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Cell and Tissue Research

, Volume 326, Issue 3, pp 671–685 | Cite as

Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD)

  • William E. SweeneyJr
  • Ellis D. Avner
Review

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes characterized by dual renal and hepatic involvement of variable severity. Despite the wide clinical spectrum of ARPKD (MIM 263200), genetic linkage studies indicate that mutations at a single locus, PKHD1 (polycystic kidney and hepatic disease 1), located on human chromosome region 6p21.1–p12, are responsible for all phenotypes of ARPKD. Identification of cystic disease genes and their encoded proteins has provided investigators with critical tools to begin to unravel the molecular and cellular mechanisms of PKD. PKD cystic epithelia share common phenotypic abnormalities despite the different genetic mutations that underlie the disease. Recent studies have shown that many cyst-causing proteins are expressed in multimeric complexes at distinct subcellular locations within epithelia. This co-expression of cystoproteins suggests that cyst formation, regardless of the underlying disease gene, results from perturbations in convergent and/or integrated signal transduction pathways. To date, no specific therapies are in clinical use for ameliorating cyst growth in ARPKD. However, studies noted in this review suggest that therapeutic targeting of the cAMP and epidermal growth factor receptor (EGFR)-axis abnormalities in cystic epithelia may translate into effective therapies for ARPKD and, by analogy, autosomal dominant polycystic kidney disease (ADPKD). A particularly promising approach appears to be the targeting of downstream intermediates of both the cAMP and EGFR axis. This review focuses on ARPKD and presents a concise summary of the current understanding of the molecular genetics and cellular pathophysiology of this disease. It also highlights phenotypic and mechanistic similarities between ARPKD and ADPKD.

Keywords

Autosomal recessive polycystic kidney disease Autosomal dominant polycystic kidney disease Molecular genetics Cellular pathophysiology Phenotype Disease mechanism 

References

  1. Adeva M, El-Youssef M, Rosetti S, Kamath PS, Kubly V, Consugar MB, Milliner DM, King BF, Torres VE, Harris PC (2006) Clinical and molecular characterizations defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine 85:1–21PubMedGoogle Scholar
  2. Belibi FA, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H, Helmkamp GM Jr, Grantham JJ (2004) Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int 66:964–973PubMedGoogle Scholar
  3. Bergmann C, Senderek J, Sedlacek B, Pegiazoglou I, Puglia P, Eggermann T, Rudnik-Schoneborn S, Furu L, Onuchic LF, De Baca M, Germino GG, Guay-Woodford L, Somlo S, Moser M, Buttner R, Zerres K (2003) Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). J Am Soc Nephrol 14:76–89PubMedGoogle Scholar
  4. Bergmann C, Senderek J, Kupper F, Schneider F, Dornia C, Windelen E, Eggermann T, Rudnik-Schoneborn S, Kirfel J, Furu L, Onuchic LF, Rossetti S, Harris PC, Somlo S, Guay-Woodford L, Germino GG, Moser M, Buttner R, Zerres K (2004a) PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 23:453–463PubMedGoogle Scholar
  5. Bergmann C, Senderek J, Schneider F, Dornia C, Kupper F, Eggermann T, Rudnik-Schoneborn S, Kirfel J, Moser M, Buttner R, Zerres K (2004b) PKHD1 mutations in families requesting prenatal diagnosis for autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 23:487–495PubMedGoogle Scholar
  6. Bergmann C, Kupper F, Dornia C, Schneider F, Senderek J, Zerres K (2005a) Algorithm for efficient PKHD1 mutation screening in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 25:225–231PubMedGoogle Scholar
  7. Bergmann C, Kupper F, Schmitt CP, Vester U, Neuhaus TJ, Senderek J, Zerres K (2005b) Multi-exon deletions of the PKHD1 gene cause autosomal recessive polycystic kidney disease (ARPKD). J Med Genet 42:e63PubMedGoogle Scholar
  8. Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, Dornia C, Rudnik-Schoneborn S, Konrad M, Schmitt CP, Seeman T, Neuhaus TJ, Vester U, Kirfel J, Buttner R, Zerres K (2005c) Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int 67:829–848PubMedGoogle Scholar
  9. Bernstein J, Slovis TL (1992) Polycystic diseases of the kidney. In: Edelmann C (ed) Pediatric kidney diseases. Little, Brown, Boston, pp 1139–1157Google Scholar
  10. Blyth H, Ockenden BG (1971) Polycystic disease of kidneys and liver presenting in childhood. J Med Genet 8:257–284PubMedCrossRefGoogle Scholar
  11. Boschelli DH, Wu B, Barrios Sosa AC, Chen JJ, Golas JM, Boschelli F (2005a) Inhibition of Src kinase activity by 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-heteroaryl-thieno[3,2-b]pyridine-6-carbonitriles. Bioorg Med Chem Lett 15:4681–4684PubMedGoogle Scholar
  12. Boschelli DH, Wu B, Barrios Sosa AC, Durutlic H, Chen JJ, Wang Y, Golas JM, Lucas J, Boschelli F (2005b) Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles. J Med Chem 48:3891–3902PubMedGoogle Scholar
  13. Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC (1992) Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 257:1125–1128PubMedGoogle Scholar
  14. Cole BR, Conley SB, Stapleton FB (1987) Polycystic kidney disease in the first year of life. J Pediatr 111:693–699PubMedGoogle Scholar
  15. Davis ID, MacRae Dell K, Sweeney WE, Avner ED (2001) Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented? Semin Nephrol 21:430–440PubMedGoogle Scholar
  16. Davis ID, Ho M, Hupertz V, Avner ED (2003) Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease. Pediatr Transplant 7:364–369PubMedGoogle Scholar
  17. Dell K, Avner E (2003) Autosomal recessive polycystic kidney disease gene reviews; genetic disease online reviews at gene tests-gene clinics. University of Washington, SeattleGoogle Scholar
  18. Dell KM, Nemo R, Sweeney WE, Levin JI, Frost P, Avner ED (2001) A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease. Kidney Int 60:1240–1248PubMedGoogle Scholar
  19. Dell K, McDonald R, Watkins SL, Avner ED (2004) Polycystic kidney disease. In: Avner ED, Harmon WE, Niaudet P (eds) Pediatric nephrology. Lippincott Williams & Wilkins, Philadelphia, pp 675–699Google Scholar
  20. Desmet VJ (1992) Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”. Hepatology 16:1069–1083PubMedGoogle Scholar
  21. Du J, Wilson PD (1995) Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD. Am J Physiol 269:C487–C495PubMedGoogle Scholar
  22. Furu L, Onuchic LF, Gharavi A, Hou X, Esquivel EL, Nagasawa Y, Bergmann C, Senderek J, Avner E, Zerres K, Germino GG, Guay-Woodford LM, Somlo S (2003) Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol 14:2004–2014PubMedGoogle Scholar
  23. Gabow PA (1993) Autosomal dominant polycystic kidney disease. N Engl J Med 329:332–342PubMedGoogle Scholar
  24. Gattone VH 2nd, Kuenstler KA, Lindemann GW, Lu X, Cowley BD Jr, Rankin CA, Calvet JP (1996) Renal expression of a transforming growth factor-alpha transgene accelerates the progression of inherited, slowly progressive polycystic kidney disease in the mouse. J Lab Clin Med 127:214–222PubMedGoogle Scholar
  25. Gattone VH 2nd, Wang X, Harris PC, Torres VE (2003) Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 9:1323–1326PubMedGoogle Scholar
  26. Grantham JJ (1996) The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: recent advances. Am J Kidney Dis 28:788–803PubMedGoogle Scholar
  27. Grantham JJ (1997a) Mechanisms of progression in autosomal dominant polycystic kidney disease. Kidney Int Suppl 63:S93–S97PubMedGoogle Scholar
  28. Grantham JJ (1997b) Renal cell proliferation and the two faces of cyclic adenosine monophosphate. J Lab Clin Med 130:460–469Google Scholar
  29. Grantham JJ (2000) Time to treat polycystic kidney diseases like the neoplastic disorders that they are. Kidney Int 57:339–340PubMedGoogle Scholar
  30. Grantham JJ, Geiser JL, Evan AP (1987) Cyst formation and growth in autosomal dominant polcystic kidney disease. Kidney Int 31:1145–1152PubMedGoogle Scholar
  31. Grantham JJ, Ye M, Davidow C, Holub B, Sharma M (1995) Evidence for a potent lipid secretagogue in the cyst fluids of patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 6:1242–1249PubMedGoogle Scholar
  32. Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD, Vojtek AB (2000) Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem 275:27354–27359PubMedGoogle Scholar
  33. Guay-Woodford L (1996) Autosomal recessive polycystic kidney disease. In: Watson M, Torres VH (eds) Polycystic kidney disease. Oxford University Press, New YorkGoogle Scholar
  34. Guay-Woodford LM (2003) Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285:F1034–F1049PubMedGoogle Scholar
  35. Guay-Woodford LM, Desmond RA (2003) Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 111:1072–1080PubMedGoogle Scholar
  36. Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, Herrin J, Holleman R, Irons DA, Primack W, Thomson PD, Waldo FB, Lunt PW, Zerres K (1995) The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1–p12: implications for genetic counseling. Am J Hum Genet 56:1101–1107PubMedGoogle Scholar
  37. Gunay-Aygun M, Avner ED, Bacallao RL, et al (2006) Autosomal recessive polycystic kidney disease NIH symposium summary statement. J Pediatr (in press)Google Scholar
  38. Harris PC, Rossetti S (2004) Molecular genetics of autosomal recessive polycystic kidney disease. Mol Genet Metab 81:75–85PubMedGoogle Scholar
  39. Hiesberger T, Bai Y, Shao X, McNally BT, Sinclair AM, Tian X, Somlo S, Igarashi P (2004) Mutation of hepatocyte nuclear factor-1{beta} inhibits Pkhd1 gene expression and produces renal cysts in mice. J Clin Invest 113:814–825PubMedGoogle Scholar
  40. Hildebrandt F, Otto E (2005) Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet 6:928–940PubMedCrossRefGoogle Scholar
  41. Hogan MC, Griffin MD, Rossetti S, Torres VE, Ward CJ, Harris PC (2003) PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression. Hum Mol Genet 12:685–698PubMedGoogle Scholar
  42. Igarashi P, Somlo S (2002) Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13:2384–2398PubMedGoogle Scholar
  43. Igarashi P, Shao X, McNally BT, Hiesberger T (2005) Roles of HNF-1beta in kidney development and congenital cystic diseases. Kidney Int 68:1944–1947PubMedGoogle Scholar
  44. Jafar TH, Stark PC, Schmid CH, Strandgaard S, Kamper AL, Maschio G, Becker G, Perrone RD, Levey AS (2005) The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease. Kidney Int 67:265–271PubMedGoogle Scholar
  45. Jiang ST, Chiou YY, Wang E, Lin HK, Lin YT, Chi YC, Wang CK, Tang MJ, Li H (2006) Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of pkd1. Am J Pathol 168:205–220PubMedGoogle Scholar
  46. Jorgensen MJ (1977) The ductal plate malformation. Acta Pathol Microbiol Scand Suppl 257:1–87PubMedGoogle Scholar
  47. Kaariainen H, Koskimies O, Norio R (1988) Dominant and recessive polycystic kidney disease in children: evaluation of clinical features and laboratory data. Pediatr Nephrol 2:296–302PubMedGoogle Scholar
  48. Kaplan BS, Fay J, Shah V, Dillon MJ, Barratt TM (1989) Autosomal recessive polycystic kidney disease. Pediatr Nephrol 3:43–49PubMedGoogle Scholar
  49. Klingel R, Dippold W, Storkel S, Meyer zum Buschenfelde KH, Kohler H (1992) Expression of differentiation antigens and growth-related genes in normal kidney, autosomal dominant polycystic kidney disease, and renal cell carcinoma. Am J Kidney Dis 19:22–30PubMedGoogle Scholar
  50. Lakshmanan J, Fisher DA (1993) An inborn error in epidermal growth factor prohormone metabolism in a mouse model of autosomal recessive polycystic kidney disease. Biochem Biophys Res Commun 196:892–901PubMedGoogle Scholar
  51. Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100:5286–5291PubMedGoogle Scholar
  52. Losekoot M, Haarloo C, Ruivenkamp C, White SJ, Breuning MH, Peters DJ (2005) Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD). Hum Genet 118:185–206PubMedGoogle Scholar
  53. Lowden DA, Lindemann GW, Merlino G, Barash BD, Calvet JP, Gattone VH 2nd (1994) Renal cysts in transgenic mice expressing transforming growth factor-alpha. J Lab Clin Med 124:386–394PubMedGoogle Scholar
  54. Lu W, Fan X, Babakhanlou H, Law T, Rifal N, Harris PC, Perez-Atayde AR, Renneke HG, Zhou J (1999) Late onset of renal and hepatic cysts in Pkd1-targeted heterozygotes. Nat Gen 21:160–161Google Scholar
  55. MacRae Dell K, Nemo R, Sweeney WE Jr, Avner ED (2004) EGF-related growth factors in the pathogenesis of murine ARPKD. Kidney Int 65:2018–2029PubMedGoogle Scholar
  56. Masyuk TV, Huang BQ, Ward CJ, Masyuk AI, Yuan D, Splinter PL, Punyashthiti R, Ritman EL, Torres VE, Harris PC, LaRusso NF (2003) Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. Gastroenterology 125:1303–1310PubMedGoogle Scholar
  57. Menezes LF, Cai Y, Nagasawa Y, Silva AM, Watkins ML, Da Silva AM, Somlo S, Guay-Woodford LM, Germino GG, Onuchic LF (2004) Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm. Kidney Int 66:1345–1355PubMedGoogle Scholar
  58. Murcia NS, Sweeney WE, Avner ED (1999) New insights into the molecular pathophysiology of polycystic kidney disease. Kidney Int 55:1187–1197PubMedGoogle Scholar
  59. Nagano J, Kitamura K, Hujer KM, Ward CJ, Bram RJ, Hopfer U, Tomita K, Huang C, Miller RT (2005) Fibrocystin interacts with CAML, a protein involved in Ca(2+) signaling. Biochem Biophys Res Commun 338:880–889PubMedGoogle Scholar
  60. Nagasawa Y, Matthiesen S, Onuchic LF, Hou X, Bergmann C, Esquivel E, Senderek J, Ren Z, Zeltner R, Furu L, Avner E, Moser M, Somlo S, Guay-Woodford L, Buttner R, Zerres K, Germino GG (2002) Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene. J Am Soc Nephrol 13:2246–2258PubMedGoogle Scholar
  61. Nakanishi K, Sweeney WE Jr, Macrae Dell K, Cotton CU, Avner ED (2001) Role of CFTR in autosomal recessive polycystic kidney disease. J Am Soc Nephrol 12:719–725PubMedGoogle Scholar
  62. Nauli SM, Zhou J (2004) Polycystins and mechanosensation in renal and nodal cilia. Bioessays 26:844–856PubMedGoogle Scholar
  63. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137PubMedGoogle Scholar
  64. Nauta J, Sweeney WE, Rutledge JC, Avner ED (1995) Biliary epithelial cells from mice with congenital polycystic kidney disease are hyperresponsive to epidermal growth factor. Pediatr Res 37:755–763PubMedGoogle Scholar
  65. Neufield TK, Douglass D, Grant M, Ye M, Silva F, Nadasdy T, Grantham JJ (1992) In vitro formation and expansion of cysts derived from human renal cortex epithelial cells. Kidney Int 41:1222–1236Google Scholar
  66. Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, Rudnik-Schoneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG (2002) PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 70:1305–1317PubMedGoogle Scholar
  67. Orellana SA, Sweeney WE, Neff CD, Avner ED (1995) Epidermal growth factor receptor expression is abnormal in murine polycystic kidney. Kidney Int 47:490–499PubMedGoogle Scholar
  68. Osathanondh V, Potter EL (1964a) Pathogenesis of polycystic kidneys. Historical survey. Arch Pathol 77:459–465PubMedGoogle Scholar
  69. Osathanondh V, Potter EL (1964b) Pathogenesis of polycystic kidneys. Survey of results of microdissection. Arch Pathol 77:510–512PubMedGoogle Scholar
  70. Osathanondh V, Potter EL (1964c) Pathogenesis of polycystic kidneys. Type 1 due to hyperplasia of interstitial portions of collecting tubules. Arch Pathol 77:466–473PubMedGoogle Scholar
  71. Pazour GJ (2004) Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease. J Am Soc Nephrol 15:2528–2536PubMedGoogle Scholar
  72. Pazour GJ, Rosenbaum JL (2002) Intraflagellar transport and cilia-dependent diseases. Trends Cell Biol 12:551–555PubMedGoogle Scholar
  73. Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG (2000) Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 151:709–718PubMedGoogle Scholar
  74. Pazour GJ, San Agustin JT, Follit JA, Rosenbaum JL, Witman GB (2002) Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol 12:R378–R380PubMedGoogle Scholar
  75. Phillips CL, Miller KJ, Filson AJ, Nurnberger J, Clendenon JL, Cook GW, Dunn KW, Overbeek PA, Gattone VH 2nd, Bacallao RL (2004) Renal cysts of inv/inv mice resemble early infantile nephronophthisis. J Am Soc Nephrol 15:1744–1755PubMedGoogle Scholar
  76. Praetorius HA, Spring KR (2001) Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184:71–79PubMedGoogle Scholar
  77. Praetorius HA, Spring KR (2003a) Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol 191:69–76PubMedGoogle Scholar
  78. Praetorius HA, Spring KR (2003b) The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens 12:517–520PubMedGoogle Scholar
  79. Praetorius HA, Spring KR (2005) A physiological view of the primary cilium. Annu Rev Physiol 67:515–529PubMedGoogle Scholar
  80. Praetorius HA, Frokiaer J, Nielsen S, Spring KR (2003) Bending the primary cilium opens Ca2+-sensitive intermediate-conductance K+ channels in MDCK cells. J Membr Biol 191:193–200PubMedGoogle Scholar
  81. Praetorius HA, Praetorius J, Nielsen S, Frokiaer J, Spring KR (2004) Beta1-integrins in the primary cilium of MDCK cells potentiate fibronectin-induced Ca2+ signaling. Am J Physiol Renal Physiol 287:F969–F978PubMedGoogle Scholar
  82. Pugh JL, Sweeney WE Jr, Avner ED (1995) Tyrosine kinase activity of the EGF receptor in murine metanephric organ culture. Kidney Int 47:774–781PubMedGoogle Scholar
  83. Richards WG, Sweeney WE, Yoder BK, Wilkinson JE, Woychik RP, Avner ED (1998) Epidermal growth factor receptor activity mediates renal cyst formation in polycystic kidney disease. J Clin Invest 101:935–939PubMedCrossRefGoogle Scholar
  84. Rohatgi R, Greenberg A, Burrow CR, Wilson PD, Satlin LM (2003) Na transport in autosomal recessive polycystic kidney disease (ARPKD) cyst lining epithelial cells. J Am Soc Nephrol 14:827–836PubMedGoogle Scholar
  85. Rohatgi R, Zavilowitz B, Vergara M, Woda C, Kim P, Satlin LM (2004) Cyst fluid composition in human autosomal recessive polycystic kidney disease. Pediatr Nephrol 20:552–553Google Scholar
  86. Rossetti S, Torra R, Coto E, Consugar M, Kubly V, Malaga S, Navarro M, El-Youssef M, Torres VE, Harris PC (2003) A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 64:391–403PubMedGoogle Scholar
  87. Roy S, Dillon MJ, Trompeter RS, Barratt TM (1997) Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors. Pediatr Nephrol 11:302–306PubMedGoogle Scholar
  88. Sato Y, Harada K, Kizawa K, Sanzen T, Furubo S, Yasoshima M, Ozaki S, Ishibashi M, Nakanuma Y (2005) Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli’s disease. Am J Pathol 166:49–60PubMedGoogle Scholar
  89. Sharp AM, Messiaen LM, Page G, Antignac C, Gubler MC, Onuchic LF, Somlo S, Germino GG, Guay-Woodford LM (2005) Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J Med Genet 42:336–349PubMedGoogle Scholar
  90. Sullivan LP, Grantham JJ (1996) Mechanisms of fluid secretion by polycystic epithelia. Kidney Int 49:1586–1591PubMedGoogle Scholar
  91. Sullivan LP, Wallace DP, Grantham JJ (1998) Chloride and fluid secretion in polycystic kidney disease. J Am Soc Nephrol 9:903–916PubMedGoogle Scholar
  92. Sun Z, Amsterdam A, Pazour GJ, Cole DG, Miller MS, Hopkins N (2004) A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development 131:4085–4093PubMedGoogle Scholar
  93. Sweeney WE, Avner ED (1996) BPK cyst fluid contains EGF and TGF-a like peptides which are motogenic and phosphorylate apical EGFR. J Am Soc Nephrol 7:1606Google Scholar
  94. Sweeney WE Jr, Avner ED (1998) Functional activity of epidermal growth factor receptors in autosomal recessive polycystic kidney disease. Am J Physiol 275:F387–F394PubMedGoogle Scholar
  95. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED (2000) Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 57:33–40PubMedGoogle Scholar
  96. Sweeney WE Jr, Hamahira K, Sweeney J, Garcia-Gatrell M, Frost P, Avner ED (2003) Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability. Kidney Int 64:1310–1319PubMedGoogle Scholar
  97. Torres VE (2004) Therapies to slow polycystic kidney disease. Nephron Exp Nephrol 98:e1–e7PubMedGoogle Scholar
  98. Torres VE (2005) Vasopressin antagonists in polycystic kidney disease. Kidney Int 68:2405–2418PubMedGoogle Scholar
  99. Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH (2004) Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 10:363–364Google Scholar
  100. Veizis IE, Cotton CU (2005) Abnormal EGF-dependent regulation of sodium absorption in ARPKD collecting duct cells. Am J Physiol Renal Physiol 288:F474–F482PubMedGoogle Scholar
  101. Veizis EI, Carlin CR, Cotton CU (2004) Decreased amiloride-sensitive Na+ absorption in collecting duct principal cells isolated from BPK ARPKD mice. Am J Physiol Renal Physiol 286:F244–F254PubMedGoogle Scholar
  102. Wallace DP, Christensen M, Reif G, Belibi F, Thrasher B, Herrell D, Grantham JJ (2002) Electrolyte and fluid secretion by cultured human inner medullary collecting duct cells. Am J Physiol Renal Physiol 283:F1337–F1350PubMedGoogle Scholar
  103. Wang S, Luo Y, Wilson PD, Witman GB, Zhou J (2004) The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area. J Am Soc Nephrol 15:592–602PubMedGoogle Scholar
  104. Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, Kubly V, Cunningham JM, Bacallao R, Ishibashi M, Milliner DS, Torres VE, Harris PC (2002) The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30:259–269PubMedGoogle Scholar
  105. Ward CJ, Yuan D, Masyuk TV, Wang X, Punyashthiti R, Whelan S, Bacallao R, Torra R, LaRusso NF, Torres VE, Harris PC (2003) Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet 12:2703–2710PubMedGoogle Scholar
  106. Welling LW, Grantham JJ (1991) Cystic and developmental diseases of the kidney. In: Brenner BMR, Rector FC (eds) The kidney. Saunders, Philadelphia, pp 1657–1694Google Scholar
  107. Wilson PD (2004a) Polycystic kidney disease. N Engl J Med 350:151–164PubMedGoogle Scholar
  108. Wilson PD (2004b) Polycystic kidney disease: new understanding in the pathogenesis. Int J Biochem Cell Biol 36:1868–1873PubMedGoogle Scholar
  109. Witzgall R (2005) New developments in the field of cystic kidney diseases. Curr Mol Med 5:455–465PubMedGoogle Scholar
  110. Xiong H, Chen Y, Yi Y, Tsuchiya K, Moeckel G, Cheung J, Liang D, Tham K, Xu X, Chen XZ, Pei Y, Zhao ZJ, Wu G (2002) A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease. Genomics 80:96–104PubMedGoogle Scholar
  111. Yamaguchi T, Pelling JC, Ramaswamy NT, Eppler JW, Wallace DP, Nagao S, Rome LA, Sullivan LP, Grantham JJ (2000) cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int 57:1460–1471PubMedGoogle Scholar
  112. Yamaguchi T, Nagao S, Wallace DP, Belibi FA, Cowley BD, Pelling JC, Grantham JJ (2003) Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983–1994PubMedGoogle Scholar
  113. Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279:40419–40430PubMedGoogle Scholar
  114. Yamaguchi T, Hempson SJ, Reif GA, Hedge AM, Wallace DP (2006) Calcium restores a normal proliferation phenotype in human polycystic kidney disease epithelial cells. J Am Soc Nephrol 17:178–187PubMedGoogle Scholar
  115. Ye M, Grant M, Sharma M, Elzinga L, Swan S, Torres VE, Grantham JJ (1992) Cyst fluid from human autosomal dominant polycystic kidneys promotes cyst formation and expansion by renal epithelial cells in vitro. J Am Soc Nephrol 3:984–994PubMedGoogle Scholar
  116. Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508–2516PubMedGoogle Scholar
  117. Zerres K, Rudnik-Schoneborn S, Steinkamm C, Mucher G (1996) Autosomal recessive polycystic kidney disease. Nephrol Dial Transplant 11 (Suppl 6):29–33PubMedGoogle Scholar
  118. Zerres K, Mücher G, Becker J, Steinkamm C, Rudnik-Schöneborn S, Heikkilä P, Rapola J, Salonen R, Germino GG, Onuchic L, Somlo S, Avner ED, Harman LA, Stockwin JM, Guay-Woodford LM (1998) Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 76:137–144PubMedGoogle Scholar
  119. Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Kunze J, Mononen T, Kaariainen H, Kirfel J, Moser M, Buettner R, Bergmann C (2004) New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene. Clin Genet 66:53–57PubMedGoogle Scholar
  120. Zhang BH, Guan KL (2000) Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. EMBO J 19:5429–5439PubMedGoogle Scholar
  121. Zhang MZ, Mai W, Li C, Cho SY, Hao C, Moeckel G, Zhao R, Kim I, Wang J, Xiong H, Wang H, Sato Y, Wu Y, Nakanuma Y, Lilova M, Pei Y, Harris RC, Li S, Coffey RJ, Sun L, Wu D, Chen XZ, Breyer MD, Zhao ZJ, McKanna JA, Wu G (2004) PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells. Proc Natl Acad Sci USA 101:2311–2316PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Children’s Research Institute, Children’s Hospital Health System of WisconsinMedical College of WisconsinMilwaukeeUSA
  2. 2.Director, Children’s Research Institute, Children’s Hospital Health System of Wisconsin, Associate Dean for Research, Children’s Corporate CenterMedical College of WisconsinWauwatosaUSA

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