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Translational research in ADPKD: lessons from animal models

Nature Reviews Nephrology volume 10, pages 587–601 (2014)Cite this article

Subjects

Key Points

  • Mice with mutations in Pkd1 or Pkd2 enable a step-by-step analysis of the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) and valuable insights into early and progressive disease stages

  • Mouse models have shown that mutations in genes encoding polycystin proteins cause renal cysts, but additional factors are also required for cyst formation

  • Renal injury accelerates the rate of cyst formation, probably by increasing the chance that cysts are formed

  • Animal studies have revealed a complex network of genetic and functional interactions between different renal cystic disease genes involved in polycystic kidney disease

  • Differences in lifespan, metabolism, renal anatomy, involved nephron segment and genetic background mean that a mouse model cannot perfectly recapitulate human ADPKD

  • The question of which mouse models of ADPKD are the most suitable to study disease mechanisms and for preclinical testing does not have a definitive answer

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, which encode polycystin-1 and polycystin-2, respectively. Rodent models are available to study the pathogenesis of polycystic kidney disease (PKD) and for preclinical testing of potential therapies—either genetically engineered models carrying mutations in Pkd1 or Pkd2 or models of renal cystic disease that do not have mutations in these genes. The models are characterized by age at onset of disease, rate of disease progression, the affected nephron segment, the number of affected nephrons, synchronized or unsynchronized cyst formation and the extent of fibrosis and inflammation. Mouse models have provided valuable mechanistic insights into the pathogenesis of PKD; for example, mutated Pkd1 or Pkd2 cause renal cysts but additional factors are also required, and the rate of cyst formation is increased in the presence of renal injury. Animal studies have also revealed complex genetic and functional interactions among various genes and proteins associated with PKD. Here, we provide an update on the preclinical models commonly used to study the molecular pathogenesis of ADPKD and test potential therapeutic strategies. Progress made in understanding the pathophysiology of human ADPKD through these animal models is also discussed.

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Figure 1: Rodent models of PKD.
Figure 2: Tissue-specific Pkd1 knockout using the Cre–loxP recombination system.
Figure 3: Disease progression in ADPKD.

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References

  1. Torres, V. E., Harris, P. C. & Pirson, Y. Autosomal dominant polycystic kidney disease. Lancet 369, 1287–1301 (2007).

    Article  PubMed  Google Scholar 

  2. Peters, D. J. M. & Sandkuijl, L. A. Genetic heterogeneity of polycystic kidney disease in Europe. Contrib. Nephrol. 128–139 (1992).

  3. Rossetti, S. et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 18, 2143–2160 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Martinez, V. et al. Renal replacement therapy in ADPKD patients: a 25-year survey based on the Catalan registry. BMC Nephrol. 14, 186 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Collins, A. J. et al. US Renal Data System 2010 Annual Data Report. Am. J. Kidney Dis. 57 (Suppl. 1), e1–e526 (2011).

    Google Scholar 

  6. Grantham, J. J., Cook, L. T., Wetzel, L. H., Cadnapaphornchai, M. A. & Bae, K. T. Evidence of extraordinary growth in the progressive enlargement of renal cysts. Clin. J. Am. Soc. Nephrol. 5, 889–896 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ravine, D. et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 343, 824–827 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Nicolau, C. et al. Abdominal sonographic study of autosomal dominant polycystic kidney disease. J. Clin. Ultrasound 28, 277–282 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Danaci, M. et al. The prevalence of seminal vesicle cysts in autosomal dominant polycystic kidney disease. Nephrol. Dial. Transplant. 13, 2825–2828 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Alpern, M. B., Dorfman, R. E., Gross, B. H., Gottlieb, C. A. & Sandler, M. A. Seminal vesicle cysts: association with adult polycystic kidney disease. Radiology 180, 79–80 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Wijdicks, E. F., Torres, V. E. & Schievink, W. I. Chronic subdural hematoma in autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 35, 40–43 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Schievink, W. I., Huston, J. III, Torres, V. E. & Marsh, W. R. Intracranial cysts in autosomal dominant polycystic kidney disease. J. Neurosurg. 83, 1004–1007 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Alehan, F. K., Gurakan, B. & Agildere, M. Familial arachnoid cysts in association with autosomal dominant polycystic kidney disease. Pediatrics 110, e3 (2002).

    Article  Google Scholar 

  14. Ecder, T. & Schrier, R. W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol. 5, 221–228 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Qian, F. J., Watnick, T. J., Onuchic, L. F. & Germino, G. G. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease. Cell 87, 979–987 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Pei, Y. et al. Somatic PKD2 mutations in individual kidney and liver cysts support a “two-hit” model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 10, 1524–1529 (1999).

    CAS  PubMed  Google Scholar 

  17. Watnick, T. et al. Mutations of PKD 1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Nat. Genet. 25, 143–144 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Ong, A. C. & Harris, P. C. Molecular basis of renal cyst formation--one hit or two? Lancet 349, 1039–1040 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Lantinga-van Leeuwen, I. S. et al. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum. Mol. Genet. 13, 3069–3077 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Happé, H. et al. Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways. Hum. Mol. Genet. 18, 2532–2542 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Wang, X., Wu, Y., Ward, C. J., Harris, P. C. & Torres, V. E. Vasopressin directly regulates cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 19, 102–108 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Torra, R., Darnell, A., Estivill, X., Botey, A. & Revert, L. Interfamilial and intrafamilial variability of clinical expression in ADPKD. Contrib. Nephrol. 115, 97–101 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Cornec-Le Gall, E. et al. Type of PKD1 mutation influences renal outcome in ADPKD. J. Am. Soc. Nephrol. 24, 1006–1013 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hateboer, N. et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet 353, 103–107 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Rossetti, S. et al. Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet 361, 2196–2201 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Rossetti, S. et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 75, 848–855 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vujic, M. et al. Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD. J. Am. Soc. Nephrol. 21, 1097–1102 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Losekoot, M. et al. Neonatal onset autosomal dominant polycystic kidney disease (ADPKD) in a patient homozygous for a PKD2 missense mutation due to uniparental disomy. J. Med. Genet. 49, 37–40 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Bergmann, C. et al. Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J. Am. Soc. Nephrol. 22, 2047–2056 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Geberth, S. et al. More adverse renal prognosis of autosomal dominant polycystic kidney disease in families with primary hypertension. J. Am. Soc. Nephrol. 6, 1643–1648 (1995).

    CAS  PubMed  Google Scholar 

  31. Brook-Carter, P. T. et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease—a contiguous gene syndrome. Nat. Genet. 8, 328–332 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Lu, W. et al. Late onset of renal and hepatic cysts in Pkd1-targeted heterozygotes. Nat. Genet. 21, 160–161 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, K., Drummond, I., Ibraghimov-Beskrovnaya, O., Klinger, K. & Arnaout, M. A. Polycystin 1 is required for the structural integrity of blood vessels. Proc. Natl Acad. Sci. USA 97, 1731–1736 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Muto, S. et al. Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Hum. Mol. Genet. 11, 1731–1742 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Lantinga-van Leeuwen, I. S. et al. Kidney-specific inactivation of the P kd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum. Mol. Genet. 16, 3188–3196 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Natoli, T. A. et al. Pkd1 and Nek8 mutations affect cell-cell adhesion and cilia in cysts formed in kidney organ cultures. Am. J. Physiol. Renal Physiol. 294, F73–F83 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Lu, W. et al. Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum. Mol. Genet. 10, 2385–2396 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, G. et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177–188 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Boulter, C. et al. Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc. Natl Acad. Sci. USA 98, 12174–12179 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pennekamp, P. et al. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr. Biol. 12, 938–943 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Lantinga-van Leeuwen, I. S. et al. Transgenic mice expressing tamoxifen-inducible Cre for somatic gene modification in renal epithelial cells. Genesis 44, 225–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Piontek, K., Menezes, L. F., Garcia-Gonzalez, M. A., Huso, D. L. & Germino, G. G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Piontek, K. B. et al. A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J. Am. Soc. Nephrol. 15, 3035–3043 (2004).

    Article  PubMed  Google Scholar 

  44. Takakura, A., Contrino, L., Beck, A. W. & Zhou, J. Pkd1 inactivation induced in adulthood produces focal cystic disease. J. Am. Soc. Nephrol. 19, 2351–2363 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shibazaki, S. et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum. Mol. Genet. 17, 1505–1516 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim, I. et al. Conditional mutation of Pkd2 causes cystogenesis and upregulates β-catenin. J. Am. Soc. Nephrol. 20, 2556–2569 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Starremans, P. G. et al. A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1. Kidney Int. 73, 1394–1405 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Patel, V. et al. Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum. Mol. Genet. 17, 1578–1590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Raphael, K. L. et al. Inactivation of Pkd1 in principal cells causes a more severe cystic kidney disease than in intercalated cells. Kidney Int. 75, 626–633 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Hassane, S. et al. Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension. Lab. Invest. 91, 24–32 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Garcia-Gonzalez, M. A. et al. Pkd1 and Pkd2 are required for normal placental development. PLoS ONE 5, e12821 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu, D. et al. A Pkd1–Fbn1 genetic interaction implicates TGF-β signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 25, 81–91 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yu, S. et al. Essential role of cleavage of polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proc. Natl Acad. Sci. USA 104, 18688–18693 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jiang, S. T. et al. Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am. J. Pathol. 168, 205–220 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hopp, K. et al. Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J. Clin. Invest. 122, 4257–4273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Herron, B. J. et al. Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis. Nat. Genet. 30, 185–189 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Pritchard, L. et al. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum. Mol. Genet. 9, 2617–2627 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Kurbegovic, A. et al. Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes. Hum. Mol. Genet. 19, 1174–1189 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Park, E. Y. et al. Cyst formation in kidney via B-Raf signaling in the PKD2 transgenic mice. J. Biol. Chem. 284, 7214–7222 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kurbegovic, A. & Trudel, M. Progressive development of polycystic kidney disease in the mouse model expressing Pkd1 extracellular domain. Hum. Mol. Genet. 22, 2361–2375 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Wang, E. et al. Progressive renal distortion by multiple cysts in transgenic mice expressing artificial microRNAs against Pkd1. J. Pathol. 222, 238–248 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Ward, C. J. et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat. Genet. 30, 259–269 (2002).

    Article  PubMed  Google Scholar 

  63. Bakeberg, J. L. et al. Epitope-tagged Pkhd1 tracks the processing, secretion, and localization of fibrocystin. J. Am. Soc. Nephrol. 22, 2266–2277 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fedeles, S. V. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 43, 639–647 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Woollard, J. R. et al. A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney Int. 72, 328–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Gallagher, A. R. et al. Biliary and pancreatic dysgenesis in mice harboring a mutation in Pk hd1. Am. J. Pathol. 172, 417–429 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim, I. et al. Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J. Am. Soc. Nephrol. 19, 455–468 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hu, B. et al. Cystogenesis in ARPKD results from increased apoptosis in collecting duct epithelial cells of Pkhd1 mutant kidneys. Exp. Cell Res. 317, 173–187 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Moser, M. et al. A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 41, 1113–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Williams, S. S., Cobo-Stark, P., James, L. R., Somlo, S. & Igarashi, P. Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease. Pediatr. Nephrol. 23, 733–741 (2008).

    Article  PubMed  Google Scholar 

  71. Garcia-Gonzalez, M. A. et al. Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum. Mol. Genet. 16, 1940–1950 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Nagasawa, Y. et al. Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene. J. Am. Soc. Nephrol. 13, 2246–2258 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Otto, E. A. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat. Genet. 34, 413–420 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Otto, E. A. et al. NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis. J. Am. Soc. Nephrol. 19, 587–592 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu, S. et al. A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in zebrafish. Development 129, 5839–5846 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Olbrich, H. et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat. Genet. 34, 455–459 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Phillips, C. L. et al. Renal cysts of inv/i nv mice resemble early infantile nephronophthisis. J. Am. Soc. Nephrol. 15, 1744–1755 (2004).

    Article  PubMed  Google Scholar 

  78. Takahashi, H. et al. A hereditary model of slowly progressive polycystic kidney disease in the mouse. J. Am. Soc. Nephrol. 1, 980–989 (1991).

    CAS  PubMed  Google Scholar 

  79. Kraus, M. R. et al. Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia. Hum. Mutat. 33, 86–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Guay-Woodford, L. M. et al. Evidence that two phenotypically distinct mouse PKD mutations, b pk and jcpk, are allelic. Kidney Int. 50, 1158–1165 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Torres, V. E. et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 10, 363–364 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Gattone, V. H., Wang, X., Harris, P. C. & Torres, V. E. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 9, 1323–1326 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, X., Gattone, V. II, Harris, P. C. & Torres, V. E. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J . Am. Soc. Nephrol. 16, 846–851 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Meijer, E. et al. Therapeutic potential of a vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug. Nephrol . Dial. Transplant. 26, 2445–2453 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Torres, V. E. et al. EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats. Kidney Int. 64, 1573–1579 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Torres, V. E. et al. Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats. Kidney Int. 66, 1766–1773 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Kim, I. et al. Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. J. Biol. Chem. 283, 31559–31566 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Happé, H. et al. Cyst expansion and regression in a mouse model of polycystic kidney disease. Kidney Int. 83, 1099–1108 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Hassane, S. et al. Pathogenic sequence for dissecting aneurysm formation in a hypomorphic polycystic kidney disease 1 mouse model. Arterioscler. Thromb. Vasc. Biol. 27, 2177–2183 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Belz, M. M. et al. Familial clustering of ruptured intracranial aneurysms in autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 38, 770–776 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Lu, W. et al. Perinatal lethality with kidney and pancreas defects, in mice with a targeted pkd1 mutation. Nat. Genet. 17, 179–181 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Pei, Y. et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am. J. Hum. Genet. 68, 355–363 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wu, G. et al. Trans-heterozygous Pkd1 and Pk d2 mutations modify expression of polycystic kidney disease. Hum. Mol. Genet. 11, 1845–1854 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Thivierge, C. et al. Overexpression of PKD1 causes polycystic kidney disease. Mol. Cell Biol. 26, 1538–1548 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Burtey, S. et al. Overexpression of PKD2 in the mouse is associated with renal tubulopathy. Nephrol. Dial. Transplant. 23, 1157–1165 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Delmas, P. et al. Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J . Biol. Chem. 277, 11276–11283 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Sharif-Naeini, R. et al. Polycystin-1 and -2 dosage regulates pressure sensing. Cell 109, 587–596 (2009).

    Article  CAS  Google Scholar 

  98. Peyronnet, R. et al. Mechanoprotection by polycystins against apoptosis is mediated through the opening of stretch-activated K2P channels. Cell Reports 1, 241–250 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Streets, A. J., Wessely, O., Peters, D. J. & Ong, A. C. Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1 mediated dephosphorylation. Hum. Mol. Genet. 22, 1924–1939 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sise, C. et al. Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography. Kidney Int. 58, 2492–2501 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Grantham, J. J., Chapman, A. B. & Torres, V. E. Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. Clin. J. Am. Soc. Nephrol. 1, 148–157 (2006).

    Article  PubMed  Google Scholar 

  102. Leonhard, W. N. et al. Scattered deletion of Pkd1 in mouse kidneys causes a cystic snowball effect and recapitulates human polycystic kidney disease. J. Am. Soc. Nephrol. (in press).

  103. Nishio, S. et al. Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation. J. Clin. Invest. 115, 910–918 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Prasad, S., McDaid, J. P., Tam, F. W., Haylor, J. L. & Ong, A. C. Pkd2 dosage influences cellular repair responses following ischemia–reperfusion injury. Am. J. Pathol. 175, 1493–1503 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bastos, A. P. et al. Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. J. Am. Soc. Nephrol. 20, 2389–2402 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Takakura, A. et al. Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Hum. Mol. Genet. 18, 2523–2531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sharma, N. et al. Proximal tubule proliferation is insufficient to induce rapid cyst formation after cilia disruption. J. Am. Soc. Nephrol. 24, 456–464 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hwang, J. H. et al. Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease. BMC Nephrol. 14, 1 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Chow, C. L. & Ong, A. C. Autosomal dominant polycystic kidney disease. Clin. Med. 9, 278–283 (2009).

    Article  Google Scholar 

  110. Bolignano, D., Mattace-Raso, F., Sijbrands, E. J. & Zoccali, C. The aging kidney revisited: a systematic review. Ageing Res. Rev. 14, 65–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Gresh, L. et al. A transcriptional network in polycystic kidney disease. EMBO J. 23, 1657–1668 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hiesberger, T. et al. Mutation of hepatocyte nuclear factor-1β inhibits Pkhd1 gene expression and produces renal cysts in mice. J. Clin. Invest. 113, 814–825 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tran, U. et al. The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing mi R-17 activity. Development 137, 1107–1116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Qian, F. et al. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat. Genet. 16, 179–183 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V. P. & Walz, G. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc. Natl Acad. Sci. USA 94, 6965–6970 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Drenth, J. P., Te Morsche, R. H., Smink, R., Bonifacino, J. S. & Jansen, J. B. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat. Genet. 33, 345–347 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Li, A. et al. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am. J. Hum. Genet. 72, 691–703 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Davila, S. et al. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat. Genet. 36, 575–577 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Guirao, B. et al. Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. Nat. Cell Biol. 12, 341–350 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Happé, H., de Heer, E. & Peters, D. J. Polycystic kidney disease: the complexity of planar cell polarity and signaling during tissue regeneration and cyst formation. Biochim. Biophys. Acta 1812, 1249–1255 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Ma, M., Tian, X., Igarashi, P., Pazour, G. J. & Somlo, S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat. Genet. 45, 1004–1012 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37, 537–543 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 12, 1115–1122 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Germino, G. G. Linking cilia to Wnts. Nat. Genet. 37, 455–457 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Fischer, E. et al. Defective planar cell polarity in polycystic kidney disease. Nat. Genet. 38, 21–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Jonassen, J. A., San, A. J., Follit, J. A. & Pazour, G. J. Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease. J. Cell Biol. 183, 377–384 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Verdeguer, F. et al. A mitotic transcriptional switch in polycystic kidney disease. Nat. Med. 16, 106–110 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Luyten, A. et al. Aberrant regulation of planar cell polarity in polycystic kidney disease. J. Am . Soc. Nephrol. 21, 1521–1532 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Saburi, S. et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat. Genet. 40, 1010–1015 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Nishio, S. et al. Loss of oriented cell division does not initiate cyst formation. J. Am. Soc. Nephrol. 21, 295–302 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zeier, M. et al. Renal histology in polycystic kidney disease with incipient and advanced renal failure. Kidney Int. 42, 1259–1265 (1992).

    Article  CAS  PubMed  Google Scholar 

  133. Okada, H. et al. Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int. 58, 587–597 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Martinez, J. R. & Grantham, J. J. Polycystic kidney disease: etiology, pathogenesis, and treatment. Dis. Mon. 41, 693–765 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Karihaloo, A. et al. Macrophages promote cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 22, 1809–1814 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Swenson-Fields, K. I. et al. Macrophages promote polycystic kidney disease progression. Kidney Int. 83, 855–864 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mrug, M. et al. Overexpression of innate immune response genes in a model of recessive polycystic kidney disease. Kidney Int. 73, 63–76 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. De Heer, E. & Peters, D. J. Innate immunity as a driving force in renal disease. Kidney Int. 73, 7–8 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Ta, M. H., Harris, D. C. & Rangan, G. K. Role of interstitial inflammation in the pathogenesis of polycystic kidney disease. Nephrology (Carlton) 18, 317–330 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Drummond, I. A. Polycystins, focal adhesions and extracellular matrix interactions. Biochim. Biophys. Acta 1812, 1322–1326 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lee, K., Battini, L. & Gusella, G. L. Cilium, centrosome and cell cycle regulation in polycystic kidney disease. Biochim. Biophys. Acta 1812, 1263–1271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Rowe, I. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 19, 488–493 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yamaguchi, T. et al. Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int. 63, 1983–1994 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Arnould, T. et al. The polycystic kidney disease 1 gene product mediates protein kinase C α-dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1. J. Biol. Chem. 273, 6013–6018 (1998).

    Article  CAS  PubMed  Google Scholar 

  145. Parnell, S. C. et al. The polycystic kidney disease-1 protein, polycystin-1, binds and activates heterotrimeric G-proteins in vitro. Biochem. Biophys. Res. Commun. 251, 625–631 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Bhunia, A. K. et al. PKD1 induces p21waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109, 157–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Boca, M. et al. Polycystin-1 induces resistance to apoptosis through the phosphatidylinositol 3-kinase/Akt signaling pathway. J. Am. Soc. Nephrol. 17, 637–647 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Shillingford, J. M. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl Acad. Sci. USA 103, 5466–5471 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Renken, C., Fischer, D. C., Kundt, G., Gretz, N. & Haffner, D. Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrol. Dial. Transplant. 26, 92–100 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Leonhard, W. N. et al. Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model. Am. J. Physiol. Renal Physiol. 300, F1193–F1202 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Song, X. et al. Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum. Mol. Genet. 18, 2328–2343 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Lal, M. et al. Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling. Hum. Mol. Genet. 17, 3105–3117 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Happé, H. et al. Altered Hippo signalling in polycystic kidney disease. J. Pathol. 224, 133–142 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Weimbs, T. Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1. Am. J. Physiol. Renal Physiol. 293, F1423–F1432 (2007).

    Article  CAS  PubMed  Google Scholar 

  155. Chang, M. Y. & Ong, A. C. Mechanism-based therapeutics for autosomal dominant polycystic kidney disease: recent progress and future prospects. Nephron Clin. Pract. 120, c25–c34 (2012).

    Article  PubMed  Google Scholar 

  156. Chang, M. Y. & Ong, A. C. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and treatment. Nephron Physiol. 108, 1–7 (2008).

    Article  CAS  Google Scholar 

  157. Torres, V. E. & Harris, P. C. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 76, 149–168 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Pan, J., Seeger-Nukpezah, T. & Golemis, E. A. The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies. Cell. Mol. Life Sci. 70, 1849–1874 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Torres, V. E. & Harris, P. C. Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities. J. Intern. Med. 261, 17–31 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Hogan, M. C. et al. randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J. Am. Soc. Nephrol. 21, 1052–1061 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ruggenenti, P. et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 68, 206–216 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Torres, V. E. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407–2418 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. van Keimpema, L. et al. Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial. Gastroenterology 137, 1661–1668 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Caroli, A. et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet 382, 1485–1495 (2013).

    Article  CAS  PubMed  Google Scholar 

  167. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  168. US National Library of Medicine. ClinicalTrials.g ov [online], (2014).

  169. Leuenroth, S. J. et al. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc. Natl Acad. Sci. USA 104, 4389–4394 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wu, G. et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat. Genet. 24, 75–78 (2000).

    Article  CAS  PubMed  Google Scholar 

  171. Wodarczyk, C. et al. A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. PLoS ONE 4, e7137 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Khonsari, R. H. et al. Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd 2). Hum. Mol. Genet. 22, 1873–1885 (2013).

    Article  CAS  PubMed  Google Scholar 

  173. Spirli, C. et al. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology 138, 360–371 (2010).

    Article  CAS  PubMed  Google Scholar 

  174. Natoli, T. A. et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med. 16, 788–792 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Thomson, R. B. et al. Histopathological analysis of renal cystic epithelia in the Pkd2WS25/− mouse model of ADPKD. Am. J. Physiol. Renal Physiol. 285, F870–F880 (2003).

    Article  CAS  PubMed  Google Scholar 

  176. Gallagher, A. R. et al. A truncated polycystin-2 protein causes polycystic kidney disease and retinal degeneration in transgenic rats. J. Am. Soc. Nephrol. 17, 2719–2730 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Mouse Genome Informatics. informat ics.jax.org [online], (2014).

  178. Katsuyama, M., Masuyama, T., Komura, I., Hibino, T. & Takahashi, H. Characterization of a novel polycystic kidney rat model with accompanying polycystic liver. Exp. Anim. 49, 51–55 (2000).

    Article  CAS  PubMed  Google Scholar 

  179. Lager, D. J., Qian, Q., Bengal, R. J., Ishibashi, M. & Torres, V. E. The pck rat: a new model that resembles human autosomal dominant polycystic kidney and liver disease. Kidney Int. 59, 126–136 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Harris, P. C. Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Curr. Opin. Nephrol. Hypertens. 11, 309–314 (2002).

    Article  PubMed  Google Scholar 

  181. Coffinier, C. et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β. Development 129, 1829–1838 (2002).

    CAS  PubMed  Google Scholar 

  182. Patel, V. et al. miR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease. Proc. Natl Acad. Sci. USA 110, 10765–10770 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Coffinier, C., Thepot, D., Babinet, C., Yaniv, M. & Barra, J. Essential role for the homeoprotein vHNF1/HNF1β in visceral endoderm differentiation. Development 126, 4785–4794 (1999).

    CAS  PubMed  Google Scholar 

  184. Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1 β gene (TCF2) associated with MODY. Nat. Genet. 17, 384–385 (1997).

    Article  CAS  PubMed  Google Scholar 

  185. Nauta, J., Ozawa, Y., Sweeney, W. E. Jr, Rutledge, J. C. & Avner, E. D. Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease. Pediatr. Nephrol. 7, 163–172 (1993).

    Article  CAS  PubMed  Google Scholar 

  186. Flaherty, L., Bryda, E. C., Collins, D., Rudofsky, U. & Montogomery, J. C. New mouse model for polycystic kidney disease with both recessive and dominant gene effects. Kidney Int. 47, 552–558 (1995).

    Article  CAS  PubMed  Google Scholar 

  187. Hou, X. et al. Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J. Clin. Invest. 109, 533–540 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ricker, J. L., Gattone, V. H., Calvet, J. P. & Rankin, C. A. Development of autosomal recessive polycystic kidney disease in BALB/c-cpk/cpk mice. J. Am. Soc. Nephrol. 11, 1837–1847 (2000).

    CAS  PubMed  Google Scholar 

  189. Yokoyama, T. et al. Reversal of left-right asymmetry: a situs inversus mutation. Science 260, 679–682 (1993).

    Article  CAS  PubMed  Google Scholar 

  190. Morgan, D. et al. Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse. Nat. Genet. 20, 149–156 (1998).

    Article  CAS  PubMed  Google Scholar 

  191. Mochizuki, T. et al. Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 395, 177–181 (1998).

    Article  CAS  PubMed  Google Scholar 

  192. Takahashi, H. et al. A new mouse model of genetically transmitted polycystic kidney disease. J. Urol. 135, 1280–1283 (1986).

    Article  CAS  PubMed  Google Scholar 

  193. Bergmann, C. et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. A m. J. Hum. Genet. 82, 959–970 (2008).

    Article  CAS  Google Scholar 

  194. Janaswami, P. M. et al. Identification and genetic mapping of a new polycystic kidney disease on mouse chromosome 8. Genomics 40, 101–107 (1997).

    Article  CAS  PubMed  Google Scholar 

  195. Upadhya, P., Birkenmeier, E. H., Birkenmeier, C. S. & Barker, J. E. Mutations in a NIMA-related kinase gene, Nek1, cause pleiotropic effects including a progressive polycystic kidney disease in mice. Proc. Natl Acad. Sci. USA 97, 217–221 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Thiel, C. et al. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am. J. Hum. Genet. 88, 106–114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Chen, C. P. et al. Prenatal diagnosis and molecular genetic analysis of short rib-polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus with a homozygous splice site mutation in intron 4 in the NEK1 gene. Taiwan. J. Obstet. Gynecol. 51, 266–270 (2012).

    Article  PubMed  Google Scholar 

  198. Atala, A., Freeman, M. R., Mandell, J. & Beier, D. R. Juvenile cystic kidneys (jck): a new mouse mutation which causes polycystic kidneys. Kidney Int. 43, 1081–1085 (1993).

    Article  CAS  PubMed  Google Scholar 

  199. Moyer, J. H. et al. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science 264, 1329–1333 (1994).

    Article  CAS  PubMed  Google Scholar 

  200. Murcia, N. S. et al. The oak ridge polycystic kidney (orpk) disease gene is required for left-right axis determination. Development 127, 2347–2355 (2000).

    CAS  PubMed  Google Scholar 

  201. Cowley, B. D. et al. Autosomal-dominant polycystic kidney disease in the rat. Kidney Int. 43, 522–534 (1993).

    Article  PubMed  Google Scholar 

  202. Bihoreau, M. T. et al. Location of the first genetic locus, PKDr1, controlling autosomal dominant polycystic kidney disease in Han:SPRDcy/+ rat. Hum. Mol. Genet. 6, 609–613 (1997).

    Article  CAS  PubMed  Google Scholar 

  203. Hoff, S. et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat. Genet. 45, 951–956 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Nauta, J. et al. New rat model that phenotypically resembles autosomal recessive polycystic kidney disease. J. Am. Soc. Nephrol. 11, 2272–2284 (2000).

    CAS  PubMed  Google Scholar 

  205. Smith, U. M. et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38, 191–196 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The Developing Interventions to halt Progression of ADPKD (DIPAK) consortium is sponsored by the Dutch Kidney Foundation (grant number CP 10.1). We acknowledge the members of the consortium for support and the Dutch Kidney Foundation for funding.

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  1. Department of Human Genetics, Leiden University Medical Center, S4-P, PO Box 9600, Albinusdreef 2, Leiden, 2333 ZA, Leiden, Netherlands

    Hester Happé & Dorien J. M. Peters

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H.H. and D.J.M.P. contributed equally to researching data for the article, discussions of its content, writing the article and review and editing of the manuscript before submission.

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Happé, H., Peters, D. Translational research in ADPKD: lessons from animal models. Nat Rev Nephrol 10, 587–601 (2014). https://doi.org/10.1038/nrneph.2014.137

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