Kidney Development, Disease, Repair and Regeneration
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About this ebook
Kidney Development, Disease, Repair and Regeneration focuses on the molecular and cellular basis of kidney development, exploring the origins of kidney lineages, the development of kidney tissue subcompartments, as well as the genetic and environmental regulation of kidney development. Special coverage is given to kidney stem cells and possible steps towards kidney repair and regeneration. Emphasis is placed on the fetal origins of postnatal renal disease and our current understanding of the molecular basis of damage and repair. Biomedical researchers across experimental nephrology and developmental biology will find this a key reference for learning how the underlying developmental mechanisms of the kidney will lead to greater advances in regenerative medicine within nephrology.
- Offers researchers a single comprehensive resource written by leaders from both the developmental biology and the experimental nephrology communities
- Focuses on understanding the molecular basis of organogenesis in the kidney as well as how this can be affected both genetically and environmentally
- Explains the underlying developmental mechanisms which influence the kidney’s inherent repair capacity
- Demonstrates how a deeper understanding of mechanisms will lead to greater advances in regenerative medicine
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Kidney Development, Disease, Repair and Regeneration - Melissa Helen Little
Kidney Development, Disease, Repair and Regeneration
Editor
Melissa H. Little
Table of Contents
Cover image
Title page
Copyright
Contributors
Foreword
Acknowledgments
Section I. Development
Introduction
Chapter 1. Zebrafish Renal Development and Regeneration
Overview
The Zebrafish Pronephros as a Model of Nephron Development and Injury
Development and Repair of the Zebrafish Mesonephros
Conclusions
Chapter 2. Early Specification and Patterning of the Intermediate Mesoderm: Genetics and Epigenetics
Introduction
Early Development of the Kidney
Epigenetic Regulation during Kidney Development
Role of Epigenetics in the Adult Kidney
Conclusions
Chapter 3. The Human Kidney: Parallels in Structure, Spatial Development, and Timing of Nephrogenesis
Introduction
Anatomic Structure of the Mature Human Kidney
Anatomic Development of the Kidney
Other Mammalian Species: How They Differ
Nephron Endowment
Conclusion
Chapter 4. RET Signaling in Ureteric Bud Formation and Branching
Short Introduction to Ureteric Bud Formation and Branching
The Role of GDNF/GFRα1/RET Signaling in Mouse Kidney Development
Mutations in RET, GFRA1, and GDNF in Human Congenital Kidney Defects
Regulation of Ret and Gdnf Gene Expression
Signaling Pathways Downstream of RET
Effects of Point Mutations That Remove RET Tyrosine Residues Involved in Signal Transduction
Genes That Act Downstream of GDNF/GFRα1/RET Signaling
Cooperation Between GDNF and FGF10 Signaling in UB Outgrowth and Branching
Does GDNF/RET Signaling Specify the Normal Pattern of UB Branching?
Cellular Mechanisms of Branching Morphogenesis and the Role of RET Signaling
Chapter 5. Quantification of Developmental Branching Morphogenesis
General Introduction
Stereotypy in Renal Branching
Challenges in Translating Renal Branching Knowledge
Chapter 6. Transcriptional Regulation of the Nephrogenic Mesenchyme and Its Progeny
Introduction
Counteraction and Cooperation Between Six2 and Wnt/β-Catenin Signaling in Regulation of Nephron Progenitors
Identification of Direct Transcriptional Targets of Six2 and β-Catenin in Nephron Progenitors
Cooperation Between Six2 and Osr1 in the Repression of Wnt4
Sall1 and Wt1 in Nephron Progenitor Programs
Maintenance of Nephron Progenitors
Gene Regulatory Networks Established by Transient Activation of Wnt/β-Catenin Signaling
Closing Remarks
Chapter 7. The Role of Growth Factors in Balancing Cap Mesenchyme Survival and Differentiation
The Cap Mesenchyme
Growth Factor Signaling in Cap Mesenchyme Differentiation
Fibroblast Growth Factor Signaling
Wnt Signaling
Bone Morphogenetic Protein Signaling
Intersections between FGF, Wnt, and BMP Pathways
Future Perspectives
Chapter 8. Notch Signaling in Nephron Segmentation
Introduction
Signal Transduction of Notch Signaling
Notch Signaling Acts after Wnt/β-Catenin Signaling during Nephrogenesis
Nephron Segmentation
Rbpj-Dependent Notch Signaling Is Essential for Nephron Segmentation
Notch Gain-of-Function Studies
Notch2 Is Activated More Effectively Than Notch1
Alagille Syndrome and Notch
Conclusion
Chapter 9. Genetic and Epigenetic Regulation of Nephron Number in the Human
Overview
Monogenic Disorders Causing Suboptimal Ureteric Bud Branching
Monogenic Disorders Affecting the Renal Progenitor Cell Pool
Subtle Renal Hypoplasia and Common Polymorphic Variants of Genes That Affect Ureteric Bud Branching
Subtle Renal Hypoplasia and Common Polymorphic Gene Variants That Regulate the Renal Progenitor Cell Pool
Epigenetic Regulation of Renal Progenitor Cells
Conclusion
Chapter 10. Formation and Maintenance of a Functional Glomerulus
Introduction
Patterning of Nephrons and Specification of Glomeruli
Development of Podocytes and SD
Formation of Glomerular Vasculature
Structure and Development of the GBM
Development of the Mesangium
Development of PECs and Bowman’s Capsule
Summary and Perspectives
Chapter 11. Maturation and Roles of Collecting Ducts and Loops of Henle in Renal Medulla Development
Introduction
Composition and Organization of the Renal Medulla
Overview of Renal Medulla Development
Medullary Collecting Ducts
The Loop of Henle
Medullary Microvasculature
Concluding Remarks
Chapter 12. Developmental Roles of the Stroma
What Is the Renal Stroma?
Developmental Origins of Renal Stromal Cells
Role of Stroma in Kidney Development
Future Directions
Chapter 13. The Origin and Regulation of the Renal Vasculature
Introduction
Anatomy of the Renal Vasculature
Mechanisms Underlying Renal Vascular Morphogenesis
Embryonic Origin of the Renal Vasculature
Lineage of Vascular Cells
Signaling Pathways and Regulatory Factors
Remaining Issues
Section II. Disease
Introduction
Chapter 14. Variation in Human Nephron Number and Association with Disease
Introduction
Estimating Nephron Number
Human Nephron Number: Variability Is the Rule
Human Nephron Number and Blood Pressure
Relationship between Glomerular Number and Glomerular Volume
Human Nephron Number and Renal Pathology
Conclusion
Chapter 15. The Effect of the In utero Environment on Nephrogenesis and Renal Function
Introduction
The Developmental Origins of Health and Disease
Evidence for Programming in the Human
Links between Impaired Kidney Development and Hypertension
Animal Models of Developmental Programming: Consequences for Kidney Development
Why Is the Kidney Susceptible to Programming?
Programming of Disease Is More than Just Nephron Number
Mechanism Contributing to the Formation of Low Nephron Endowment
Conclusion
Chapter 16. Wilms’ Tumor: A Case of Persistence of the Nephrogenic Mesenchyme
The History of Wilms’ Tumors
Identification of WT1 Gene
Structure of WT1
Molecular Studies on the Function of WT1 in the Nephrogenic Mesenchyme
Embryonic Expression of WT1 and Phenotypes of WT1 Mutant Mice
Other Tumor Suppressor Genes for Wilms’ Tumor
The Cell of Origin for Wilms’ Tumor
Other Influences on Kidney Progenitor Cell Expansion
Relationship of Wilms’ Tumors to Nephron Progenitor Cells
Conclusion
Chapter 17. Wnt, Notch, and Tubular Pathology
Wnt and Notch
Wnt and Notch in Acute Kidney Injury Repair
Wnt and Notch in Kidney Fibrosis
Wnt and Notch in Polycystic Kidney Disease
Wnt and Notch in Renal Cell Cancer
Conclusion
Chapter 18. Regulation of Ureteric Bud Outgrowth and the Consequences of Disrupted Development
Introduction
Nephric Duct Development and UB Outgrowth
Ureteric Budding Site Determination and GDNF-Dependent UB Outgrowth
GDNF–Independent Induction of UB Outgrowth
Common Human Disease Caused by Abnormal UB Outgrowth
Conclusions
Chapter 19. Vesicoureteral Obstruction and Vesicoureteral Reflux: Different Congenital Defects With a Common Cause
Introduction
Development of the Urinary Tract
Conclusion
Chapter 20. Polycystic Kidney Diseases and Other Hepatorenal Fibrocystic Diseases: Clinical Phenotypes, Molecular Pathobiology, and Variation between Mouse and Man
Introduction
Hepatorenal Fibrocystic Diseases: Clinical Phenotypes
Hepatorenal Fibrocystic Diseases: Genetic Defects and Molecular Pathobiology
Genetic Testing
Mouse Models
Conclusion
Chapter 21. Genetic Aspects of Human Congenital Anomalies of the Kidney and Urinary Tract
Introduction
Budding Hypothesis
HNF1β Nephropathy
RET, Hirschsprung Disease, and CAKUT
ITGA8 Mutations in Autosomal Recessive Bilateral Kidney Agenesis
PAX2 in Renal Coloboma Syndrome
EYA1, SIX1, and SIX5 in Branchiootorenal Syndrome
Renal Tubular Dysgenesis
BMP4
Other Genes Involved in CAKUT
Ureteral Anomalies
Bladder Anomalies with Functional Bladder Outflow Obstruction
Detection of Chromosomal Microimbalances
Concepts of Oligogenic Inheritance
MiRNAs as Potential Regulators of Renal Developmental Genes
Conclusions
Chapter 22. Inherited Kidney Disorders in the Age of Genomics
Introduction
From DNA to Genomics
Interpretation of NGS Data
Impact of NGS in the Nephrology Field
NGS Challenges
Personalized Therapeutics
Conclusions and Future Directions
Chapter 23. Fibrosis: A Failure of Normal Repair and a Common Pathway to Organ Failure
Fibrosis is a Characteristic Feature of Chronic Kidney Diseases
Injury–Repair Processes Gone Awry
Cellular Mechanisms of Fibrosis
Source of Fibrogenic Cells
Molecular Pathways in Fibrogenesis
Matrix Turnover
Resolution of Fibrosis
Section III. Repair
Introduction
Chapter 24. Postnatal Cell Turnover in the Nephron Epithelium: What Can This Tell Us?
Postnatal Glomerular Epithelial Cell Turnover
Glomerular Cell Turnover in Disease
Postnatal Tubular Epithelial Cell Turnover
Conclusion
Chapter 25. Plasticity within the Collecting Ducts: What Role Does This Play in Response to Injury?
Development of the Collecting Duct
Acute Kidney Injury and Response of the CD
CD-Specific Mechanisms of Epithelial Injury and Repair
Summary
Chapter 26. The Onset and Resolution of Renal Fibrosis: A Human Perspective
Introduction
Renin-Angiotensin System
Transforming Growth Factor-β
Connective Tissue Growth Factor
Epigenetic Control of Renal Fibrosis
Conclusions
Chapter 27. The Molecular Response to Renal Injury: How Does Chronic Renal Damage Suppress Normal Repair Processes?
The Renal Response to Chronic Kidney Disease
Adaptive Repair in the Kidney
Risk Factors and Features of Maladaptive Repair
Maladaptive Repair and Recurrent AKI
Mechanisms of Cell Cycle Control
Cell Cycle Control in Healthy and Diseased Kidneys
Senescent Cells, G2/M Arrest, and Kidney Injury
Epigenetic Changes after AKI
Pericytes and Kidney Scarring
Microvascular Loss and Renal Hypoxia
Conclusions
Chapter 28. Investigating the Process of Renal Epithelial Repair to Develop New Therapies
Introduction
Cellular Origins of Epithelial Cells during Repair
Targeting Epithelial Repair Pathways
Preventing Maladaptive Responses after AKI to Promote Repair
Conclusions
Chapter 29. Evidence for Renal Progenitors in the Human Kidney
Introduction
Renal Progenitors in the Human Nephron
Tubular-Committed Progenitors
Tubular Progenitors in the Pathogenesis of Kidney Disorders
Renal Progenitors in the Glomerulus of Adult Human Kidney
Glomerular Progenitors in the Pathogenesis of Kidney Disorders
Human Progenitor Cultures and Their Possible Application for Kidney Disease Modeling
Conclusion
Chapter 30. Label-Retaining Cells and Progenitor Cells in Renal Epithelial Homeostasis and Regeneration
Stem Cells in Adult Organs
Markers and Labels of Stem Cells
Label-Retaining Cells in the Kidney Papilla
A Genetic Label for Renal LRCs
Label-Retaining Cells Proliferate in a Restricted Compartment at the Top of the Papilla
In Vivo Demonstration of Migration of LRCs from the Papilla in Response to Ischemic Injury
SDF1/CXCR4 Cause Proliferation and Migration of LRCs in Response to Ischemic Injury
Microarray Analysis of LRCs: The Wnt Pathway
Controversies in Renal Stem Cells
Multiple Pools of Stem Cells in the Kidney?
Conclusion
Chapter 31. A Reparative Role for Macrophages in Kidney Disease
Introduction
Macrophage Phenotype
Reparative Macrophages in Kidney Disease
The Potential for Macrophage Therapy in Kidney Disease
Frontiers of Kidney Macrophage Research
Conclusion
Chapter 32. The Use of Mesenchymal Stromal Cells for Treating Renal Injury and Promoting Allograft Survival after Renal Transplantation
Introduction
Mesenchymal Stromal Cells
Immunomodulatory Properties of MSCs
Reparative Properties of MSCs
Experimental Models of MSCs in Acute Kidney Injury and after Transplantation
Mesenchymal Stromal Cells for Clinical Therapeutic Use
Clinical Data of MSCs in Kidney Injury and after Renal Transplantation
Potential Risks
Conclusions
Section IV. Regeneration
Introduction
Chapter 33. Reprogramming to Kidney
Introduction
Reprogramming to Pluripotency
How Does Reprogramming to Pluripotency Occur?
Directed Differentiation of Pluripotent Cells
Direct Reprogramming: Fate Conversion from One Somatic Cell Type to Another
Pioneer versus Lineage-Specifying Factors
Evidence that Reprogramming to Nephron Progenitor is Feasible
Overlapping Actions for the Nephron Progenitor Reprogramming Genes Suggests Redundancy
Alternative Options for the Specification of CM
Transcription Factors Required for Reprogramming to Mature Renal Cell Types
Challenges to Direct Reprogramming and Cellular Therapies Using Reprogrammed Cells
Conclusion
Chapter 34. From Development to Regeneration: Kidney Reconstitution In vitro and In vivo
Strategies for Regenerative Medicine of the Kidney
Lessons from Kidney Development in Frogs and Mice
Nephron Progenitors in the Mouse Embryonic Kidney
The Newly Identified Origin of the Kidney
Generation of Nephron Progenitors In vitro
Reconstitution of 3D Kidney Structures from Nephron Progenitors
Generation of the Ureteric Bud In vitro
Challenges for Reconstitution of a Functional Kidney In vitro
Kidney Reconstitution In vivo
Conclusions
Chapter 35. Directing the Differentiation of Pluripotent Stem Cells to Renal End Points
Introduction
Pluripotent Stem Cells
Kidney Development
Differentiation Formats, Inducers, and Cell Lines
Animal Cap in Fertilized Eggs of Amphibians
Differentiation of Mouse ESCs and iPSCs into Kidney Lineages
Human ESCs and iPSCs
Cell Therapy, Disease Modeling, and Toxicology
Hurdles to Overcome
Conclusions
Chapter 36. Patient-Derived Induced Pluripotent Stem Cells to Target Kidney Disease
Induced Pluripotent Stem Cells
Induced Pluripotent Stem Cells Targeting the Kidney
Cell Memory and iPS Differentiation
Generating Specific Mature Renal Cell Types From iPS Cells
Potential Application of iPS Cell-Derived Kidney Podocytes
Applications of iPS Cells in Disease Modeling and Toxicity Screening
Understanding an Inherited Basis of Kidney Disease Using iPS Cells
Developing Novel Treatments Based on iPS Disease Modeling of Inherited Kidney Disease
Gene Targeting and Editing of iPS Cells
Cell Replacement Strategies
Conclusion
Chapter 37. Xenotransplantation in the Kidney: A Historical Perspective
Introduction
Xenotransplantation of Developed Kidneys
Transplantation of Developing Kidneys
Allotransplantation of Renal Primordia
Xenotransplantation of Renal Primordia
Xenotransplantation of Pig Renal Primordia
Use of Non-renal Precursor Cells Integrated into Renal Primordia or Xenobiotic Nephrogenesis
Challenges in the Application of Embryonic Kidney Transplantation
Recapitulation of Filtration, Reabsorption, and Secretion
Conclusions
Chapter 38. Use of the Nephrogenic Niche in Xeno-Embryos for Kidney Regeneration
Introduction
Niche in the Blastocyst
Niche in the Growing Embryo
Niche in the Adult Organ
Conclusions
Chapter 39. Human Fetal Kidney for Regenerative Medicine: From Embryonic Rudiments to Renal Stem/Progenitor Cells
Introduction
Pre- and Post-Mesenchymal-to-Epithelial Transition Stages of Nephrogenesis
Human Embryonic Kidney Rudiments
Biomarking the hFK and Wilms’ Tumor as a Step for Progenitor Cell Identification
Isolation of Expandable Human Nephric Progenitor Cells From Fetal Kidney
Identification of WT Stem Cells
Clinical Relevance and Concluding Remarks
Chapter 40. Renal Replacement Approaches Using Deceased Donor Cell Sources
Introduction
Section I
Section II
Section III
Conclusions
Chapter 41. Tissue Engineering through Additive Manufacturing: Hope for a Bioengineered Kidney?
Additive Manufacturing Meets Tissue Engineering
Strategies for Building Kidney Tissue through Additive Manufacturing
Renal Tissue Design Considerations for Regenerative Applications
Considerations for Tissue Maturation
Summary
Chapter 42. Decellularized Whole Organ Scaffolds for the Regeneration of Kidneys
Introduction
Tissue Engineering Strategy
Extracellular Matrix
Whole Organ Decellularization
Re-endothelialization
Renal Recellularization
In vivo Functionality
Conclusions
Index
Copyright
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Contributors
Qais Al-Awqati, Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
H.H. Arts, Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands
Anthony Atala, Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
Felicity J. Barnes, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
Ariela Benigni, IRCCS — Istituto di Ricerche Farmacologiche Mario Negri
, Centro Anna Maria Astori, Science & Technology Park Kilometro Rosso Bergamo, Italy
John F. Bertram, Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC, Australia
M. Jane Black, Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, Australia
Joseph V. Bonventre
Renal Division and Biomedical Engineering Division, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA
Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA, USA
Harvard Stem Cell Institute, Cambridge, MA, USA
Deborah A. Buffington, Innovative BioTherapies, Incorporated, Ann Arbor, MI, USA
Kevin T. Bush, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Qi Cao, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
Thomas Carroll, Departments of Molecular Biology and Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, TX, USA
Melanie Cosgrove, Department of Experimental Medicine, McGill University, Montreal, QC, Canada
Frank Costantini, Department of Genetics and Development, Columbia University, New York, NY, USA
Luise Cullen-McEwen, Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, Australia
Alan J. Davidson, Department of Molecular Medicine & Pathology, School of Medical Sciences, Faculty of Medical Health Sciences, The University of Auckland, Auckland, New Zealand
Benjamin Dekel
Pediatric Stem Cell Research Institute, Edmond & Lili Safra Children’s Hospital, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Division of Pediatric Nephrology, Edmond & Lili Safra Children’s Hospital, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Rachel C. Dodd, Department of Molecular Medicine & Pathology, School of Medical Sciences, Faculty of Medical Health Sciences, The University of Auckland, Auckland, New Zealand
Gregory R. Dressler, Department of Pathology, University of Michigan, Ann Arbor, MI, USA
Jeremy S. Duffield
Research & Development, Biogen, Cambridge, MA, USA
Departments of Medicine & Pathology, University of Washington, Seattle, WA, USA
Klaudyna Dziedzic, Pediatric Stem Cell Research Institute, Edmond & Lili Safra Children’s Hospital, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
David A. Ferenbach
Renal Division and Biomedical Engineering Division, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA
Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
Julia B. Finkelstein, Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Paul Goodyer
Department of Pediatrics, McGill University, Montreal, QC, Canada
Department of Human Genetics, McGill University, Montreal, QC, Canada
L.M. Guay-Woodford, Center for Translational Science, Children’s National Health System, Washington, DC, USA
Marc R. Hammerman, Renal Division, Departments of Medicine, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
David C.H. Harris, Sydney Medical School – Western Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
Michael J. Hiatt, Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA
Wendy E. Hoy, Centre for Chronic Disease, University of Queensland, Brisbane, QLD, Australia
Michael D. Hughson, Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA
Jennifer C. Huling
Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Winston-Salem, NC, USA
H. David Humes
Innovative BioTherapies, Incorporated, Ann Arbor, MI, USA
The University of Michigan, Ann Arbor, MI, USA
Benjamin D. Humphreys
Renal Division, Brigham and Women’s Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Harvard Stem Cell Institute, Cambridge, MA, USA
Roger Ilagan, Division of Regenerative Medicine, United Therapeutics Corporation, Research Triangle Park, NC, USA
Nine V.A.M. Knoers, Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
Raphael Kopan, Division of Developmental Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Jordan A. Kreidberg, Department of Medicine, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Callie S. Kwartler, Departments of Molecular Biology and Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, TX, USA
Laura Lasagni, Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
Elena Lazzeri, Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
Melissa H. Little, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
Weining Lu, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA
Daniela Macconi, IRCCS — Istituto di Ricerche Farmacologiche Mario Negri
, Centro Anna Maria Astori, Science & Technology Park Kilometro Rosso Bergamo, Italy
Douglas G. Matsell, Child and Family Research Institute, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
Andrew P. McMahon, Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, WM Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
Cathy Mendelsohn, Departments of Urology, Genetics and Development and Pathology, Columbia University, New York, NY, USA
Marcus J. Moeller, Department of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany
Karen M. Moritz, School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia
Sanjay K. Nigam
Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Department of Medicine, University of California, San Diego, La Jolla, CA, USA
Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
Ryuichi Nishinakamura, Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
A.K. O’Connor, Center for Translational Science, Children’s National Health System, Washington, DC, USA
Juan A. Oliver, Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
Kenji Osafune, Center for iPS Cell Research and Application (CiRA), Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
Leif Oxburgh, Center for Molecular Medicine, Maine Medical Center Research Institute, ME, USA
Joo-Seop Park
Division of Pediatric Urology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Division of Developmental Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Anna Peired, Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
Christopher J. Pino, Innovative BioTherapies, Incorporated, Ann Arbor, MI, USA
Oren Pleniceanu, Pediatric Stem Cell Research Institute, Edmond & Lili Safra Children’s Hospital, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Sharon Presnell, Organovo, Inc., San Diego, CA, USA
Victor G. Puelles, Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC, Australia
Susan E. Quaggin, Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Ton J. Rabelink
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
Department of Nephrology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
Egon Ranghini, Department of Pathology, University of Michigan, Ann Arbor, MI, USA
Scott Rapoport, Division of Regenerative Medicine, United Therapeutics Corporation, Research Triangle Park, NC, USA
Marlies E.J. Reinders, Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
Giuseppe Remuzzi
IRCCS — Istituto di Ricerche Farmacologiche Mario Negri
, Centro Anna Maria Astori, Science & Technology Park Kilometro Rosso Bergamo, Italy
Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
Sharon D. Ricardo, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
Paola Romagnani
Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
Pediatric Nephrology Unit, Meyer Children’s Hospital, University of Florence, Florence, Italy
Rizaldy P. Scott, Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Maria Luisa S. Sequeira Lopez, University of Virginia School of Medicine, Charlottesville, VA, USA
Benjamin Shepherd, Division of Regenerative Medicine, United Therapeutics Corporation, Research Triangle Park, NC, USA
Kieran M. Short, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
Ian M. Smyth
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, Australia
Katalin Susztak, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Megan R. Sutherland, CHU Sainte-Justine Research Center and the University of Montreal, Montreal, QC, Canada
Atsuhiro Taguchi, Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
Yiping Wang, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
Stefanie Weber, Pediatrics II, University Children’s Hospital Essen, Essen, Germany
Angela J. Westover, Innovative BioTherapies, Incorporated, Ann Arbor, MI, USA
Takashi Yokoo, Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
James J. Yoo, Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
Jing Yu, Department of Cell Biology, Child Health Research Center, the Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
Foreword
According to ancient Greek mythology the Titan Prometheus was punished by Zeus for stealing fire from the gods and handing it over to mortal humans. His punishment consisted of being chained to the Caucasus mountains, where he had to suffer an eagle feasting daily on his liver, which would then regenerate overnight. Out of this mythology arose the great hope that all organs, if damaged, could regenerate. Unfortunately, in humans the enormous regenerative capacity of the liver seems to be the exception rather than the rule. Nonetheless, all organs, including the kidney, have some ability to regenerate or repair injured renal structures. In nephrology this is most obvious in the case of acute tubular injury. The limitations for renal regeneration may be imposed by the very complicated intrinsic anatomical structure of the nephron and the functional interconnection of its different components as the basic building blocks of the kidney. Therefore, and in spite of some regeneration of damaged nephron segments, the overall renal function declines in many forms of renal injury. This leads to progression of injury and chronic kidney disease (CKD), which remains a major problem with unfortunately a dearth of effective therapeutic interventions. It is because of this that possible regenerative therapeutic approaches, whether to prevent or slow down progression of CKD or even for replacement of destroyed nephrons, are increasingly attracting interest. In this context one has to recall that such regenerative therapeutic interventions will draw on the basic understanding of normal embryonic developmental of the kidney, and that understanding the molecular basis of these processes will be the key to the development of regenerative therapies for chronic renal disease.
In this book Professor Melissa Little has successfully undertaken the very difficult task of bringing together and editing texts encompassing the vast amount of information, ranging from basic embryology of the kidney all the way to exploring potential ways of using this basic knowledge to repair or regenerate parts or even entire nephrons or their function. The list of authors reads like a Who’s who
of experts for all aspects of kidney development, injury response, cell differentiation and de-differentiation, repair processes, their signaling processes and the specific cells involved, and the various types of stem cells and their biology, with special emphasis on the potential therapeutic use of renal and non-renal adult and embryonic stem cells.
In order to connect these various aspects into a logical and understandable framework the initial chapters are devoted to the basics of renal development. They expand to illustrate the similarities and differences between developmental processes and those recapitulated during renal injury and repair using various model systems. This includes aspects of genetics and epigenetics during development as well as in disease processes. Having described this for the entire kidney, subsequent chapters explore these aspects for specific nephron segments, from the glomerulus down to the collecting tubule and upper urinary tract, and also for the renal vasculature and stroma. For each nephron segment, diseases resulting from genetic and environmental developmental abnormalities are discussed in terms of their molecular and cellular pathogenesis. Finally, mechanisms and limitations of repair and/or regeneration of specific cell types along the nephron are critically analyzed.
In this context, the use of lineage tracing has been critical to differentiate regeneration from intrarenal versus bone-marrow derived progenitor cells. Furthermore, it appears that instead of a single type of kidney stem cell to replace lost or damaged kidney tissue, there are nephron segment-specific progenitor cells which give rise to new cells within each kidney compartment. Equally important is the identification of pathways that govern the proliferation and differentiation of regeneration-competent cells, and the signals that inhibit their activity after injury. In addition to the possibility of intra-renal repair and regeneration of nephrons, the possibilities of growing entirely new structural and functional nephrons or even kidneys are discussed and the creation of bio-engineered kidneys or partial replacement of kidney functions are addressed.
The authors point out the potential for the application of many of these novel regenerative approaches, but also caution about the many remaining hurdles. These include problems of adequately identifying renal stem cell populations and assessing their therapeutic potential. Also the unique architecture of the kidney complicates the anatomical and functional integration of stem cell–derived nephrons. This may apply even more to the functional capacity of a bioengineered organ to partially or completely replace the endogenous kidney. In spite of these difficulties, the road ahead for regenerative therapy is exciting and many obstacles may be overcome based on the enormous strides forward achieved in genetics, molecular and cell biology, and especially stem cell biology.
Taken together this book provides a state of the art compendium of our present knowledge and of future perspectives for all aspects of regenerative kidney repair and therapy. As such it represents a pioneering and gigantic step forward in this exciting new field. Just as Prometheus brought fire to mortal humans, the authors of this excellent text bring light and hope to all of us nephrologists dwelling in the present penumbra surrounding the therapy of acute and chronic kidney injury.
Detlef Schlöndorff
Detlef Schlöndorff, MD is currently visiting professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, USA, and Editor-in-Chief of Kidney International. He is Professor Emeritus of the Ludwig Maximilians University of Munich, Germany.
Acknowledgments
The kidneys, from the perspectives of functional diversity and cellular complexity, are one of the most remarkable organs in our body. This has undoubtedly contributed to the challenge of replacing renal function. Indeed, at a point in history where chronic renal disease is rapidly increasing in prevalence, the need for alternative approaches to ensuring ongoing renal function is acute. Fully understanding the organ itself is surely the basis upon which such solutions will arise. My personal foray into the biology of the kidney commenced as an Honours student in Physiology examining the rate of production and degradation of angiotensinogen in a rat model. Serendipitously, I moved from this to a research position in childhood cancer, focussing on the molecular basis of the childhood kidney cancer, Wilms’ tumour, at a time just before the WT1 gene was identified. As a postdoctoral researcher in the United Kingdom, under the mentorship of Professor Nicholas Hastie (then of the MRC Human Genetics Unit, Edinburgh) we began to unravel the link between WT1 and kidney/gonad development and dysmorphogenesis, identifying mutations in the developmental anomaly syndrome, Denys Drash syndrome. This piqued my interest in how the development of this fascinating organ was controlled. What followed was not only a journey through kidney biology, but one that ranged across developmental molecular biology, through systems biology, experimental nephrology and ultimately stem cell biology and regenerative medicine. Hence, bringing together this collection of stories is a reflection of my own scientific journey. For the first time in one location, the reader can bridge that spectrum from how the kidney forms, what can go wrong, how the organ attempts to cope with injury and finally how we might build on this knowledge to recreate structure and function. The end product is the work of many. As always, my family deserves special mention for their endless patience with my obsession for work. Having their love and support makes me human and the interspersed chaos and joy of normal life brings the light and colour that makes the rest worth it. I particularly thank my son, Nathaniel Rhoades, who helped me with production of graphic plates. The dedicated work of my own team of researchers (past and present), not only in generating some of the science discussed within these pages but continuing to deliver in response to my tireless enthusiasm, definitely needs acknowledgement. I thank Jeff Rossetti and Edward Taylor for calmly overseeing the project as timelines walked into the distance. Most of all, I am indebted to the spectacular scientists who wrote the component chapters. You are also my heroes, colleagues and mentors, and I thank you for your contributions to the book in the face of the many clinical, scientific and personal demands on your own lives. I particularly thank Lisa Guay-Woodford and Weining Lu who accepted either more than was first anticipated or were brought in late with short timelines. In building this book, I have learnt much from the individual chapters and the perspective of each set of authors on their particular areas of expertise. To see it complete reinforces my conviction that it was time to marry together these seemingly disparate areas of research around the commonality of the clinical challenge that is kidney failure. Revealing, but exciting, is what there is yet to understand and what might be achieved in the coming decades.
Professor Melissa H. Little, NHMRC Senior Principal Research Fellow, Murdoch Children’s Research Institute & Department of Pediatric University of Melbourne, Australia
Section I
Development
Outline
Introduction
Chapter 1. Zebrafish Renal Development and Regeneration
Chapter 2. Early Specification and Patterning of the Intermediate Mesoderm: Genetics and Epigenetics
Chapter 3. The Human Kidney: Parallels in Structure, Spatial Development, and Timing of Nephrogenesis
Chapter 4. RET Signaling in Ureteric Bud Formation and Branching
Chapter 5. Quantification of Developmental Branching Morphogenesis
Chapter 6. Transcriptional Regulation of the Nephrogenic Mesenchyme and Its Progeny
Chapter 7. The Role of Growth Factors in Balancing Cap Mesenchyme Survival and Differentiation
Chapter 8. Notch Signaling in Nephron Segmentation
Chapter 9. Genetic and Epigenetic Regulation of Nephron Number in the Human
Chapter 10. Formation and Maintenance of a Functional Glomerulus
Chapter 11. Maturation and Roles of Collecting Ducts and Loops of Henle in Renal Medulla Development
Chapter 12. Developmental Roles of the Stroma
Chapter 13. The Origin and Regulation of the Renal Vasculature
Introduction
A functioning kidney is vital for life. While most are familiar with the excretory functions of the kidney, this complex organ also modulates fluid volume, blood pressure, red cell count and bone density, thereby acting as a central regulator of homeostasis. While a fundamental understanding of normal organ morphogenesis is clearly relevant for the interpretation of congenital anomaly, there is a growing appreciation that normal kidney morphogenesis is crucial for long term renal function. In humans, as in most mammals, nephron formation is a fetal event with final nephron number set before or near birth. Evidence in humans for a 10 fold variation in nephron number between individuals, no capacity to form new nephrons after birth and a clear inverse relationship between nephron number and renal disease, has refocussed our attention on how the kidney forms and what determines an optimal outcome.
In all amniotes, three excretory organs formed during embryogenesis. The permanent kidney in humans (and all mammals) is the third of these structures to form; the metanephros. Despite this, there are lessons to be learnt even from the non-mammalian kidney. The molecular paradigms described in pronephric development in the fish show remarkable parallels with those used for the elaboration of the much more complex mammalian metanephros. Chapter 1 will describe the differences in approach to nephron endowment, repair and response to growth that exist in fish. The developmental origin of these excretory structures is addressed in Chapter 2. Studies on metanephric development have focussed on mammalian models such as mouse, rat, sheep, pig and baboon. Of these, mouse is the most amenable to genetic manipulation, including lineage tracing to investigate cellular ontogeny as well as compartment specific gene deletion or activation. The accessibily of such model organisms, together with the simplicity of genetic manipulation and visualisation, has allowed us to acquire much information about morphogenesis in simpler excretory organs. While studies of kidney morphogenesis in mouse have significantly improved our knowledge of the pathways involved in kidney morphogenesis, a mouse is not a human. Indeed, substantial differences exist in the histological structure or kidneys between different mammals. Chapter 3 will address human kidney morphogenesis and how this differs from morphogenesis in other model organisms. Understanding these differences may also inform us about approaches to modify development or repair in the human.
The metanephros is generated from four major progenitor populations that give rise to the branching collecting duct tree (ureteric bud), the nephrons (cap mesenchyme), interstitial elements, including the mesangium and pericytes (stroma) and the vasculature (vascular progenitors). Chapter 4 discusses the regulation of patterning of the ureteric epithelium. The challenge in studying morphogenesis in all mammalian species remains the size and cellular complexity. Chapter 5 begins to address this in the mouse, illustrating both what level of quantitative morphogenetic analyses might be possible as well as highlighting what we have missed to date. The nephrons arise from the cap mesenchyme. Our understanding of what specifies this population and how the balance between self-renewal and commitment to nephron formation is regulated is discussed in Chapters 6 and 7. The nascent nephron has to undergo substantial elongation, patterning and segmentation to generate the required functional compartmentalisation essential for nephron function (Chapter 8). Regulation of nephron number in the human is discussed in Chapter 9. Most critical for nephron function is the differentiation of a vascularised glomerulus with podocytes and endothelial cells forming a functional glomerular basement membrane. The molecular regulation of this process will be discussed in Chapter 10. Chapter 11 then discusses how different segments of these elongating and maturing nephrons are directed to the appropriate location to form the final organ. The influence of the surrounding stroma on this process is covered by Chapter 12. Finally, our current understanding of how the vasculature of the kidney arises will be presented in Chapter 13.
Chapter 1
Zebrafish Renal Development and Regeneration
Rachel C. Dodd, and Alan J. Davidson Department of Molecular Medicine & Pathology, School of Medical Sciences, Faculty of Medical Health Sciences, The University of Auckland, Auckland, New Zealand
Abstract
The zebrafish is a useful genetic and embryological model system for investigating renal development, regeneration, and disease. In Zebrafish, kidney development progresses through two types of kidney: the pronephros, a fully functional, two-nephron embryonic kidney and the mesonephros, the adult kidney comprising hundreds of nephrons. Zebrafish nephrons show considerable conservation in structure and function compared with mammalian nephrons, with both exhibiting a common glomerular architecture and a similar tubule segmentation pattern. Unlike mammals, however, the zebrafish mesonephric kidney maintains a nephron progenitor population into adulthood and continues to generate new nephrons throughout life in response to growth or injury. The zebrafish model is used to study nephron formation and to understand the neonephrogenic
growth/regenerative response, which may lead to the development of novel therapies for the treatment of human renal disease.
Keywords
Embryo; Kidney; Mesonephros; Nephron; Pronephros; Regeneration; Zebrafish
Overview
The vertebrate kidney plays critical roles in body fluid homeostasis and metabolic waste removal via blood filtration and the excretion/absorption of solutes and water. The workhorse of the kidney is the nephron, which is structurally and functionally conserved among vertebrates and comprises two major parts: the glomerular blood filter and the renal tubules. The ultrafiltrate produced by the glomerulus enters the tubules and is sequentially modified via selective solute reabsorption and secretion [1]. In general, the tubule can be broadly divided into proximal tubule segments, where the bulk of filtrate reabsorption takes place; intermediate segments for the concentration of urine (found only in reptiles, birds, and mammals); and distal tubule segments, where more specialized fine-tuning of salt and acid–base balance takes place. This process is vital for the regulation of electrolyte levels, osmolarity, blood pressure, and pH balance, and disruption of nephron function manifests as a variety of clinical conditions.
How the nephron forms during kidney organogenesis remains poorly understood, in part because the complex architecture of the mammalian kidney renders close investigation of nephrogenesis a challenge. In contrast, lower vertebrate models such as the zebrafish develop comparatively simple embryonic kidneys. The transparency of zebrafish embryos coupled with their external development, rapid growth, and a range of genetic tools means that gene expression and function can be readily assessed at a high cellular resolution. As a result, the zebrafish is providing new insights into how the nephron forms during embryogenesis.
Nephron regeneration also has recently become the focus of intense study. The mammalian nephron has a limited capacity for regeneration but is able to repair localized lesions in the proximal tubule. However, the ability of mammals to generate nephrons is restricted to stages of embryonic or early postnatal life, when the kidney is undergoing organogenesis. In contrast, zebrafish and other teleosts retain the ability to generate new nephrons during adulthood in response to growth or injury. This pathway of de novo nephron formation (called neonephrogenesis) is poorly understood but might provide key insights into developing novel regeneration-based therapies for humans. This chapter focuses on the use of zebrafish to understand nephrogenesis in both developmental and regenerative contexts. How zebrafish have advanced our understanding of the developmental pathways controlling nephron formation, as well as an examination of the neonephrogenic
response that occurs in the adult zebrafish kidney, are discussed.
The Zebrafish Pronephros as a Model of Nephron Development and Injury
Overview of the Zebrafish Pronephros
Whereas the mammalian pronephros is vestigial and restricted to the nephric duct lineage, the zebrafish pronephros is a fully functional kidney that is essential for osmoregulation in the free-swimming embryo. The zebrafish pronephros consists of two bilaterally paired nephrons that are fused rostrally at the midline, via a shared glomerulus, and caudally at the cloaca [2] (Figure 1.1). The zebrafish glomerulus shows a high degree of conservation with mammalian glomeruli, with centrally located fenestrated endothelial cells supported by mesangial cells [3], a thick glomerular basement membrane, and an outer layer of podocytes with long, interdigitating foot processes. Zebrafish podocytes are linked together via slit diaphragm
protein bridges and express a number of genes identified from mammalian studies as being important for podocyte function, including slit diaphragm components (nephrin, neph1, podocin), glomerular basement membrane adhesion (integrin α3), and electronegative surface charge (podocalyxin) [4–7].
Linking the glomerulus to the tubules is a short neck region made up of low cuboidal epithelial cells and scattered multiciliated cells [6]. The neck region is not found in mammals but has been observed in other fish species; it is likely to play a role in propelling the filtrate from the glomerulus into the proximal tubule [8,9]. In support of this, disruptions in cilia function lead to a characteristic accumulation of fluid in the neck region, resulting in bilateral dilatations or cysts
that compress the adjacent glomerulus [5,10,11]. The neck region is characterized by the expression of the pax2a transcription factor and a salt-and-pepper
pattern of genes implicated in cilia function, including rfx2, foxj1a, and dnah9 [6,12]. Although the neck region was initially thought to function as a tubule segment, it lacks expression of conserved proximal tubule genes, does not exhibit a brush border, and fails to take up fluorescent tracers that pass through the glomerular filter [6]. Instead, knockdown studies of pathways required for podocyte formation suggest that neck cells may be more closely related to the podocyte lineage, perhaps sharing a common progenitor [6].
The pronephric tubules exhibit a segmentation pattern that is characterized by two proximal tubule segments (proximal convoluted tubule [PCT] and proximal straight tubule [PST]) and two distal segments (distal early [DE] and distal late [DL]), as revealed by the expression of segment-specific genes and cellular morphology [12–15] (Figure 1.1). As in mammals, the zebrafish proximal tubule segments display all the hallmarks of highly absorptive epithelia, including a prominent brush border, uptake of fluorescent tracers, expression of megalin and cubilin (encoding endocytic scavenging receptors), and specific solute transporters [12,16]. The DE and DL segments express NaCl transporters (slc12a1 and slc12a3, respectively), as well as the chloride channel clcnkb, and are likely to play a key role in NaCl reabsorption similar to that of the distal nephron in mammalians. Notable differences in tubule structure between zebrafish and mammals include a lack of the loop of Henle in zebrafish, which is an adaptation for concentrating the urine in metanephric kidneys, and the presence of motile multiciliated cells in the zebrafish PCT, PST, and DE segments.
Induction of the Zebrafish Pronephros from the Intermediate Mesoderm
As in all vertebrates, the zebrafish pronephros develops from the intermediate mesoderm during embryogenesis. However, zebrafish differ from other model vertebrates in that the pronephros arises in situ from most of the intermediate mesoderm, and there is not extensive migration of nephric duct precursors, such as that seen in mammalian embryos (Figure 1.2). As a result, the different cell types along the proximodistal axis of the nephron arise from progenitors laid out along the anteroposterior axis of the intermediate mesoderm. The zebrafish intermediate mesoderm can first be discerned shortly after the end of gastrulation by the expression of the transcription factor genes pax2a, pax8, osr1, and lhx1a [17–19]. Of these genes, pax2a and pax8 play a key role as inducers of pronephros development in zebrafish. Embryos deficient in pax2a and pax8 fail to form pronephric tubules and lack the expression of a number of early acting renal genes, including the transcription factor hnf1b [13]. This result is consistent with mouse studies in which embryos deficient in both Pax2 and Pax8 do not form the nephric duct (the earliest renal lineage to be specified in mammals), and there is a corresponding failure in mesonephric and metanephric kidney induction [20]. How Pax2/8 specify renal fates remains poorly understood and in mammals is complicated by their roles at multiple stages and in different cell types during kidney development. A number of candidate targets of Pax2 and Pax8 have recently been identified in the mouse using microarray profiling and include several other renal transcriptional regulators, such as Lhx1, Gata3, Mecom, and Plac8 [21]. This suggests that Pax2/8 act near the top of a much larger transcriptional network that controls the specification of kidney fate (Figure 1.3). During pronephros development in zebrafish, the expression of Lhx1, Mecom, and Plac8 orthologs also is dependent on Pax2/8, suggesting that the Pax2/8 transcriptional cascade is conserved across vertebrates (unpublished observations and Refs [19,22]).
Figure 1.1 Schematic showing the development and structure of the zebrafish pronephros.
The pronephros derives from bilateral stripes of intermediate mesoderm (blue) that are discernible after gastrulation by the expression of transcription factor genes such as pax2a and pax8. As development proceeds, the intermediate mesoderm can be subdivided into podocyte/neck segment progenitors, rostral progenitors, and caudal progenitors. Podocyte/neck cells migrate toward the midline and fuse (indicated by arrows). By 48 h after fertilization, the pronephros comprises a two-nephron structure with a shared glomerulus (green ovals), two proximal convoluted tubule segments (red), two proximal straight tubule segments (yellow), two distal early segments (blue), and two distal late segments (purple).
Figure 1.2 Comparison of zebrafish (left) and mouse (right) kidney development from the intermediate mesoderm.
Both zebrafish and mouse kidneys derive from the intermediate mesoderm along the trunk (blue). Unlike other vertebrate models, the zebrafish pronephros differentiates in situ from most of the anteroposterior axis of the intermediate mesoderm, such that progenitors along this axis sequentially give rise to the different cell types of the pronephric nephron (see Figure 1.1 for details). By contrast, during mouse kidney development, the rostral intermediate mesoderm gives rise to nephric duct precursors that migrate caudally and induce the formation of the mesonephros and metanephros.
Formation of the Pronephric Glomerulus
Laser ablation studies have demonstrated that podocytes arise from the rostral-most domain of the pax2/8/lhx1a+ intermediate mesoderm, adjacent to somite 3 [6]. In addition to expressing pax2/8/lhx1a, this region also expresses the zinc finger transcription factors Wilms’ tumor suppressor 1a (wt1a) and odd-skipped related 1 (osr1) [10,23]. During later stages of pronephros development, these podocyte progenitors initiate expression of mafba and wt1b, migrate to the midline [6], and fuse (Figures 1.1 and 1.4). During this time, there is transient expression of the Notch target gene hey1 in these cells (discussed in more detail below). Expression of podocyte differentiation markers
such as nephrin, podocin, integrin α3, and podocalyxin become expressed just before fusion, concomitant with a downregulation of pax2/8, lhx1a, osr1, and hey1 and stronger expression of wt1a [6]. These molecular and morphological patterns suggest a sequential process whereby the intermediate mesoderm is converted into podocyte progenitors, followed by their terminal differentiation (Figure 1.4). Vascular sprouts from the overlying dorsal aorta invade the mass of fused podocytes and establish the glomerular capillary tuft, followed by mesangial cell recruitment [3]. Glomerular filtration initiates around 48 h after fertilization, with mature size selectivity being achieved 4 days after fertilization [5].
Considerable evidence in mammals has implicated WT1 as a key regulator of podocyte fate [24–28]. Consistent with this, morpholino-mediated knockdown of wt1a in zebrafish causes a reduction, but not a complete loss, of podocyte progenitors and a failure of these cells to express differentiation markers such as nephrin and podocalyxin [6,29,30]. Knockdown of the wt1b paralog alone does affect early podocyte development, but at later stages it leads to the formation of neck cysts in some animals [30]. Embryos deficient in wt1a and wt1b seem to lack all podocytes, neck cells, and a portion of the proximal tubule [30,31]. While these data suggest that wt1a and wt1b may act redundantly during podocyte, neck, and proximal tubule development, a more detailed analysis of the doubly deficient phenotype is needed to understand the cause of these defects, given that endogenous transcripts for wt1a and wt1b have not been reported in proximal tubule progenitors. Furthermore, wt1b expression persists in podocytes in wt1a-deficient embryos, yet the podocytes still fail to undergo terminal differentiation [6]. This result suggests that wt1a and wt1b have independent functions, at least with regard to podocyte terminal differentiation.
Figure 1.3 Overview of gene expression changes during podocyte formation in zebrafish.
Podocyte formation during zebrafish pronephros development is characterized by the sequential differentiation of the intermediate mesoderm, first into podocyte progenitors and then mature podocytes. Selected genes expressed by cells at each stage are listed. The expression patterns of Notch ligands (jagged2 and jagged3), the Notch target hey1, and functional in vivo studies (see text for details) suggest that Notch signaling operates during the early, but not late phases, of podocyte formation.
Figure 1.4 Proposed gene regulatory network controlling proximodistal patterning of the intermediate mesoderm in zebrafish.
Diffusion of retinoic acid (blue) across the rostral domain of the intermediate mesoderm likely establishes the proximodistal pattern of the pronephros through a morphogenetic gradient. Pax2/8 and Hnf1b are key regulators of tubule segmentation and maturation, acting downstream or in parallel with RA signaling, although the targets of these transcription factors are still being identified. Mecom, a potential Pax2/8 target, may repress RA signaling. Irx3b, a potential Hnf1b target, is needed to maintain the identity of the distal early segment. Hnf1b factors also play a role in restricting podocyte fate, acting upstream or in parallel to the Wt1a/Notch pathway. Putative positive and negative interactions are indicated with green and red lines, respectively.
An antagonistic relationship may exist between wt1a and pax2a in zebrafish because pax2a mutants show ectopic expression of wt1a and vegf (normally restricted to podocytes) in the neck region [32]. This suggests that in the absence of pax2a, the neck region may adopt a podocyte fate. Mammalian studies have provided good evidence that WT1 can directly repress Pax2 expression based on in vitro promoter assays, and observations in vivo have revealed an inverse relationship between WT1 and Pax2 expression in podocytes [33,34]. Although wt1a and pax2a are coexpressed during early stages of podocyte development, the finding that pax2a transcripts are downregulated around the time that wt1a expression increases suggests that the antagonistic relationship between Wt1 and Pax2 homologs is conserved in zebrafish.
In mammals the Notch pathway is required for podocyte formation during metanephric kidney formation, and a similar role is conserved in zebrafish [6,35–37]. Knockdown of rbpj (a transcriptional mediator of Notch) or the Notch ligands jagged2 and jagged3 reduces the number of podocytes, similar to what occurs in wt1a-deficient embryos, but does not block their differentiation [6]. Embryos deficient in both wt1a and rbpj lack all podocytes, suggesting that these two factors act together, perhaps in a partially redundant fashion, to induce podocyte fate. One possibility is that Notch signaling and Wt1a converge on common downstream targets, with both pathways contributing fractionally to the final transcription level of the target. In support of this, Rbpj and Wt1 physically associate, and the Notch pathway and Wt1 show additive stimulatory effects on the mouse Hey1 promoter in vitro [6]. The role of hey1 in zebrafish podocytes is not clear, but its transient expression suggests that Notch signaling is restricted to the progenitor phase and is downregulated before terminal differentiation (Figure 1.4). Notch signaling does not seem to be compatible with the fully differentiated state of podocytes; ectopic Notch activation in podocytes induces a de-differentiated-like phenotype characterized by reactivation of Pax2 and Jagged expression and a downregulation of WT1 and mature
markers such as Nephrin and Podocin [36,38].
Osr1, encoding a zinc finger transcription factor belonging to the odd-skipped family of genes, has recently been shown to play a role in zebrafish podocyte formation [31]. Knockdown of osr1 leads to a glomerular phenotype similar to that of wt1a-deficient embryos, including fewer podocytes that remain in a progenitor state and fail to express nephrin and podocin [17,31]. Expression of wt1a is unaffected in osr1-deficient embryos, ruling out that osr1 acts as an upstream inducer of wt1a [17], but it may act downstream or parallel to wt1a and the Notch pathway [31]. Support for the latter pathway comes from Drosophila work, where the odd-skipped gene family, downstream of Notch, has been implicated in promoting morphological changes associated with joint formation during leg development [39]. One potential target of osr1 is the lhx1a gene, which is lost in osr1 knockdown embryos. Morpholino-mediated knockdown of lhx1a does not cause an overt podocyte defect (our unpublished observations). However, overexpression of a constitutively active version of Lhx1a has been reported to partially restore nephrin expression in osr1-deficient animals, raising the possibility that an osr1 → lhx1a → nephrin pathway may exist in zebrafish [31]. This is a surprising result because lhx1a downregulates around the time that nephrin becomes expressed [6], and nephrin is considered a WT1 target [40]. Thus, further work is needed to clarify the requirement of lhx1a in the podocyte lineage.
Proximodistal Patterning of the Pronephros
Dynamic Expression Patterns of Renal Transcription Factor Genes
Development of the segmental pattern of the tubule is vital for establishing the regulated reabsorption and secretion of solutes. Currently, there is only a poor understanding of the developmental pathways that establish nephron segmentation and maintain segment identity. This is an area where the zebrafish model excells because gene function can be easily assessed using morpholinos or reverse genetic approaches, and the relatively linear tubules of the pronephros facilitate fine mapping of gene expression patterns. Proximodistal subdivisions of the pax2/pax8/lhx1a+ intermediate mesoderm are evident shortly after gastrulation has completed, with rostrally restricted expression of wt1a and jagged2 (including both podocyte/neck progenitors and some proximal tubule progenitors) and caudally restricted expression of the zinc finger transcription factor gene mecom [12,15,41,42]. Following this early rostral–caudal patterning, additional transcription factor genes are expressed in nested domains, including the iroquois homeobox protein 3b (irx3b) that demarcates progenitors of the PST and DE segments [15]. The expression domains of many of these transcription factors fluctuate over the course of kidney development, but further studies are needed to elucidate how many of these changes reflect alterations in gene expression and how many result from changes in cell migration or cell shape [15]. By 24 h after fertilization, the four nephron segments (PCT, PST, DE, and DL) can be distinguished based on the expression of distinct cohorts of solute transporter genes and transcription factors (Figure 1.1). For instance, the PCT is demarcated by expression of slc20a1a, the PST by trpm7, the DE segment by slc12a1, and the DL segment by slc12a3 [12,14].
Role of the Retinoic Acid Pathway
Retinoic acid (RA), the active derivative of vitamin A, is a diffusible morphogen that exerts its effects through concentration-dependent activity and plays a major role in establishing the proximodistal pattern of the pronephros (Wingert et al. [12]). Upon entering the nucleus, RA binds to the RA receptor (RAR) family of transcription factors, resulting in transcriptional activation of RA-responsive target genes [43]. Studies have examined the effects of blocking RA signaling during zebrafish development, either in mutants deficient in aldh1a2 (encoding an enzyme responsible for RA synthesis) or via the application of pathway inhibitors such as diethylaminobenzaldehyde that blocks Aldh1a2. When the RA pathway is compromised during gastrulation, the resulting RA-deficient embryos lack podocytes, show a reduction in the length of the proximal segments, and have an expansion of the distal segments [12,44]. Exogenous RA treatment induces the opposite phenotype and proximalizes
the pronephros, resulting in tubules made up of PCT and PST segments only. Adding RA and diethylaminobenzaldehyde for different lengths of time varies the severity of the proximalization
and distalization
phenotypes, respectively, leading to the suggestion that the pronephric segmentation pattern is set by a gradient of RA, similar to that proposed for the hindbrain [12,45,46]. Consistent with such a model, expression of aldh1a2 is restricted to the anterior paraxial mesoderm, adjacent to proximal nephron progenitors, during early stages of pronephros development [12]. Direct visualization of RA gradients in the zebrafish embryo was recently achieved using a fluorescent reporter capable of detecting free RA [47]. This reporter showed that in the early postgastrula embryo a gradient of RA extends out from the upper trunk and is likely to encompass rostral portions of the intermediate mesoderm, consistent with the notion that a morphogenic gradient specifies different nephron fates. Whether a nephron-patterning role for RA is conserved across vertebrates remains uncertain. While RA is needed for the branching of the mammalian metanephric-collecting duct system, a requirement for nephrogenesis has not been shown [48–52]. Despite this, a number of RA biosynthetic and degradative pathway genes are expressed during mammalian nephron formation, and it is possible that redundancy between these genes masks a patterning role for RA in mammals [53].
Establishment of Proximodistal Segment Identities Downstream of RA
How RA modulates patterning of the pronephros remains largely unknown. It is clear that RA exerts its actions on the intermediate mesoderm at very early stages of pronephros development. In the case of glomerular fates, the effect of RA may be direct; the wt1a promoter is bound by members of the RAR family and is responsive to RA concentrations in vivo [54]. In addition to a loss of wt1a, RA-deficient embryos also fail to express jagged2 (consistent with a lack of podocyte specification) and show an expansion of the caudal domain marker mecom [12,41].
In the case of tubule progenitors, there is growing evidence that several transcription factors act downstream of RA, either directly or indirectly, to establish pronephric segment boundaries. Mecom was initially identified as an oncogene for myeloid tumors in mice, and null mutants die around embryonic day 10.5, with widespread abnormalities including hypocellular mesonephroi [55,56]. During pronephros development in zebrafish, RA signaling seems to restrict mecom expression to the caudal domain of the intermediate mesoderm, where RA concentrations are low [15,31] (Figure 1.3). Knockdown of mecom results in a proximalized pronephros phenotype, similar to that of embryos exposed to exogenous RA, and suggests that Mecom antagonizes RA signaling [41]. Consistent with this, treating mecom-deficient embryos with low concentrations of exogenous RA enhances the proximalized phenotype, suggesting that mecom deficiency sensitizes the intermediate mesoderm to the proximalizing effects of RA. How exactly Mecom interacts with the RA pathway is not yet known. Mecom can interfere directly with the stimulatory action of RARs on its own promoter, raising the possibility that it acts during pronephros development as a direct repressor of RA target genes [57]. How