page 993 Kidney Repair By Exogenous Stem/Precursor Cells......Page 994 Other Bone Marrow-Derived Cells......Page 995 Concluding Remarks......Page 996 References......Page 997 III: Fluid and Electrolyte Regulation and Dysregulation......Page 1002 Biochemical and Molecular Characteristics of ENaC......Page 1004 ENaC/Degenerin Gene Family......Page 1005 Structure and Function of ENaC......Page 1006 Intracellular Trafficking of ENaC......Page 1007 Localization within the Kidney and Other Organs......Page 1008 Functional Domains within ENaC Subunits......Page 1009 Cation Permeation and Selectivity......Page 1013 ENaC Regulation......Page 1014 Cellular Regulation......Page 1015 Hormonal Regulation......Page 1023 ENaC and Human Disorders......Page 1024 References......Page 1025 Introduction......Page 1040 Major Classes of Identified Anion Channels......Page 1041 CLC Cl− Channels......Page 1042 CFTR......Page 1047 Ca2+-Activated Cl− Channels (CaCC): TMEM16/Anoctamin......Page 1051 Solute Carrier 26 Transporters......Page 1054 Volume-Regulated Anion Channels......Page 1055 Other Cl− Channels......Page 1056 Polycystic Kidney Disease......Page 1060 Summary......Page 1062 References......Page 1063 Introduction......Page 1068 The Physiology of NaCl Co-Transporters in the Kidney......Page 1069 The Loop-Diuretic-Sensitive Na+-K+-2Cl− Co-Transporter 2 (NKCC2)......Page 1070 The Thiazide-Sensitive Na+-Cl− Co-Transporter......Page 1072 The Loop-Diuretic-Sensitive Na+-K+-2Cl− Co-Transporter 2 (NKCC2)......Page 1073 Genes, Promoters, and Phylogenetic Analysis......Page 1074 The Thiazide-Sensitive-Na+-Cl− Co-Transporter......Page 1075 The Loop-Diuretic-Sensitive Na+-K+-2Cl− Co-Transporter 2 (NKCC2)......Page 1076 Ion or Diuretic Affinity Modifier Domains or Residues......Page 1077 The Na-Coupled Chloride Co-Transporters Form Homodimers......Page 1079 Regulation of Sodium Cation-Coupled Co-Transporters......Page 1080 Gitelman’s Disease......Page 1088 Bartter’s Disease......Page 1089 Pseudohypoaldosteronism Type II/Familial Hypekalemia Hypertension......Page 1090 References......Page 1091 Introduction......Page 1102 Net Fluxes......Page 1103 Transport Forces......Page 1106 Cytosolic Concentrations......Page 1108 Luminal Membrane......Page 1109 Peritubular Membrane......Page 1116 Coordination of Entry and Exit......Page 1121 The Lateral Intercellular Space......Page 1123 The Tight Junction......Page 1127 Convergence on NHE3......Page 1130 Modulation of the Na,K-ATPase......Page 1132 Neural and Humoral Factors......Page 1134 Volume Expansion and Pressure Natriuresis......Page 1138 Glomerulotubular Balance......Page 1140 Perspective......Page 1142 References......Page 1143 Anatomic Considerations......Page 1164 Salt Transport by Thin Descending and Thin Ascending Segments......Page 1165 NaCl Absorption in Thick Ascending Limb......Page 1166 Origin of Transepithelial Voltage......Page 1175 Coupling of Substrate Utilization to Ion Transport......Page 1176 Regulation of Salt Absorption in TAL......Page 1177 Electophysiologic Considerations......Page 1181 The Connecting Tubule......Page 1184 References......Page 1191 The Aldosterone Sensitive Distal Nephron (ASDN)......Page 1202 Aldosterone Action in Non-ASDN Cells......Page 1205 Aldosterone and the Epithelial Sodium Channel ENaC......Page 1206 Genomic Actions of Aldosterone......Page 1215 How Does Transcriptional Regulation Lead to Transport Regulation?......Page 1220 Conclusion......Page 1224 References......Page 1225 Approaches to Identify Genes and Mutations that Contribute to Human Disease......Page 1234 Overview of Renal Salt Homeostasis......Page 1235 Disorders of the Renin–Angiotensin–Aldosterone System......Page 1237 Mutations that Cause Hypertension without Activation of MR......Page 1242 Disorders of the Renin–Angiotensin–Aldosterone System......Page 1246 Mutations Affecting Renal Ion Channels, Transporters and their Regulators......Page 1248 Genetic Studies of Essential Hypertension in the General Population......Page 1252 New Insights into Basic Physiology, Prevention, and Therapeutics from Genetic Studies......Page 1253 References......Page 1255 History of Cardiac Hormones: Anatomical Studies......Page 1262 History of Cardiac Hormones: Physiological Studies......Page 1263 Family of Cardiac Natriuretic Hormones: Synthesis of Three Prohormones......Page 1264 Origination of Peptide Hormones from Prohormones......Page 1265 Tissue-Specific Expression of ProANP Gene......Page 1266 Processing of Atrial Natriuretic Peptide Prohormone in Kidney......Page 1267 Enhancement of ProANP Gene Expression......Page 1268 Natriuretic Peptide Hormones and Hypertension......Page 1270 Brain Natriuretic Peptide Prohormone Gene......Page 1271 ANP......Page 1272 Cardiac Hormones: LANP, Vessel Dilator, and Kaliuretic Peptide......Page 1273 BNP and CNP......Page 1275 Adrenal Natriuretic Peptides, Adrenomedullin and Proadrenomedullin N-Terminal 20 Peptide: Biologic Effects......Page 1276 Guanylin, Lymphoguanylin, Renoguanylin, and Uroguanylin: Biologic Effects......Page 1277 ANP Prohormone System and Expression in Gastrointestinal Tract......Page 1278 Number of ANP Receptors per Cell......Page 1279 Vessel Dilator and LANP Receptors......Page 1280 Influence of Acute Renal Failure on Circulating Concentration of Cardiac Hormones......Page 1281 Atrial Natriuretic Peptide Prohormone Gene Expression in Invertebrates and Plants......Page 1282 ANP and Urodilatin......Page 1283 Vessel Dilator......Page 1284 Congestive Heart Failure......Page 1285 The Kidney Hormone Urodilatin also has Anti-Cancer Effects......Page 1286 Ras......Page 1287 MEK 1/2 Kinases......Page 1288 Localization of Cardiac Hormones to the Nucleus of Pancreatic Adenocarcinomas......Page 1289 References......Page 1290 Sodium Intake and Sodium Balance......Page 1304 Concept of Effective Arterial Blood volume......Page 1305 Afferent Sensing Mechanisms in Congestive Heart Failure......Page 1307 Effector Mechanisms in Congestive Heart Failure......Page 1308 Presinusoidal Versus Postsinusoidal Obstruction and Ascites Formation......Page 1313 Afferent Limb of Sodium Retention: Overfill Versus Underfill Mechanisms......Page 1315 Hyperdynamic Circulation in Cirrhosis......Page 1317 Effector Mechanisms in Cirrhosis......Page 1320 Nephrotic Syndrome......Page 1324 Effects of Manipulations to Expand Central Blood Volume......Page 1325 Peripheral Capillary Mechanisms of Edema Formation......Page 1327 Neurohumoral Control of Enhanced Tubular Sodium Excretion......Page 1328 Intrinsic Renal Disease......Page 1330 Disorders of Effector Mechanisms that Regulate Renal Sodium Transport......Page 1331 References......Page 1332 Blood Pressure Classification for Hypertension Treatment......Page 1340 Blood Pressure Control Systems are Time-Dependent......Page 1341 The Renal–Body Fluid Feedback Mechanism for Long-Term BP Regulation......Page 1342 Renal Mechanisms of Hypertension......Page 1343 Generalized Increases in Preglomerular Resistance Cause Salt-Insensitive Hypertension......Page 1344 Non-Homeogeneous Increases