Advertisement

Cilia and Polycystic Kidney Disease

  • Dawn E. Landis
  • Scott J. Henke
  • Bradley K. YoderEmail author
Chapter

Abstract

The primary cilium is a nearly ubiquitous microtubule-based structure present on most mammalian cell types. The exact function of the primary cilium in the kidney is still being assessed, but data indicate that it is an important signaling and sensory center. The cilium allows cells to respond to external environmental cues by regulating a wide range of pathways, and the cilium has been implicated as a mechanosensor detecting fluid movement across the surface of cells. Pathways currently associated with the cilium include hedgehog, Jak/Stat, mTOR, purinergic, and planar cell polarity. The clinical importance of the cilium is evident by data showing that mutations in many ciliary proteins cause a group of disorders collectively called the ciliopathies, the most common of which is polycystic kidney disease (PKD). Patients with ciliopathies frequently exhibit cystic kidney and liver disease, but can also present with a wide spectrum of phenotypes and developmental defects. Currently it is unknown which of the many ciliary pathways are responsible for the development of cyst pathology. This chapter will discuss the current understanding of the role that primary cilia have in the kidney and models of how disruption of ciliary functions may contribute to cystogenesis.

Keywords

Primary cilium Polycystic kidney disease Ciliopathy Intraflagellar transport Signaling Kidney 

References

  1. 1.
    Haycraft CJ, Swoboda P, Taulman PD, Thomas JH, Yoder BK. The C. elegans homolog of the murine cystic kidney disease gene Tg737 functions in a ciliogenic pathway and is disrupted in osm-5 mutant worms. Development. 2001;128(9):1493–505.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Yoder BK, Hou X, Guay-Woodford LM. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol: JASN. 2002;13(10):2508–16.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Qin H, Rosenbaum JL, Barr MM. An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons. Curr Biol: CB. 2001;11. England:457–61.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. N Engl J Med. 2011;364(16):1533–43.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011;26(7):1039–56.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Takiar V, Caplan MJ. Polycystic kidney disease: pathogenesis and potential therapies. Biochim Biophys Acta. 2011;1812. Netherlands: 2010 Elsevier B.V:1337–43.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Fisch C, Dupuis-Williams P. Ultrastructure of cilia and flagella – back to the future! Biol Cell. 2011;103. England:249–70.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Singla V, Reiter JF. The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science. 2006;313:629–33.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Mukhopadhyay S, Rohatgi R. G-protein-coupled receptors, hedgehog signaling and primary cilia. Semin Cell Dev Biol. 2014;33:63–72.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Berbari NF, O’Connor AK, Haycraft CJ, Yoder BK. The primary cilium as a complex signaling center. Curr Biol: CB. 2009;19. England:R526–35.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Pazour GJ, Witman GB. The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol. 2003;15(1):105–10.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Rossman CM, Lee RM, Forrest JB, Newhouse MT. Nasal cilia in normal man, primary ciliary dyskinesia and other respiratory diseases: analysis of motility and ultrastructure. Eur J Respir Dis Suppl. 1983;127:64–70.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Escudier E, Duquesnoy P, Papon JF, Amselem S. Ciliary defects and genetics of primary ciliary dyskinesia. Paediatr Respir Rev. 2009;10(2):51–4.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Sharma N, Berbari NF, Yoder BK. Ciliary dysfunction in developmental abnormalities and diseases. Curr Top Dev Biol. 2008;85. United States:371–427.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Veland IR, Awan A, Pedersen LB, Yoder BK, Christensen ST. Primary cilia and signaling pathways in mammalian development, health and disease. Nephron Physiol. 2009;111. Switzerland:39–53.CrossRefGoogle Scholar
  16. 16.
    Taulman PD, Haycraft CJ, Balkovetz DF, Yoder BK. Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell. 2001;12(3):589–99.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Veerman AJ, van Delden L, Feenstra L, Leene W. The immotile cilia syndrome: phase contrast light microscopy, scanning and transmission electron microscopy. Pediatrics. 1980;65(4):698–702.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Delp MH. Kartagener’s triad; situs inversus, absent frontal sinuses with maxillary ethmoid and sphenoid infection, and bronchiectasis. J Kans Med Soc. 1946;47:93–6.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Lee L. Riding the wave of ependymal cilia: genetic susceptibility to hydrocephalus in primary ciliary dyskinesia. J Neurosci Res. 2013;91(9):1117–32.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Baccetti B, Afzelius BA. The biology of the sperm cell. Monogr Dev Biol. 1976;10:1–254.Google Scholar
  21. 21.
    Hirokawa N, Tanaka Y, Okada Y. Cilia, KIF3 molecular motor and nodal flow. Curr Opin Cell Biol. 2012;24(1):31–9.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Harvey RP. Links in the left/right axial pathway. Cell. 1998;94(3):273–6.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 1998;95(6):829–37.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Okada Y, Nonaka S, Tanaka Y, Saijoh Y, Hamada H, Hirokawa N. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell. 1999;4(4):459–68.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokawa N. Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis. J Cell Biol. 1999;145(4):825–36.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Raya A, Kawakami Y, Rodriguez-Esteban C, Ibanes M, Rasskin-Gutman D, Rodriguez-Leon J, et al. Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature. 2004;427(6970):121–8.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Takao D, Nemoto T, Abe T, Kiyonari H, Kajiura-Kobayashi H, Shiratori H, et al. Asymmetric distribution of dynamic calcium signals in the node of mouse embryo during left-right axis formation. Dev Biol. 2013;376(1):23–30.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Bataille S, Demoulin N, Devuyst O, Audrezet MP, Dahan K, Godin M, et al. Association of PKD2 (polycystin 2) mutations with left-right laterality defects. Am J Kidney Dis: Off J Natl Kidney Found. 2011;58(3):456–60.CrossRefGoogle Scholar
  29. 29.
    Schottenfeld J, Sullivan-Brown J, Burdine RD. Zebrafish curly up encodes a Pkd2 ortholog that restricts left-side-specific expression of southpaw. Development. 2007;134(8):1605–15.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, Horst J, et al. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr Biol. 2002;12(11):938–43.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Hoey DA, Downs ME, Jacobs CR. The mechanics of the primary cilium: an intricate structure with complex function. J Biomech. 2011. Elsevier Ltd. 45(1):17–26PubMedCrossRefGoogle Scholar
  32. 32.
    Inglis PN, Ou G, Leroux MR, Scholey JM. The sensory cilia of Caenorhabditis elegans. WormBook: Online Rev C elegans Biol. 2007;8:1–22.Google Scholar
  33. 33.
    Ostrowski LE, Dutcher SK, Lo CW. Cilia and models for studying structure and function. Proc Am Thorac Soc. 2011;8(5):423–9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Yamamoto M, Kataoka K. Electron microscopic observation of the primary cilium in the pancreatic islets. Arch Histologicum Japonicum = Nihon soshikigaku kiroku. 1986;49(4):449–57.Google Scholar
  35. 35.
    Williams CL, Masyukova SV, Yoder BK. Normal ciliogenesis requires synergy between the cystic kidney disease genes MKS-3 and NPHP-4. J Am Soc Nephrol: JASN. 2010;21. United States:782–93.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, et al. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol. 2011;192. United States:1023–41.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Rohlich P. The sensory cilium of retinal rods is analogous to the transitional zone of motile cilia. Cell Tissue Res. 1975;161(3):421–30.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Shiba D, Yamaoka Y, Hagiwara H, Takamatsu T, Hamada H, Yokoyama T. Localization of Inv in a distinctive intraciliary compartment requires the C-terminal ninein-homolog-containing region. J Cell Sci. 2009;122(Pt 1):44–54.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Blacque OE, Sanders AA. Compartments within a compartment: what C. elegans can tell us about ciliary subdomain composition, biogenesis, function, and disease. Organogenesis. 2014;10(1):126–37.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Jauregui AR, Nguyen KC, Hall DH, Barr MM. The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol. 2008;180(5):973–88.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Mukhopadhyay S, Lu Y, Qin H, Lanjuin A, Shaham S, Sengupta P. Distinct IFT mechanisms contribute to the generation of ciliary structural diversity in C. elegans. EMBO J. 2007;26(12):2966–80.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, Rosenbaum JL. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol. 1998;141(4):993–1008.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hao L, Acar S, Evans J, Ou G, Scholey JM. Analysis of intraflagellar transport in C. elegans sensory cilia. Methods Cell Biol. 2009;93:235–66.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Kozminski KG, Beech PL, Rosenbaum JL. The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J Cell Biol. 1995;131(6 Pt 1):1517–27.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Ou G, Blacque OE, Snow JJ, Leroux MR, Scholey JM. Functional coordination of intraflagellar transport motors. Nature. 2005;436(7050):583–7.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Scholey JM. Intraflagellar transport. Annu Rev Cell Dev Biol. 2003;19:423–43.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Ou G, Koga M, Blacque OE, Murayama T, Ohshima Y, Schafer JC, et al. Sensory ciliogenesis in Caenorhabditis elegans: assignment of IFT components into distinct modules based on transport and phenotypic profiles. Mol Biol Cell. 2007;18. United States:1554–69.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Delaval B, Bright A, Lawson ND, Doxsey S. The cilia protein IFT88 is required for spindle orientation in mitosis. Nat Cell Biol. 2011;13(4):461–8.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Jonassen JA, Sanagustin J, Baker SP, Pazour GJ. Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation. J Am Soc Nephrol: JASN. 2012;23(4):641–51.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Keady BT, Le YZ, Pazour GJ. IFT20 is required for opsin trafficking and photoreceptor outer segment development. Mol Biol Cell. 2011;22(7):921–30.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Finetti F, Paccani SR, Riparbelli MG, Giacomello E, Perinetti G, Pazour GJ, et al. Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nat Cell Biol. 2009;11(11):1332–9.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Follit JA, Tuft RA, Fogarty KE, Pazour GJ. The intraflagellar transport protein IFT20 is associated with the Golgi complex and is required for cilia assembly. Mol Biol Cell. 2006;17(9):3781–92.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Broekhuis JR, Rademakers S, Burghoorn J, Jansen G. SQL-1, homologue of the Golgi protein GMAP210, modulates intraflagellar transport in C. elegans. J Cell Sci. 2013;126(Pt 8):1785–95.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Deane JA, Cole DG, Seeley ES, Diener DR, Rosenbaum JL. Localization of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles. Curr Biol. 2001;11(20):1586–90.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, et al. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol. 2000;151(3):709–18.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Blacque OE, Li C, Inglis PN, Esmail MA, Ou G, Mah AK, et al. The WD repeat-containing protein IFTA-1 is required for retrograde intraflagellar transport. Mol Biol Cell. 2006;17(12):5053–62.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Piperno G, Siuda E, Henderson S, Segil M, Vaananen H, Sassaroli M. Distinct mutants of retrograde intraflagellar transport (IFT) share similar morphological and molecular defects. J Cell Biol. 1998;143(6):1591–601.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Halbritter J, Bizet AA, Schmidts M, Porath JD, Braun DA, Gee HY, et al. Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet. 2013;93(5):915–25.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Schmidts M, Vodopiutz J, Christou-Savina S, Cortes CR, McInerney-Leo AM, Emes RD, et al. Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am J Hum Genet. 2013;93(5):932–44.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A. 2008;105(11):4242–6.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Berbari NF, Johnson AD, Lewis JS, Askwith CC, Mykytyn K. Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors. Mol Biol Cell. 2008;19(4):1540–7.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Wojtyniak M, Brear AG, O’Halloran DM, Sengupta P. Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization in C. elegans. J Cell Sci. 2013;126(Pt 19):4381–95.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Jenkins PM, Zhang L, Thomas G, Martens JR. PACS-1 mediates phosphorylation-dependent ciliary trafficking of the cyclic-nucleotide-gated channel in olfactory sensory neurons. J Neurosci: Off J Soc Neurosci. 2009;29(34):10541–51.CrossRefGoogle Scholar
  64. 64.
    Nakamura T, Gold GH. A cyclic nucleotide-gated conductance in olfactory receptor cilia. Nature. 1987;325(6103):442–4.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Guadiana SM, Semple-Rowland S, Daroszewski D, Madorsky I, Breunig JJ, Mykytyn K, et al. Arborization of dendrites by developing neocortical neurons is dependent on primary cilia and type 3 adenylyl cyclase. J Neurosci: Off J Soc Neurosci. 2013;33(6):2626–38.CrossRefGoogle Scholar
  66. 66.
    Iwanaga T, Miki T, Takahashi-Iwanaga H. Restricted expression of somatostatin receptor 3 to primary cilia in the pancreatic islets and adenohypophysis of mice. Biomed Res. 2011;32(1):73–81.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Kwon RY, Temiyasathit S, Tummala P, Quah CC, Jacobs CR. Primary cilium-dependent mechanosensing is mediated by adenylyl cyclase 6 and cyclic AMP in bone cells. FASEB J: Off Publ Fed Am Soc Exp Biol. 2010;24(8):2859–68.CrossRefGoogle Scholar
  68. 68.
    Lazard D, Barak Y, Lancet D. Bovine olfactory cilia preparation: thiol-modulated odorant-sensitive adenylyl cyclase. Biochim Biophys Acta. 1989;1013(1):68–72.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Sklar PB, Anholt RR, Snyder SH. The odorant-sensitive adenylate cyclase of olfactory receptor cells. Differential stimulation by distinct classes of odorants. J Biol Chem. 1986;261(33):15538–43.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Wang Z, Phan T, Storm DR. The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J Neurosci: Off J Soc Neurosci. 2011;31(15):5557–61.CrossRefGoogle Scholar
  71. 71.
    Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. Vertebrate Smoothened functions at the primary cilium. Nature. 2005;437(7061):1018–21.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 2005;1(4):e53.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Huangfu D, Anderson KV. Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005;102(32):11325–30.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K, et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol. 2005;287(2):378–89.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Ward HH, Brown-Glaberman U, Wang J, Morita Y, Alper SL, Bedrick EJ, et al. A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1. Mol Biol Cell. 2011;22. United States:3289–305.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Verhey KJ, Dishinger J, Kee HL. Kinesin motors and primary cilia. Biochem Soc Trans. 2011;39. England:1120–5.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kee HL, Dishinger JF, Blasius TL, Liu CJ, Margolis B, Verhey KJ. A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia. Nat Cell Biol. 2012;14(4):431–7.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kee HL, Verhey KJ. Molecular connections between nuclear and ciliary import processes. Cilia. 2013;2(1):11.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Breslow DK, Koslover EF, Seydel F, Spakowitz AJ, Nachury MV. An in vitro assay for entry into cilia reveals unique properties of the soluble diffusion barrier. J Cell Biol. 2013;203(1):129–47.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Dishinger JF, Kee HL, Jenkins PM, Fan S, Hurd TW, Hammond JW, et al. Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol. 2010;12(7):703–10.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Fan S, Whiteman EL, Hurd TW, McIntyre JC, Dishinger JF, Liu CJ, et al. Induction of Ran GTP drives ciliogenesis. Mol Biol Cell. 2011;22(23):4539–48.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Najafi M, Maza NA, Calvert PD. Steric volume exclusion sets soluble protein concentrations in photoreceptor sensory cilia. Proc Natl Acad Sci U S A. 2012;109(1):203–8.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Francis SS, Sfakianos J, Lo B, Mellman I. A hierarchy of signals regulates entry of membrane proteins into the ciliary membrane domain in epithelial cells. J Cell Biol. 2011;193(1):219–33.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Duning K, Rosenbusch D, Schluter MA, Tian Y, Kunzelmann K, Meyer N, et al. Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS1-associated tight junction protein. J Biol Chem. 2010;285(44):33584–8.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Lin YC, Niewiadomski P, Lin B, Nakamura H, Phua SC, Jiao J, et al. Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. Nat Chem Biol. 2013;9(7):437–43.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Benzing T, Schermer B. Transition zone proteins and cilia dynamics. Nat Genet. 2011;43. United States:723–4.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Omran H. NPHP proteins: gatekeepers of the ciliary compartment. J Cell Biol. 2010;190. United States:715–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Winkelbauer ME, Schafer JC, Haycraft CJ, Swoboda P, Yoder BK. The C. elegans homologs of nephrocystin-1 and nephrocystin-4 are cilia transition zone proteins involved in chemosensory perception. J Cell Sci. 2005;118. England:5575–87.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, et al. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet. 2011;43(8):776–84.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Reiter JF, Skarnes WC. Tectonic, a novel regulator of the hedgehog pathway required for both activation and inhibition. Genes Dev. 2006;20(1):22–7.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2011;7(10):556–66.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, et al. Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol: JASN. 2006;17(4):1015–25.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996;87(6):979–87.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    AbouAlaiwi WA, Takahashi M, Mell BR, Jones TJ, Ratnam S, Kolb RJ, et al. Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ Res. 2009;104(7):860–9.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Leeuwen ISL-V, Leonhard WN, Avd W, Breuning MH, Heer ED, Peters DJM. Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum Mol Genet. 2007;16:3188–96.CrossRefGoogle Scholar
  96. 96.
    Sharma N, Malarkey EB, Berbari NF, O’Connor AK, GBV H, Mrug M, et al. Proximal tubule proliferation is insufficient to induce rapid cyst formation after cilia disruption. J Am Soc Nephrol. 2013;24:456–64.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet. 2002;30(3):259–69.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, et al. Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol: JASN. 2011;22(10):1809–14.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Rossetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol: JASN. 2007;18(5):1374–80.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Wheatley DN. Landmarks in the first hundred years of primary (9+0) cilium research. Cell Biol Int. 2005;29(5):333–9.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Moyer JH, Lee-Tischler MJ, Kwon HY, Schrick JJ, Avner ED, Sweeney WE, et al. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science. 1994;264(5163):1329–33.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Murcia NS, Richards WG, Yoder BK, Mucenski ML, Dunlap JR, Woychik RP. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Development. 2000;127(11):2347–55.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Yoder BK, Tousson A, Millican L, Wu JH, Bugg CE Jr, Schafer JA, et al. Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium. Am J Physiol Renal Physiol. 2002;282(3):F541–52.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Lehman JM, Michaud EJ, Schoeb TR, Aydin-Son Y, Miller M, Yoder BK. The oak ridge polycystic kidney mouse: modeling ciliopathies of mice and men. Dev Dyn: Off Publ Am Assoc Anatomists. 2008;237(8):1960–71.CrossRefGoogle Scholar
  105. 105.
    Barr MM, Sternberg PW. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature. 1999;401(6751):386–9.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Barr MM, DeModena J, Braun D, Nguyen CQ, Hall DH, Sternberg PW. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr Biol: CB. 2001;11(17):1341–6.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Ward CJ, Yuan D, Masyuk TV, Wang X, Punyashthiti R, Whelan S, et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet. 2003;12(20):2703–10.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Davenport JR, Watts AJ, Roper VC, Croyle MJ, van Groen T, Wyss JM, et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol: CB. 2007;17(18):1586–94.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Piontek KB, Huso DL, Grinberg A, Liu L, Bedja D, Zhao H, et al. A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J Am Soc Nephrol. 2004;15:3035–43.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med. 2007;13(12):1490–5.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Kim I, Ding T, Fu Y, Li C, Cui L, Li A, et al. Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin. J Am Soc Nephrol: JASN. 2009;20(12):2556–69.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Patel V, Li L, Cobo-Stark P, Shao X, Somlo S, Lin F, et al. Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum Mol Genet. 2008;17:1578–90.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet. 2013;45(9):1004–12.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Praetorius HA, Frokiaer J, Nielsen S, Spring KR. Bending the primary cilium opens Ca2+−sensitive intermediate-conductance K+ channels in MDCK cells. J Membr Biol. 2003;191(3):193–200.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Praetorius HA, Spring KR. Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol. 2003;191(1):69–76.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Praetorius HA, Spring KR. The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens. 2003;12(5):517–20.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003;33(2):129–37.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Xu C, Rossetti S, Jiang L, Harris PC, Brown-Glaberman U, Wandinger-Ness A, et al. Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling. Am J Physiol Renal Physiol. 2007;292(3):F930–45.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Yoshiba S, Shiratori H, Kuo IY, Kawasumi A, Shinohara K, Nonaka S, et al. Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science. 2012;338(6104):226–31.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Cano DA, Sekine S, Hebrok M. Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology. 2006;131(6):1856–69.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, et al. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest. 2004;114(10):1433–43.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Casuscelli J, Schmidt S, DeGray B, Petri ET, Celic A, Folta-Stogniew E, et al. Analysis of the cytoplasmic interaction between polycystin-1 and polycystin-2. Am J Physiol Renal Physiol. 2009;297(5):F1310–5.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Oatley P, Talukder MM, Stewart AP, Sandford R, Edwardson JM. Polycystin-2 induces a conformational change in polycystin-1. Biochemistry. 2013;52(31):5280–7.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Mamenko M, Zaika O, Jin M, O’Neil RG, Pochynyuk O. Purinergic activation of Ca2+-permeable TRPV4 channels is essential for mechano-sensitivity in the aldosterone-sensitive distal nephron. PLoS One. 2011;6(8):e22824.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cressman VL, Lazarowski E, Homolya L, Boucher RC, Koller BH, Grubb BR. Effect of loss of P2Y(2) receptor gene expression on nucleotide regulation of murine epithelial Cl(−) transport. J Biol Chem. 1999;274(37):26461–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Raghavan V, Rbaibi Y, Pastor-Soler NM, Carattino MD, Weisz OA. Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia. Proc Natl Acad Sci U S A. 2014;111(23):8506–11.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Burnstock G, Evans LC, Bailey MA. Purinergic signalling in the kidney in health and disease. Purinergic Signal. 2014;10(1):71–101.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Chang MY, Lu JK, Tian YC, Chen YC, Hung CC, Huang YH, et al. Inhibition of the P2X7 receptor reduces cystogenesis in PKD. J Am Soc Nephrol: JASN. 2011;22(9):1696–706.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103(14):5466–71.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Fischer DC, Jacoby U, Pape L, Ward CJ, Kuwertz-Broeking E, Renken C, et al. Activation of the AKT/mTOR pathway in autosomal recessive polycystic kidney disease (ARPKD). Nephrol Dial Transplant: Off Publ Eur Dial Transplant Assoc – Eur Renal Assoc. 2009;24(6):1819–27.CrossRefGoogle Scholar
  131. 131.
    Becker JU, Opazo Saez A, Zerres K, Witzke O, Hoyer PF, Schmid KW, et al. The mTOR pathway is activated in human autosomal-recessive polycystic kidney disease. Kidney Blood Press Res. 2010;33(2):129–38.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Dere R, Wilson PD, Sandford RN, Walker CL. Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. PLoS One. 2010;5(2):e9239.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Ong AC, Harris PC, Davies DR, Pritchard L, Rossetti S, Biddolph S, et al. Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue. Kidney Int. 1999;56(4):1324–33.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Bell PD, Fitzgibbon W, Sas K, Stenbit AE, Amria M, Houston A, et al. Loss of primary cilia upregulates renal hypertrophic signaling and promotes cystogenesis. J Am Soc Nephrol: JASN. 2011;22(5):839–48.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol. 2010;12(11):1115–22.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Serra AL, Poster D, Kistler AD, Krauer F, Raina S, Young J, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820–9.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):830–40.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Canaud G, Knebelmann B, Harris PC, Vrtovsnik F, Correas JM, Pallet N, et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: what is the appropriate serum level? Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2010;10(7):1701–6.CrossRefGoogle Scholar
  139. 139.
    Shillingford JM, Leamon CP, Vlahov IR, Weimbs T. Folate-conjugated rapamycin slows progression of polycystic kidney disease. J Am Soc Nephrol: JASN. 2012;23(10):1674–81.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Chuang PY, He JC. JAK/STAT signaling in renal diseases. Kidney Int. 2010;78. United States:231–4.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Wang H, Yang Y, Sharma N, Tarasova NI, Timofeeva OA, Winkler-Pickett RT, et al. STAT1 activation regulates proliferation and differentiation of renal progenitors. Cell Signal. 2010;22(11):1717–26.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell. 2002;109(2):157–68.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Kim H, Kang AY, Ko AR, Park HC, So I, Park JH, et al. Calpain-mediated proteolysis of polycystin-1 C-terminus induces JAK2 and ERK signal alterations. Exp Cell Res. 2014;320(1):62–8.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Talbot JJ, Shillingford JM, Vasanth S, Doerr N, Mukherjee S, Kinter MT, et al. Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci U S A. 2011;108(19):7985–90.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, et al. Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell. 2006;10(1):57–69.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Olsan EE, Mukherjee S, Wulkersdorfer B, Shillingford JM, Giovannone AJ, Todorov G, et al. Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease. Proc Natl Acad Sci U S A. 2011;108(44):18067–72.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Zeier M, Fehrenbach P, Geberth S, Mohring K, Waldherr R, Ritz E. Renal histology in polycystic kidney disease with incipient and advanced renal failure. Kidney Int. 1992;42(5):1259–65.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Ibrahim S. Increased apoptosis and proliferative capacity are early events in cyst formation in autosomal-dominant, polycystic kidney disease. Sci World J. 2007;7:1757–67.CrossRefGoogle Scholar
  149. 149.
    Zheng D, Wolfe M, Cowley BD Jr, Wallace DP, Yamaguchi T, Grantham JJ. Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease. J Am Soc Nephrol: JASN. 2003;14(10):2588–95.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Meijer E, Boertien WE, Nauta FL, Bakker SJ, van Oeveren W, Rook M, et al. Association of urinary biomarkers with disease severity in patients with autosomal dominant polycystic kidney disease: a cross-sectional analysis. Am J Kidney Dis: Off J Natl Kidney Found. 2010;56(5):883–95.CrossRefGoogle Scholar
  151. 151.
    Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol: JASN. 2011;22(2):317–26.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    May-Simera H, Kelley MW. Examining planar cell polarity in the mammalian cochlea. Methods Mol Biol. 2012;839:157–71.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    McNeill H. Planar cell polarity and the kidney. J Am Soc Nephrol: JASN. 2009;20(10):2104–11.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Carroll TJ, Yu J. The kidney and planar cell polarity. Curr Top Dev Biol. 2012;101:185–212.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Goggolidou P. Wnt and planar cell polarity signaling in cystic renal disease. Organogenesis. 2014;10(1):86–95.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, Carroll TJ. Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet. 2009;41(7):793–9.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Adler PN, Krasnow RE, Liu J. Tissue polarity points from cells that have higher frizzled levels towards cells that have lower frizzled levels. Curr Biol. 1997;7(12):940–9.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Vinson CR, Adler PN. Directional non-cell autonomy and the transmission of polarity information by the frizzled gene of Drosophila. Nature. 1987;329(6139):549–51.PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Borovina A, Superina S, Voskas D, Ciruna B. Vangl2 directs the posterior tilting and asymmetric localization of motile primary cilia. Nat Cell Biol. 2010;12(4):407–12.PubMedCrossRefGoogle Scholar
  160. 160.
    Cui C, Chatterjee B, Lozito TP, Zhang Z, Francis RJ, Yagi H, et al. Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton. PLoS Biol. 2013;11(11):e1001720.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Jones C, Roper VC, Foucher I, Qian D, Banizs B, Petit C, et al. Ciliary proteins link basal body polarization to planar cell polarity regulation. Nat Genet. 2008;40(1):69–77.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, et al. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet. 2005;37(10):1135–40.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Borovina A, Ciruna B. IFT88 plays a cilia- and PCP-independent role in controlling oriented cell divisions during vertebrate embryonic development. Cell Rep. 2013;5(1):37–43.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Romaker D, Puetz M, Teschner S, Donauer J, Geyer M, Gerke P, et al. Increased expression of secreted frizzled-related protein 4 in polycystic kidneys. J Am Soc Nephrol: JASN. 2009;20(1):48–56.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Fischer E, Legue E, Doyen A, Nato F, Nicolas JF, Torres V, et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet. 2006;38(1):21–3.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Mao Y, Mulvaney J, Zakaria S, Yu T, Morgan KM, Allen S, et al. Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development. 2011;138(5):947–57.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Saburi S, Hester I, Fischer E, Pontoglio M, Eremina V, Gessler M, et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat Genet. 2008;40(8):1010–5.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Mei X, Westfall TA, Zhang Q, Sheffield VC, Bassuk AG, Slusarski DC. Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms. Dev Biol. 2014;392(2):245–55.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Nishio S, Tian X, Gallagher AR, Yu Z, Patel V, Igarashi P, et al. Loss of oriented cell division does not initiate cyst formation. J Am Soc Nephrol: JASN. 2010;21(2):295–302.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Tripathi P, Guo Q, Wang Y, Coussens M, Liapis H, Jain S, et al. Midline signaling regulates kidney positioning but not nephrogenesis through Shh. Dev Biol. 2010;340(2):518–27.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Cain JE, Islam E, Haxho F, Blake J, Rosenblum ND. GLI3 repressor controls functional development of the mouse ureter. J Clin Invest. 2011;121(3):1199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Cain JE, Islam E, Haxho F, Chen L, Bridgewater D, Nieuwenhuis E, et al. GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells. PLoS One. 2009;4(10):e7313.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Hu MC, Mo R, Bhella S, Wilson CW, Chuang PT, Hui CC, et al. GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development. 2006;133(3):569–78.PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Yu J, Carroll TJ, McMahon AP. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development. 2002;129(22):5301–12.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Cohen MM Jr. Hedgehog signaling update. Am J Med Genet A. 2010;152A(8):1875–914.PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Tran PV, Talbott GC, Turbe-Doan A, Jacobs DT, Schonfeld MP, Silva LM, et al. Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models. J Am Soc Nephrol: JASN. 2014;25:2201–12.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Ozturk H, Tuncer MC, Buyukbayram H. Nitric oxide regulates expression of sonic hedgehog and hypoxia-inducible factor-1alpha in an experimental model of kidney ischemia-reperfusion. Ren Fail. 2007;29(3):249–56.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Zhou D, Li Y, Zhou L, Tan RJ, Xiao L, Liang M, et al. Sonic hedgehog is a novel tubule-derived growth factor for interstitial fibroblasts after kidney injury. J Am Soc Nephrol. 2014;25:2187–200.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Raychowdhury MK, Ramos AJ, Zhang P, McLaughin M, Dai XQ, Chen XZ, et al. Vasopressin receptor-mediated functional signaling pathway in primary cilia of renal epithelial cells. Am J Physiol Renal Physiol. 2009;296(1):F87–97.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Nedvetsky PI, Tamma G, Beulshausen S, Valenti G, Rosenthal W, Klussmann E. Regulation of aquaporin-2 trafficking. Handb Exp Pharmacol. 2009;190:133–57.CrossRefGoogle Scholar
  181. 181.
    Saigusa T, Reichert R, Guare J, Siroky BJ, Gooz M, Steele S, et al. Collecting duct cells that lack normal cilia have mislocalized vasopressin-2 receptors. Am J Physiol Renal Physiol. 2012;302(7):F801–8.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Marion V, Schlicht D, Mockel A, Caillard S, Imhoff O, Stoetzel C, et al. Bardet-Biedl syndrome highlights the major role of the primary cilium in efficient water reabsorption. Kidney Int. 2011;79(9):1013–25.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Calvet JP. Strategies to inhibit cyst formation in ADPKD. Clin J Am Soc Nephrol. 2008;3(4):1205–11.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    D’Angelo A, Mioni G, Ossi E, Lupo A, Valvo E, Maschio G. Alterations in renal tubular sodium and water transport in polycystic kidney disease. Clin Nephrol. 1975;3(3):99–105.PubMedPubMedCentralGoogle Scholar
  185. 185.
    Yamaguchi T, Nagao S, Kasahara M, Takahashi H, Grantham JJ. Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am J Kidney Dis. 1997;30(5):703–9.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Chen NX, Moe SM, Eggleston-Gulyas T, Chen X, Hoffmeyer WD, Bacallao RL, et al. Calcimimetics inhibit renal pathology in rodent nephronophthisis. Kidney Int. 2011;80(6):612–9.PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Aihara M, Fujiki H, Mizuguchi H, Hattori K, Ohmoto K, Ishikawa M, et al. Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury. J Pharmacol Exp Ther. 2014;349(2):258–67.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol: JASN. 2014;26:39–47.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Sabbatini M, Russo L, Cappellaio F, Troncone G, Bellevicine C, De Falco V, et al. Effects of combined administration of rapamycin, tolvaptan, and AEZ-131 on the progression of polycystic disease in PCK rats. Am J Physiol Renal Physiol. 2014;306(10):F1243–50.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Dawn E. Landis
    • 1
  • Scott J. Henke
    • 1
  • Bradley K. Yoder
    • 1
    Email author
  1. 1.Department of Cell, Developmental and Integrative BiologyUniversity of Alabama at Birmingham Medical SchoolBirminghamUSA

Personalised recommendations