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Zebrafish Models of Kidney Damage and Repair

  • Zebrafish as a Model for Pathobiology (Wolfram Goessling, Section Editor)
  • Published:
Current Pathobiology Reports

Abstract

The vertebrate kidney possesses the capacity to repair damaged nephrons, and this potential is conserved regardless of the complexity of species-specific kidneys. However, many aquatic vertebrates possess the ability to not only repair existing nephrons, but also generate new nephrons after injury. Adult zebrafish have the ability to recover from acute renal injury not only by replacing lost injured epithelial cells of endogenous nephrons, but by also generating de novo nephrons. This strong regeneration potential, along with other unique characteristics such as the high degree of genetic conservation with humans, the ease of harvesting externally fertilized, transparent embryos, the accessibility to larval and adult kidneys, and the ability to perform whole organism phenotypic small molecule screens, has positioned zebrafish as a unique vertebrate model to study kidney injury. In this review, we provide an overview of the contribution of zebrafish larvae/adult studies to the understanding of renal regeneration, diseases, and therapeutic discovery.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Thadhani R, Pascual M, Bonventre JV (1996) Acute renal failure. N Engl J Med 334(22):1448–1460

    Article  CAS  PubMed  Google Scholar 

  2. Chertow GM et al (2005) Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 16(11):3365–3370

    Article  PubMed  Google Scholar 

  3. Lameire N, Van Biesen W, Vanholder R (2006) The changing epidemiology of acute renal failure. Nature clinical practice. Nephrology 2(7):364–377

    PubMed  Google Scholar 

  4. Bellomo R, Kellum JA, Ronco C (2012) Acute kidney injury. Lancet 380(9843):756–766

    Article  PubMed  Google Scholar 

  5. Lameire NH et al (2013) Acute kidney injury: an increasing global concern. Lancet 382:170–179

    Article  PubMed  Google Scholar 

  6. Rewa O, Bagshaw SM (2014) Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 10(4):193–207

    Article  CAS  PubMed  Google Scholar 

  7. Bucaloiu ID et al (2012) Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int 81(5):477–485

    Article  PubMed  Google Scholar 

  8. Chawla LS et al (2012) The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int 79(12):1361–1369

    Article  Google Scholar 

  9. Coca SG, Singanamala S, Parikh CR (2012) Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 81(5):442–448

    Article  PubMed Central  PubMed  Google Scholar 

  10. Murugan R, Kellum JA (2011) Acute kidney injury: what’s the prognosis? Nat Rev Nephrol 7(4):209–217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Wald R et al (2012) Risk of chronic dialysis and death following acute kidney injury. Am J Med 125(6):585–593

    Article  PubMed  Google Scholar 

  12. Wu VC et al (2011) Acute-on-chronic kidney injury at hospital discharge is associated with long-term dialysis and mortality. Kidney Int 80(11):1222–1230

    Article  PubMed  Google Scholar 

  13. Molitoris BA et al (2012) Designing clinical trials in acute kidney injury. Clin J Am Soc Nephrol 7(5):842–843

    Article  PubMed  Google Scholar 

  14. Davidson AJ (2011) Uncharted waters: nephrogenesis and renal regeneration in fish and mammals. Pediatr Nephrol 26(9):1435–1443

    Article  PubMed  Google Scholar 

  15. Bacallao R, Fine LG (1989) Molecular events in the organization of renal tubular epithelium: from nephrogenesis to regeneration. Am J Physiol 257(6 Pt 2):F913–F924

    CAS  PubMed  Google Scholar 

  16. Sharfuddin AA, Molitoris BA (2011) Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 7(4):189–200

    Article  CAS  PubMed  Google Scholar 

  17. Bonventre JV (2003) Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol 14(Suppl 1):S55–S61

    Article  PubMed  Google Scholar 

  18. Bussolati B et al (2005) Isolation of renal progenitor cells from adult human kidney. Am J Pathol 166(2):545–555

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Humphreys BD et al (2008) Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2(3):284–291

    Article  CAS  PubMed  Google Scholar 

  20. Loverre A et al (2008) Increase of proliferating renal progenitor cells in acute tubular necrosis underlying delayed graft function. Transplantation 85(8):1112–1119

    Article  PubMed  Google Scholar 

  21. • Cianciolo Cosentino C et al (2013) Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol 24(6):943–953. This publication validates the strategy that discoveries made using a zebrafish embryonic screening model are directly translatable to mammalian models of AKI

  22. • Diep CQ et al (2011) Identification of adult nephron progenitors capable of kidney regeneration in zebrafish. Nature 470(7332):95–100. This publication identifies a stem/progenitor cell in the adult zebrafish that is important for driving neo-nephrogenesis

  23. Wingert RA et al (2007) The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet 3(10):1922–1938

    Article  CAS  PubMed  Google Scholar 

  24. Drummond IA et al (1998) Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function. Development 125(23):4655–4667

    CAS  PubMed  Google Scholar 

  25. Zhou W et al (2010) Characterization of mesonephric development and regeneration using transgenic zebrafish. Am J Physiol 299(5):F1040–F1047

    CAS  Google Scholar 

  26. Reimschuessel R (2001) A fish model of renal regeneration and development. ILAR J 42(4):285–291

    Article  CAS  PubMed  Google Scholar 

  27. Karasawa T et al (2011) Calreticulin binds to gentamicin and reduces drug-induced ototoxicity. Toxicol Sci 124(2):378–387

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Lopez-Novoa JM et al (2011) New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 79(1):33–45

    Article  CAS  PubMed  Google Scholar 

  29. Cianciolo Cosentino C et al (2010) Intravenous microinjections of zebrafish larvae to study acute kidney injury. J Vis Exp. doi:10.3791/2079

    Google Scholar 

  30. Hentschel DM et al (2005) Acute renal failure in zebrafish: a novel system to study a complex disease. Am J Physiol Renal Physiol 288(5):F923–F929

    Article  CAS  PubMed  Google Scholar 

  31. Bonventre JV, Yang L (2011) Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121(11):4210–4221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Hartman HA, Lai HL, Patterson LT (2007) Cessation of renal morphogenesis in mice. Dev Biol 310(2):379–387

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Johnson CS, Holzemer NF, Wingert RA (2011) Laser ablation of the zebrafish pronephros to study renal epithelial regeneration. J Vis Exp 54

  34. Palmyre A et al (2014) Collective epithelial migration drives kidney repair after acute injury. PLoS One 9(7):e101304

    Article  PubMed Central  PubMed  Google Scholar 

  35. Arlt VM, Stiborova M, Schmeiser HH (2002) Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 17(4):265–277

    Article  CAS  PubMed  Google Scholar 

  36. Ding YJ, Chen YH (2012) Developmental nephrotoxicity of aristolochic acid in a zebrafish model. Toxicol Appl Pharmacol 261(1):59–65

    Article  CAS  PubMed  Google Scholar 

  37. Sato N et al (2004) Acute nephrotoxicity of aristolochic acids in mice. J Pharm Pharmacol 56(2):221–229

    Article  CAS  PubMed  Google Scholar 

  38. Vanherweghem JL et al (1993) Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341(8842):387–391

    Article  CAS  PubMed  Google Scholar 

  39. Tryggvason K, Patrakka J, Wartiovaara J (2006) Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 354(13):1387–1401

    Article  CAS  PubMed  Google Scholar 

  40. Tryggvason K, Wartiovaara J (2005) How does the kidney filter plasma? Physiology (Bethesda) 20:96–101

    Article  Google Scholar 

  41. Hentschel DM et al (2007) Rapid screening of glomerular slit diaphragm integrity in larval zebrafish. Am J Physiol Renal Physiol 293(5):F1746–F1750

    Article  CAS  PubMed  Google Scholar 

  42. Ryan GB, Rodewald R, Karnovsky MJ (1975) An ultrastructural study of the glomerular slit diaphragm in aminonucleoside nephrosis. Lab Invest 33(5):461–468

    CAS  PubMed  Google Scholar 

  43. He B et al (2011) Podocin-green fluorescence protein allows visualization and functional analysis of podocytes. J Am Soc Nephrol 22(6):1019–1023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Huang J et al (2013) A zebrafish model of conditional targeted podocyte ablation and regeneration. Kidney Int 83(6):1193–1200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. • Zhou W, Hildebrandt F (2012) Inducible podocyte injury and proteinuria in transgenic zebrafish. J Am Soc Nephrol 23(6):1039–1047. This publication describes the generation of a zebrafish transgenic model for the study of glomerular pathogenesis and podocyte regeneration

  46. Curado S, Stainier DY, Anderson RM (2008) Nitroreductase-mediated cell/tissue ablation in zebrafish: a spatially and temporally controlled ablation method with applications in developmental and regeneration studies. Nat Protoc 3(6):948–954

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Pisharath H, Parsons MJ (2009) Nitroreductase-mediated cell ablation in transgenic zebrafish embryos. Methods Mol Biol 546:133–143

    Article  CAS  PubMed  Google Scholar 

  48. Appel D et al (2009) Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 20(2):333–343

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Grouls S et al (2012) Lineage specification of parietal epithelial cells requires beta-catenin/Wnt signaling. J Am Soc Nephrol 23(1):63–72

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Sander V et al (2015) The small molecule probe PT-Yellow labels the renal proximal tubules in zebrafish. Chem Commun (Camb) 51(2):395–398

    Article  CAS  Google Scholar 

  51. Driever W et al (1996) A genetic screen for mutations affecting embryogenesis in zebrafish. Development 123:37–46

    CAS  PubMed  Google Scholar 

  52. Bingham C et al (2001) Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 68(1):219–224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Mochizuki T et al (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272(5266):1339–1342

    Article  CAS  PubMed  Google Scholar 

  54. Sun Z et al (2004) A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development 131(16):4085–4093

    Article  CAS  PubMed  Google Scholar 

  55. Kishimoto N et al (2008) Cystic kidney gene seahorse regulates cilia-mediated processes and Wnt pathways. Dev Cell 14(6):954–961

    Article  CAS  PubMed  Google Scholar 

  56. Li J, Sun Z (2011) Qilin is essential for cilia assembly and normal kidney development in zebrafish. PLoS One 6(11):e27365

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Pedersen LB, Rosenbaum JL (2008) Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol 85:23–61

    Article  CAS  PubMed  Google Scholar 

  58. Smith LA et al (2006) Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. J Am Soc Nephrol 17(10):2821–2831

    Article  CAS  PubMed  Google Scholar 

  59. Cao Y et al (2009) Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc Natl Acad Sci USA 106(51):21819–21824

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Hellman NE et al (2010) The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch. Proc Natl Acad Sci USA 107(43):18499–18504

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Huang L et al (2014) A possible zebrafish model of polycystic kidney disease: knockdown of wnt5a causes cysts in zebrafish kidneys. J Vis Exp 94:e52156–e52156

    Google Scholar 

  62. Hildebrandt F, Attanasio M, Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20(1):23–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Lin F et al (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100(9):5286–5291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Pazour GJ, Witman GB (2003) The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol 15(1):105–110

    Article  CAS  PubMed  Google Scholar 

  65. Yoder BK (2007) Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol 18(5):1381–1388

    Article  CAS  PubMed  Google Scholar 

  66. Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13(10):2508–2516

    Article  CAS  PubMed  Google Scholar 

  67. Lansbury PT Jr (2004) Back to the future: the ‘old-fashioned’ way to new medications for neurodegeneration. Nat Med 10(Suppl):S51–S57

    Article  PubMed  Google Scholar 

  68. Lee JA et al (2012) Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. J Med Chem 55(10):4527–4538

    Article  CAS  PubMed  Google Scholar 

  69. Murphey RD et al (2006) A chemical genetic screen for cell cycle inhibitors in zebrafish embryos. Chem Biol Drug Des 68(4):213–219

    Article  CAS  PubMed  Google Scholar 

  70. Sams-Dodd F (2005) Target-based drug discovery: is something wrong? Drug Discov Today 10(2):139–146

    Article  CAS  PubMed  Google Scholar 

  71. Lawrence S (2007) Drug output slows in 2006. Nat Biotechnol 25(10):1073

    Article  CAS  Google Scholar 

  72. Kamb A (2005) Opinion: what’s wrong with our cancer models? Nat Rev Drug Discov 4(2):161–165

    Article  CAS  PubMed  Google Scholar 

  73. Prior M et al (2014) Back to the future with phenotypic screening. ACS Chem Neurosci 5(7):503–513

    Article  CAS  PubMed  Google Scholar 

  74. Deo RC, MacRae CA (2011) The zebrafish: scalable in vivo modeling for systems biology. Wiley Interdiscip Rev Syst Biol Med 3(3):335–346

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10(7):507–519

    Article  CAS  PubMed  Google Scholar 

  76. Peal DS et al (2011) Novel chemical suppressors of long QT syndrome identified by an in vivo functional screen. Circulation 123(1):23–30

    Article  PubMed Central  PubMed  Google Scholar 

  77. Burns CG et al (2005) High-throughput assay for small molecules that modulate zebrafish embryonic heart rate. Nat Chem Biol 1(5):263–264

    Article  CAS  PubMed  Google Scholar 

  78. Peterson RT et al (2004) Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol 22(5):595–599

    Article  CAS  PubMed  Google Scholar 

  79. Milan DJ et al (2003) Drugs that induce repolarization abnormalities cause bradycardia in zebrafish. Circulation 107(10):1355–1358

    Article  PubMed  Google Scholar 

  80. Hao J et al (2010) In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem Biol 5(2):245–253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. White RM et al (2011) DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature 471(7339):518–522

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Kokel D et al (2010) Rapid behavior-based identification of neuroactive small molecules in the zebrafish. Nat Chem Biol 6(3):231–237

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Rihel J et al (2010) Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science 327(5963):348–351

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. North TE et al (2007) Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447(7147):1007–1011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. de Groh ED et al (2010) Inhibition of histone deacetylase expands the renal progenitor cell population. J Am Soc Nephrol 21(5):794–802

    Article  PubMed Central  PubMed  Google Scholar 

  86. Novitskaya T et al (2014) A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury. Am J Physiol Renal Physiol 306(5):F496–F504

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The laboratory of Neil Hukriede was supported by the National Institutes of Health Grants 2R01 DK069403, 1RC4 DK090770, 2R01 HD053287, and 1P30DK079307. The laboratory of Maria Cecilia Cirio was supported by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina, FONCyT, PICT 2013. The laboratory of Mark de Caestecker was supported by National Institutes of Health Grants 1R01 HL093057 and 1RC4DK090770.

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Authors and Affiliations

  1. Instituto de Fisiología, Biología Molecular y Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

    Maria Cecilia Cirio

  2. Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, TN, USA

    Mark P. de Caestecker

  3. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA

    Mark P. de Caestecker

  4. Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Neil A. Hukriede

  5. Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, USA

    Neil A. Hukriede

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  1. Maria Cecilia Cirio
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  2. Mark P. de Caestecker
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  3. Neil A. Hukriede
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Correspondence to Neil A. Hukriede.

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This article is part of the Topical Collection on Zebrafish as a Model for Pathobiology.

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Cirio, M.C., de Caestecker, M.P. & Hukriede, N.A. Zebrafish Models of Kidney Damage and Repair. Curr Pathobiol Rep 3, 163–170 (2015). https://doi.org/10.1007/s40139-015-0080-4

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