Translational research in ADPKD: Lessons from animal models

Nature Reviews Nephrology

Volumn 10, Issue 10, 2014, Pages 587-601

  Happé, Hester ^a   Peters, Dorien J M ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

POLYCYSTIN 1; POLYCYSTIN 2; POLYCYSTIC KIDNEY DISEASE 1 PROTEIN; POLYCYSTIC KIDNEY DISEASE 2 PROTEIN; POLYCYSTIN;

ANIMAL MODEL; CELL POLARITY; EPITHELIUM CELL; EUKARYOTIC FLAGELLUM; EXPERIMENTAL NEPHRITIS; EXPERIMENTAL RENAL FIBROSIS; EXPERIMENTAL UROGENITAL DISEASE; GENE DISRUPTION; GENE INACTIVATION; GENE INTERACTION; GENE OVEREXPRESSION; GENETIC MODEL; GENOTYPE PHENOTYPE CORRELATION; HUMAN; KIDNEY INJURY; KIDNEY POLYCYSTIC DISEASE; KINETICS; MOLECULAR PATHOLOGY; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW; RODENT MODEL; SIGNAL TRANSDUCTION; TRANSLATIONAL RESEARCH; ANIMAL; DISEASE COURSE; DISEASE MODEL; GENE DOSAGE; GENE EXPRESSION; GENETICS; MOUSE; MUTATION;

ANIMALS; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; GENE DOSAGE; GENE EXPRESSION; MICE; MUTATION; POLYCYSTIC KIDNEY, AUTOSOMAL DOMINANT; TRPP CATION CHANNELS;

EID: 84926250149     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2014.137     Document Type: Review

References (205)

1. Torres, V. E., Harris, P. C. & Pirson, Y. Autosomal dominant polycystic kidney disease. Lancet 369, 1287-1301 (2007).
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).
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).
5. Collins, A. J. et al. US Renal Data System 2010 Annual Data Report. Am. J. Kidney Dis. 57 (Suppl. 1), e1-e526 (2011).
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).
7. Ravine, D. et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 343,824-827 (1994).
8. Nicolau, C. et al. Abdominal sonographic study of autosomal dominant polycystic kidney disease. J. Clin. Ultrasound 28, 277-282 (2000).
9. Danaci, M. et al. The prevalence of seminal vesicle cysts in autosomal dominant polycystic kidney disease. Nephrol. Dial. Transplant. 13, 2825-2828 (1998).
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).
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).
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).
13. Alehan, F. K., Gurakan, B. & Agildere, M. Familial arachnoid cysts in association with autosomal dominant polycystic kidney disease. Pediatrics 110, e3 (2002).
14. Ecder, T. & Schrier, R. W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol. 5, 221-228 (2009).
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).
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).
17. Watnick, T. et al. Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Nat. Genet. 25, 143-144 (2000).
18. Ong, A. C. & Harris, P. C. Molecular basis of renal cyst formation-one hit or two? Lancet 349, 1039-1040 (1997).
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).
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).
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).
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).
23. Cornec-Le Gall, E. et al. Type of PKD1 mutation influences renal outcome in ADPKD. J. Am. Soc. Nephrol. 24, 1006-1013 (2013).
24. Hateboer, N. et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet 353, 103-107 (1999).
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).
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).
27. Vujic, M. et al. Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD. J. Am. Soc. Nephrol. 21, 1097-1102 (2010).
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).
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).
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).
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).
32. Lu, W. et al. Late onset of renal and hepatic cysts in Pkd1-targeted heterozygotes. Nat. Genet. 21, 160-161 (1999).
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).
34. Muto, S. et al. Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Hum. Mol. Genet. 11, 1731-1742 (2002).
35. Lantinga-van Leeuwen, I. S. et al. 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. 16, 3188-3196 (2007).
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).
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).
38. Wu, G. et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177-188 (1998).
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).
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).
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).
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).
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).
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).
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).
46. Kim, I. et al. Conditional mutation of Pkd2 causes cystogenesis and upregulates β-catenin. J. Am. Soc. Nephrol. 20, 2556-2569 (2009).
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).
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).
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).
50. Hassane, S. et al. Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension. Lab. Invest. 91, 24-32 (2011).
51. Garcia-Gonzalez, M. A. et al. Pkd1 and Pkd2 are required for normal placental development. PLoS ONE 5, e12821 (2010).
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).
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).
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).
55. Hopp, K. et al. Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J. Clin. Invest. 122, 4257-4273 (2012).
56. Herron, B. J. et al. Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis. Nat.Genet. 30, 185-189 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
66. Gallagher, A. R. et al. Biliary and pancreatic dysgenesis in mice harboring a mutation in Pkhd1. Am. J. Pathol. 172, 417-429 (2008).
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).
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).
69. Moser, M. et al. A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 41, 1113-1121 (2005).
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).
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).
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).
73. Otto, E. A. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking cilia and left-right axis determination. Nat. Genet. 34, 413-420 (2003).
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).
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).
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).
77. Phillips, C. L. et al. Renal cysts of inv/inv mice resemble early infantile nephronophthisis. J. Am. Soc. Nephrol. 15, 1744-1755 (2004).
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).
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).
80. Guay-Woodford, L. M. et al. Evidence that two phenotypically distinct mouse PKD mutations, bpk and jcpk, are allelic. Kidney Int. 50, 1158-1165 (1996).
81. Torres, V. E. et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 10, 363-364 (2004).
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).
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).
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).
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).
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).
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).
88. Happé, H. et al. Cyst expansion and regression in a mouse model of polycystic kidney disease. Kidney Int. 83, 1099-1108 (2013).
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).
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).
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).
92. Pei, Y. et al. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am. J. Hum. Genet. 68, 355.363 (2001).
93. Wu, G. et al. Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Hum. Mol. Genet. 11, 1845.1854 (2002).
94. Thivierge, C. et al. Overexpression of PKD1 causes polycystic kidney disease. Mol. Cell Biol. 26, 1538.1548 (2006).
95. Burtey, S. et al. Overexpression of PKD2 in the mouse is associated with renal tubulopathy. Nephrol. Dial. Transplant. 23, 1157.1165 (2008).
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).
97. Sharif-Naeini, R. et al. Polycystin-1 and -2 dosage regulates pressure sensing. Cell 109, 587.596 (2009).
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).
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).
100. Sise, C. et al. Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography. Kidney Int. 58, 2492.2501 (2000).
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).
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).
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).
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).
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).
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).
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).
109. Chow, C. L. & Ong, A. C. Autosomal dominant polycystic kidney disease. Clin. Med. 9, 278.283 (2009).
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).
111. Gresh, L. et al. A transcriptional network in polycystic kidney disease. EMBO J. 23,1657.1668 (2004)
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).
113. Tran, U. et al. The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity. Development 137, 1107-1116 (2010).
114. Qian, F. et al. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat. Genet. 16, 179-183 (1997).
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).
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).
117. Li, A. et al. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am. J. Hum. Genet. 72, 691-703 (2003).
118. Davila, S. et al. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat. Genet. 36, 575-577 (2004).
119. Guirao, B. et al. Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. Nat. Cell Biol. 12, 341-350 (2010).
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).
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).
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).
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).
124. Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 12, 1115-1122 (2010).
125. Germino, G. G. Linking cilia to Wnts. Nat. Genet. 37, 455-457 (2005).
126. Fischer, E. et al. Defective planar cell polarity in polycystic kidney disease. Nat. Genet. 38, 21-23 (2006).
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).
128. Verdeguer, F. et al. A mitotic transcriptional switch in polycystic kidney disease. Nat. Med. 16, 106-110 (2010).
129. Luyten, A. et al. Aberrant regulation of planar cell polarity in polycystic kidney disease. J. Am. Soc. Nephrol. 21, 1521-1532 (2010)
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).
131. Nishio, S. et al. Loss of oriented cell division does not initiate cyst formation. J. Am. Soc. Nephrol. 21, 295-302 (2010).
132. Zeier, M. et al. Renal histology in polycystic kidney disease with incipient and advanced renal failure. Kidney Int. 42, 1259-1265 (1992).
133. Okada, H. et al. Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation. Kidney Int. 58, 587-597 (2000).
134. Martinez, J. R. & Grantham, J. J. Polycystic kidney disease: etiology, pathogenesis, and treatment. Dis. Mon. 41, 693-765 (1995).
135. Karihaloo, A. et al. Macrophages promote cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 22, 1809-1814 (2011).
136. Swenson-Fields, K. I. et al. Macrophages promote polycystic kidney disease progression. Kidney Int. 83, 855-864 (2013).
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).
138. De Heer, E. & Peters, D. J. Innate immunity as a driving force in renal disease. Kidney Int. 73, 7-8 (2008).
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).
140. Drummond, I. A. Polycystins, focal adhesions and extracellular matrix interactions. Biochim. Biophys. Acta 1812, 1322-1326 (2011).
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).
142. Rowe, I. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 19, 488-493 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
153. Happé, H. et al. Altered Hippo signalling in polycystic kidney disease. J. Pathol. 224,133-142 (2011).
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).
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).
156. Chang, M. Y. & Ong, A. C. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and treatment. Nephron Physiol. 108, 1-7 (2008).
157. Torres, V. E. & Harris, P. C. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 76, 149-168 (2009).
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).
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).
160. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830-840 (2010).
161. Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820-829 (2010).
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).
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).
164. Torres, V. E. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407-2418 (2012).
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).
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).
167. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01233869 (2014).
168. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02115659 (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).
170. Wu, G. et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat. Genet. 24, 75-78 (2000).
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).
172. Khonsari, R. H. et al. Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2). Hum. Mol. Genet. 22, 1873-1885 (2003)
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).
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).
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).
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).
177. Mouse Genome Informatics. informatics.jax.org [online], http://www.informatics.jax.org/phenotypes.shtml (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).
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).
180. Harris, P. C. Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Curr. Opin. Nephrol. Hypertens. 11, 309-314 (2002).
181. Coffinier, C. et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β. Development 129, 1829-1838 (2002).
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).
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).
184. Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1 β gene (TCF2) associated with MODY. Nat. Genet. 17, 384-385 (1997).
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).
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).
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).
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).
189. Yokoyama, T. et al. Reversal of left-right asymmetry: a situs inversus mutation. Science 260, 679-682 (1993).
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).
191. Mochizuki, T. et al. Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 395, 177-181
192. Takahashi, H. et al. A new mouse model of genetically transmitted polycystic kidney disease. J. Urol. 135, 1280-1283 (1986).
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. Am. J. Hum. Genet. 82, 959-970 (2008).
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).
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).
196. Thiel, C. et al. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am. J. Hum. Genet. 88, 106-114 (2011).
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).
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).
199. Moyer, J. H. et al. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. Science 264, 1329-1333 (1994).
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).
201. Cowley, B. D. et al. Autosomal-dominant polycystic kidney disease in the rat. Kidney Int. 43, 522-534 (1993)
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).
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).
204. Nauta, J. et al. New rat model that phenotypically resembles autosomal recessive polycystic kidney disease. J. Am. Soc. Nephrol. 11, 2272-2284 (2000).
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).