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Fundamental insights into autosomal dominant polycystic kidney disease from human-based cell models

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Abstract

Several animal- and human-derived models are used in autosomal dominant polycystic kidney disease (ADPKD) research to gain insight in the disease mechanism. However, a consistent correlation between animal and human ADPKD models is lacking. Therefore, established human-derived models are relevant to affirm research results and translate findings into a clinical set-up. In this review, we give an extensive overview of the existing human-based cell models. We discuss their source (urine, nephrectomy and stem cell), immortalisation procedures, genetic engineering, kidney segmental origin and characterisation with nephron segment markers. We summarise the most studied pathways and lessons learned from these different ADPKD models. Finally, we issue recommendations for the derivation of human-derived cell lines and for experimental set-ups with these cell lines.

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References

  1. Cornec-Le Gall E, Torres VE, Harris PC (2017) Genetic complexity of autosomal dominant polycystic kidney and liver diseases. J Am Soc Nephrol. https://doi.org/10.1681/ASN.2017050483

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Duley IT, Jones RH (1992) Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 41:1311–1319

    Article  CAS  PubMed  Google Scholar 

  3. Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, Charasse C, Whebe B, Renaudineau E, Jousset P, Guillodo MP, Grall-Jezequel A, Saliou P, Ferec C, Le Meur Y (2013) Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 24:1006–1013. https://doi.org/10.1681/ASN.2012070650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG (2000) Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature 408:990–994. https://doi.org/10.1038/35050128

    Article  CAS  PubMed  Google Scholar 

  5. Calvet JP (2015) The role of calcium and cyclic AMP in PKD. In: Li X (ed) Polycystic kidney disease. Codon Publications, Brisbane (AU). https://doi.org/10.15586/codon.pkd.2015.ch8

    Chapter  Google Scholar 

  6. Ibraghimov-Beskrovnaya O, Natoli TA (2011) mTOR signaling in polycystic kidney disease. Trends Mol Med 17:625–633. https://doi.org/10.1016/j.molmed.2011.06.003

    Article  CAS  PubMed  Google Scholar 

  7. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367:2407–2418. https://doi.org/10.1056/NEJMoa1205511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu ASL, El-Ters M, Winklhofer FT (2015) Clinical trials in autosomal dominant polycystic kidney disease. In: Li X (ed) Polycystic kidney disease. Codon Publications, Brisbane (AU). https://doi.org/10.15586/codon.pkd.2015.ch6

    Chapter  Google Scholar 

  9. Song X, Di Giovanni V, He N, Wang K, Ingram A, Rosenblum ND, Pei Y (2009) 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. https://doi.org/10.1093/hmg/ddp165

    Article  CAS  PubMed  Google Scholar 

  10. Grantham JJ (2009) Autosomal dominant polycystic kidney disease. Ann Transplant 14:86–90

    Google Scholar 

  11. Wilson PD, Schrier RW, Breckon RD, Gabow PA (1986) A new method for studying human polycystic kidney disease epithelia in culture. Kidney Int 30:371–378

    Article  CAS  PubMed  Google Scholar 

  12. Loghman-Adham M, Nauli SM, Soto CE, Kariuki B, Zhou J (2003) Immortalized epithelial cells from human autosomal dominant polycystic kidney cysts. Am J Physiol Renal Physiol 285:F397–F412. https://doi.org/10.1152/ajprenal.00310.2002

    Article  PubMed  Google Scholar 

  13. Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, Ingber DE, Loghman-Adham M, Zhou J (2006) Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol 17:1015–1025. https://doi.org/10.1681/ASN.2005080830

    Article  CAS  PubMed  Google Scholar 

  14. Rossetti S, Chauveau D, Walker D, Saggar-Malik A, Winearls CG, Torres VE, Harris PC (2002) A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int 61(5):1588–1599. https://doi.org/10.1046/j.1523-1755.2002.00326.x

    Article  CAS  PubMed  Google Scholar 

  15. Streets AJ, Newby LJ, O'Hare MJ, Bukanov NO, Ibraghimov-Beskrovnaya O, Ong AC (2003) Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion. J Am Soc Nephrol 14(7):1804–1815

    Article  CAS  PubMed  Google Scholar 

  16. Parker E, Newby LJ, Sharpe CC, Rossetti S, Streets AJ, Harris PC, O'Hare MJ, Ong AC (2007) Hyperproliferation of PKD1 cystic cells is induced by insulin-like growth factor-1 activation of the Ras/Raf signalling system. Kidney Int 72(2):157–165. https://doi.org/10.1038/sj.ki.5002229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fragiadaki M, Lannoy M, Themanns M, Maurer B, Leonhard WN, Peters DJ, Moriggl R, Ong AC (2017) STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease. Kidney Int 91(3):575–586. https://doi.org/10.1016/j.kint.2016.10.039

    Article  CAS  PubMed  Google Scholar 

  18. Streets AJ, Magayr TA, Huang L, Vergoz L, Rossetti S, Simms RJ, Harris PC, Peters DJ, Ong AC (2017) Parallel microarray profiling identifies ErbB4 as a determinant of cyst growth in ADPKD and a prognostic biomarker for disease progression. Am J Physiol Renal Physiol 312(4):F577–F588. https://doi.org/10.1152/ajprenal.00607.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xu C, Rossetti S, Jiang L, Harris PC, Brown-Glaberman U, Wandinger-Ness A, Bacallao R, Alper SL (2007) 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 292(3):F930–F945. https://doi.org/10.1152/ajprenal.00285.2006

    Article  CAS  PubMed  Google Scholar 

  20. Xu C, Shmukler BE, Nishimura K, Kaczmarek E, Rossetti S, Harris PC, Wandinger-Ness A, Bacallao RL, Alper SL (2009) Attenuated, flow-induced ATP release contributes to absence of flow-sensitive, purinergic Cai2+ signaling in human ADPKD cyst epithelial cells. Am J Physiol Renal Physiol 296(6):F1464–F1476. https://doi.org/10.1152/ajprenal.90542.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Herbert BS, Grimes BR, Xu WM, Werner M, Ward C, Rossetti S, Harris P, Bello-Reuss E, Ward HH, Miller C, Gattone VH 2nd, Phillips CL, Wandinger-Ness A, Bacallao RL (2013) A telomerase immortalized human proximal tubule cell line with a truncation mutation (Q4004X) in polycystin-1. PLoS One 8(1):e55191. https://doi.org/10.1371/journal.pone.0055191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mekahli D, Decuypere JP, Sammels E, Welkenhuyzen K, Schoeber J, Audrezet MP, Corvelyn A, Dechenes G, Ong AC, Wilmer MJ, van den Heuvel L, Bultynck G, Parys JB, Missiaen L, Levtchenko E, De Smedt H (2014) Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin. Pflugers Arch 466(8):1591–1604. https://doi.org/10.1007/s00424-013-1394-x

    Article  CAS  PubMed  Google Scholar 

  23. Wilmer MJ, Saleem MA, Masereeuw R, Ni L, van der Velden TJ, Russel FG, Mathieson PW, Monnens LA, van den Heuvel LP, Levtchenko EN (2010) Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters. Cell Tissue Res 339(2):449–457. https://doi.org/10.1007/s00441-009-0882-y

    Article  PubMed  Google Scholar 

  24. Wilmer MJ, Kluijtmans LA, van der Velden TJ, Willems PH, Scheffer PG, Masereeuw R, Monnens LA, van den Heuvel LP, Levtchenko EN (2011) Cysteamine restores glutathione redox status in cultured cystinotic proximal tubular epithelial cells. Biochim Biophys Acta 1812(6):643–651. https://doi.org/10.1016/j.bbadis.2011.02.010

    Article  CAS  PubMed  Google Scholar 

  25. Freedman BS, Lam AQ, Sundsbak JL, Iatrino R, Su X, Koon SJ, Wu M, Daheron L, Harris PC, Zhou J, Bonventre JV (2013) Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations. J Am Soc Nephrol 24(10):1571–1586. https://doi.org/10.1681/ASN.2012111089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Freedman BS (2015) Modeling kidney disease with iPS cells. Biomark Insights 10(Suppl 1):153–169. https://doi.org/10.4137/BMI.S20054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Carone FA, Nakamura S, Schumacher BS, Punyarit P, Bauer KD (1989) Cyst-derived cells do not exhibit accelerated growth or features of transformed cells in vitro. Kidney Int 35(6):1351–1357

    Article  CAS  PubMed  Google Scholar 

  28. Wallace DP, Grantham JJ, Sullivan LP (1996) Chloride and fluid secretion by cultured human polycystic kidney cells. Kidney Int 50(4):1327–1336

    Article  CAS  PubMed  Google Scholar 

  29. Charron AJ, Nakamura S, Bacallao R, Wandinger-Ness A (2000) Compromised cytoarchitecture and polarized trafficking in autosomal dominant polycystic kidney disease cells. J Cell Biol 149(1):111–124. https://doi.org/10.1083/jcb.149.1.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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(2):129–137. https://doi.org/10.1038/ng1076

    Article  CAS  PubMed  Google Scholar 

  31. de Almeida RM, Clendenon SG, Richards WG, Boedigheimer M, Damore M, Rossetti S, Harris PC, Herbert BS, Xu WM, Wandinger-Ness A, Ward HH, Glazier JA, Bacallao RL (2016) Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD. Hum Genomics 10(1):37. https://doi.org/10.1186/s40246-016-0095-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hajarnis S, Lakhia R, Yheskel M, Williams D, Sorourian M, Liu XQ, Aboudehen K, Zhang SR, Kersjes K, Galasso R, Li J, Kaimal V, Lockton S, Davis S, Flaten A, Johnson JA, Holland WL, Kusminski CM, Scherer PE, Harris PC, Trudel M, Wallace DP, Igarashi P, Lee EC, Androsavich JR, Patel V (2017) MicroRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism. Nat Commun 8. doi: Artn 14395. https://doi.org/10.1038/Ncomms14395

  33. Ben-Dov IZ, Tan YC, Morozov P, Wilson PD, Rennert H, Blumenfeld JD, Tuschl T (2014) Urine microRNA as potential biomarkers of autosomal dominant polycystic kidney disease progression: description of miRNA profiles at baseline. PLoS ONE 9 (1). doi: ARTN e86856. https://doi.org/10.1371/journal.pone.0086856

  34. Lakhia R, Hajarnis S, Williams D, Aboudehen K, Yheskel M, Xing C, Hatley ME, Torres VE, Wallace DP, Patel V (2016) MicroRNA-21 aggravates cyst growth in a model of polycystic kidney disease. J Am Soc Nephrol 27(8):2319–2330. https://doi.org/10.1681/Asn.2015060634

    Article  CAS  PubMed  Google Scholar 

  35. Huang J, Zhou S, Niu X, Hu B, Li Q, Zhang F, Zhang X, Cai X, Lou Y, Liu F, Xu C, Wang Y (2017) Generation of special autosomal dominant polycystic kidney disease iPSCs with the capability of functional kidney-like cell differentiation. Stem Cell Res Ther 8(1):196. https://doi.org/10.1186/s13287-017-0645-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV (2015) Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715. https://doi.org/10.1038/ncomms9715

    Article  CAS  PubMed  Google Scholar 

  37. Huang CY, Ho MC, Lee JJ, Hwang DY, Ko HW, Cheng YC, Hsu YH, Lu HE, Chen HC, Hsieh PCH (2017) Generation of induced pluripotent stem cells derived from an autosomal dominant polycystic kidney disease patient with a p.Ser1457fs mutation in PKD1. Stem Cell Res 24:139–143. https://doi.org/10.1016/j.scr.2017.09.004

    Article  CAS  PubMed  Google Scholar 

  38. Mekahli D, Sammels E, Luyten T, Welkenhuyzen K, van den Heuvel LP, Levtchenko EN, Gijsbers R, Bultynck G, Parys JB, De Smedt H, Missiaen L (2012) Polycystin-1 and polycystin-2 are both required to amplify inositol-trisphosphate-induced Ca2+ release. Cell Calcium 51(6):452–458. https://doi.org/10.1016/j.ceca.2012.03.002

    Article  CAS  PubMed  Google Scholar 

  39. Battini L, Fedorova E, Macip S, Li X, Wilson PD, Gusella GL (2006) Stable knockdown of polycystin-1 confers integrin-alpha2beta1-mediated anoikis resistance. J Am Soc Nephrol 17(11):3049–3058. https://doi.org/10.1681/ASN.2006030234

    Article  CAS  PubMed  Google Scholar 

  40. Subramanian B, Ko WC, Yadav V, DesRochers TM, Perrone RD, Zhou J, Kaplan DL (2012) The regulation of cystogenesis in a tissue engineered kidney disease system by abnormal matrix interactions. Biomaterials 33(33):8383–8394. https://doi.org/10.1016/j.biomaterials.2012.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang E, Hsieh-Li HM, Chiou YY, Chien YL, Ho HH, Chin HJ, Wang CK, Liang SC, Jiang ST (2010) Progressive renal distortion by multiple cysts in transgenic mice expressing artificial microRNAs against Pkd1. J Pathol 222:238–248. https://doi.org/10.1002/path.2765

    Article  CAS  PubMed  Google Scholar 

  42. Woo YM, Shin Y, Hwang JA, Hwang YH, Lee S, Park EY, Kong HK, Park HC, Lee YS, Park JH (2015) Epigenetic silencing of the MUPCDH gene as a possible prognostic biomarker for cyst growth in ADPKD. Sci Rep 5:15238. https://doi.org/10.1038/srep15238

    Article  CAS  PubMed  Google Scholar 

  43. Pinto CS, Raman A, Reif GA, Magenheimer BS, White C, Calvet JP, Wallace DP (2016) Phosphodiesterase isoform regulation of cell proliferation and fluid secretion in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 27(4):1124–1134. https://doi.org/10.1681/ASN.2015010047

    Article  CAS  PubMed  Google Scholar 

  44. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP (2011) Tolvaptan inhibits ERK-dependent cell proliferation, Cl(−) secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 301(5):F1005–F1013. https://doi.org/10.1152/ajprenal.00243.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ahuja D, Saenz-Robles MT, Pipas JM (2005) SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene 24:7729–7745. https://doi.org/10.1038/sj.onc.1209046

    Article  CAS  PubMed  Google Scholar 

  46. Arndt GM, MacKenzie KL (2016) New prospects for targeting telomerase beyond the telomere. Nat Rev Cancer 16(8):508–524. https://doi.org/10.1038/nrc.2016.55

    Article  CAS  PubMed  Google Scholar 

  47. MacKay K, Striker LJ, Pinkert CA, Brinster RL, Striker GE (1987) Glomerulosclerosis and renal cysts in mice transgenic for the early region of SV40. Kidney Int 32(6):827–837

    Article  CAS  PubMed  Google Scholar 

  48. Mckay RDG, Jat PS, Lamazan G (1993) Method for manipulation of the cell types of eukaryotes. Google Patents

  49. Loeber G, Tevethia MJ, Schwedes JF, Tegtmeyer P (1989) Temperature-sensitive mutants identify crucial structural regions of simian virus 40 large T antigen. J Virol 63:4426–4430

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Demeulemeester J, De Rijck J, Gijsbers R, Debyser Z (2015) Retroviral integration: site matters: mechanisms and consequences of retroviral integration site selection. Bioessays 37(11):1202–1214. https://doi.org/10.1002/bies.201500051

    Article  PubMed  PubMed Central  Google Scholar 

  51. Liu Z, Li Q, Li K, Chen L, Li W, Hou M, Liu T, Yang J, Lindvall C, Bjorkholm M, Jia J, Xu D (2013) Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene 32(36):4203–4213. https://doi.org/10.1038/onc.2012.441

    Article  CAS  PubMed  Google Scholar 

  52. Nouwen EJ, Dauwe S, van der Biest I, De Broe ME (1993) Stage- and segment-specific expression of cell-adhesion molecules N-CAM, A-CAM, and L-CAM in the kidney. Kidney Int 44(1):147–158

    Article  CAS  PubMed  Google Scholar 

  53. Knepper MA, Brooks HL (2001) Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney. Curr Opin Nephrol Hypertens 10(5):655–659

    Article  CAS  PubMed  Google Scholar 

  54. Yamada H, Yamazaki S, Moriyama N, Hara C, Horita S, Enomoto Y, Kudo A, Kawakami H, Tanaka Y, Fujita T, Seki G (2003) Localization of NBC-1 variants in human kidney and renal cell carcinoma. Biochem Biophys Res Commun 310(4):1213–1218

    Article  CAS  PubMed  Google Scholar 

  55. Damkier HH, Nielsen S, Praetorius J (2007) Molecular expression of SLC4-derived Na+-dependent anion transporters in selected human tissues. Am J Physiol Regul Integr Comp Physiol 293(5):R2136–R2146. https://doi.org/10.1152/ajpregu.00356.2007

    Article  CAS  PubMed  Google Scholar 

  56. Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, Inui K (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13(4):866–874

    CAS  PubMed  Google Scholar 

  57. Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai Y, Sophasan S, Endou H (2004) Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci 94(3):297–304

    Article  CAS  PubMed  Google Scholar 

  58. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 84(21):7735–7738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Maunsbach AB, Marples D, Chin E, Ning G, Bondy C, Agre P, Nielsen S (1997) Aquaporin-1 water channel expression in human kidney. J Am Soc Nephrol 8(1):1–14

    CAS  PubMed  Google Scholar 

  60. van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG (2002) The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol 13(3):595–603

    PubMed  Google Scholar 

  61. Cordon-Cardo C, O’Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR (1990) Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38(9):1277–1287. https://doi.org/10.1177/38.9.1974900

    Article  CAS  PubMed  Google Scholar 

  62. Ernest S, Rajaraman S, Megyesi J, Bello-Reuss EN (1997) Expression of MDR1 (multidrug resistance) gene and its protein in normal human kidney. Nephron 77(3):284–289

    Article  CAS  PubMed  Google Scholar 

  63. Baer PC, Nockher WA, Haase W, Scherberich JE (1997) Isolation of proximal and distal tubule cells from human kidney by immunomagnetic separation. Technical note. Kidney Int 52(5):1321–1331

    Article  CAS  PubMed  Google Scholar 

  64. Hennigar RA, Schulte BA, Spicer SS (1985) Heterogeneous distribution of glycoconjugates in human kidney tubules. Anat Rec 211(4):376–390. https://doi.org/10.1002/ar.1092110403

    Article  CAS  PubMed  Google Scholar 

  65. Piela-Smith TH, Korn JH (1995) Aminopeptidase N: a constitutive cell-surface protein on human dermal fibroblasts. Cell Immunol 162(1):42–48. https://doi.org/10.1006/cimm.1995.1049

    Article  CAS  PubMed  Google Scholar 

  66. Lorkowski G, Zijderhand-Bleekemolen JE, Erdos EG, von Figura K, Hasilik A (1987) Neutral endopeptidase-24.11 (enkephalinase). Biosynthesis and localization in human fibroblasts. Biochem J 248(2):345–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Olerud JE, Usui ML, Seckin D, Chiu DS, Haycox CL, Song IS, Ansel JC, Bunnett NW (1999) Neutral endopeptidase expression and distribution in human skin and wounds. J Invest Dermatol 112(6):873–881. https://doi.org/10.1046/j.1523-1747.1999.00596.x

    Article  CAS  PubMed  Google Scholar 

  68. Grantham JJ, Geiser JL, Evan AP (1987) Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31(5):1145–1152

    Article  CAS  PubMed  Google Scholar 

  69. Murata F, Tsuyama S, Suzuki S, Hamada H, Ozawa M, Muramatsu T (1983) Distribution of glycoconjugates in the kidney studied by use of labeled lectins. J Histochem Cytochem 31(1A Suppl):139–144

    Article  PubMed  Google Scholar 

  70. Biner HL, Arpin-Bott MP, Loffing J, Wang X, Knepper M, Hebert SC, Kaissling B (2002) Human cortical distal nephron: distribution of electrolyte and water transport pathways. J Am Soc Nephrol 13(4):836–847

    PubMed  Google Scholar 

  71. Chang MY, A CMO (2017) Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfx262

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Luyten A, Su X, Gondela S, Chen Y, Rompani S, Takakura A, Zhou J (2010) Aberrant regulation of planar cell polarity in polycystic kidney disease. J Am Soc Nephrol 21(9):1521–1532. https://doi.org/10.1681/ASN.2010010127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Patel V, Li L, Cobo-Stark P, Shao X, Somlo S, Lin F, Igarashi P (2008) Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum Mol Genet 17(11):1578–1590. https://doi.org/10.1093/hmg/ddn045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Grimm DH, Cai Y, Chauvet V, Rajendran V, Zeltner R, Geng L, Avner ED, Sweeney W, Somlo S, Caplan MJ (2003) Polycystin-1 distribution is modulated by polycystin-2 expression in mammalian cells. J Biol Chem 278(38):36786–36793. https://doi.org/10.1074/jbc.M306536200

    Article  CAS  PubMed  Google Scholar 

  77. Geng L, Okuhara D, Yu Z, Tian X, Cai Y, Shibazaki S, Somlo S (2006) Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J Cell Sci 119(Pt 7):1383–1395. https://doi.org/10.1242/jcs.02818

    Article  CAS  PubMed  Google Scholar 

  78. Chang MY, Parker E, Ibrahim S, Shortland JR, Nahas ME, Haylor JL, Ong AC (2006) Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models. Nephrol Dial Transplant 21(8):2078–2084. https://doi.org/10.1093/ndt/gfl150

    Article  CAS  PubMed  Google Scholar 

  79. Ta MH, Liuwantara D, Rangan GK (2015) Effects of pyrrolidine dithiocarbamate on proliferation and nuclear factor-kappaB activity in autosomal dominant polycystic kidney disease cells. BMC Nephrol 16:212. https://doi.org/10.1186/s12882-015-0193-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Venugopal J, Blanco G (2016) Ouabain enhances ADPKD cell apoptosis via the intrinsic pathway. Front Physiol 7:107. https://doi.org/10.3389/fphys.2016.00107

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hanaoka K, Guggino WB (2000) cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol 11(7):1179–1187

    CAS  PubMed  Google Scholar 

  82. Gonzalez-Perrett S, Kim K, Ibarra C, Damiano AE, Zotta E, Batelli M, Harris PC, Reisin IL, Arnaout MA, Cantiello HF (2001) Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc Natl Acad Sci U S A 98(3):1182–1187

    Article  CAS  PubMed  Google Scholar 

  83. Vandorpe DH, Chernova MN, Jiang L, Sellin LK, Wilhelm S, Stuart-Tilley AK, Walz G, Alper SL (2001) The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel. J Biol Chem 276(6):4093–4101. https://doi.org/10.1074/jbc.M006252200

    Article  CAS  PubMed  Google Scholar 

  84. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci U S A 96(7):3934–3939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Du J, Ding M, Sours-Brothers S, Graham S, Ma R (2008) Mediation of angiotensin II-induced Ca2+ signaling by polycystin 2 in glomerular mesangial cells. Am J Physiol Renal Physiol 294(4):F909–F918. https://doi.org/10.1152/ajprenal.00606.2007

    Article  CAS  PubMed  Google Scholar 

  86. Miyagi K, Kiyonaka S, Yamada K, Miki T, Mori E, Kato K, Numata T, Sawaguchi Y, Numaga T, Kimura T, Kanai Y, Kawano M, Wakamori M, Nomura H, Koni I, Yamagishi M, Mori Y (2009) A pathogenic C terminus-truncated polycystin-2 mutant enhances receptor-activated Ca2+ entry via association with TRPC3 and TRPC7. J Biol Chem 284(49):34400–34412. https://doi.org/10.1074/jbc.M109.015149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pedrozo Z, Criollo A, Battiprolu PK, Morales CR, Contreras-Ferrat A, Fernandez C, Jiang N, Luo X, Caplan MJ, Somlo S, Rothermel BA, Gillette TG, Lavandero S, Hill JA (2015) Polycystin-1 is a cardiomyocyte mechanosensor that governs L-type Ca2+ channel protein stability. Circulation 131(24):2131–2142. https://doi.org/10.1161/CIRCULATIONAHA.114.013537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li Y, Wright JM, Qian F, Germino GG, Guggino WB (2005) Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling. J Biol Chem 280(50):41298–41306. https://doi.org/10.1074/jbc.M510082200

    Article  CAS  PubMed  Google Scholar 

  89. Li Y, Santoso NG, Yu S, Woodward OM, Qian F, Guggino WB (2009) Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling with implications for polycystic kidney disease. J Biol Chem 284(52):36431–36441. https://doi.org/10.1074/jbc.M109.068916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sammels E, Devogelaere B, Mekahli D, Bultynck G, Missiaen L, Parys JB, Cai Y, Somlo S, De Smedt H (2010) Polycystin-2 activation by inositol 1,4,5-trisphosphate-induced Ca2+ release requires its direct association with the inositol 1,4,5-trisphosphate receptor in a signaling microdomain. J Biol Chem 285(24):18794–18805. https://doi.org/10.1074/jbc.M109.090662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Santoso NG, Cebotaru L, Guggino WB (2011) Polycystin-1, 2, and STIM1 interact with IP(3) R to modulate ER Ca release through the PI3K/Akt pathway. Cell Physiol Biochem 27(6):715–726. https://doi.org/10.1159/000330080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Anyatonwu GI, Estrada M, Tian X, Somlo S, Ehrlich BE (2007) Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc Natl Acad Sci U S A 104(15):6454–6459. https://doi.org/10.1073/pnas.0610324104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Morel N, Vandenberg G, Ahrabi AK, Caron N, Desjardins F, Balligand JL, Horie S, Devuyst O (2009) PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta. Pflugers Arch 457(4):845–856. https://doi.org/10.1007/s00424-008-0561-y

    Article  CAS  PubMed  Google Scholar 

  94. 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(1):178–187. https://doi.org/10.1681/ASN.2005060645

    Article  CAS  PubMed  Google Scholar 

  95. Weber KH, Lee EK, Basavanna U, Lindley S, Ziegelstein RC, Germino GG, Sutters M (2008) Heterologous expression of polycystin-1 inhibits endoplasmic reticulum calcium leak in stably transfected MDCK cells. Am J Physiol Renal Physiol 294(6):F1279–F1286. https://doi.org/10.1152/ajprenal.00348.2007

    Article  CAS  PubMed  Google Scholar 

  96. Mekahli D, Parys JB, Bultynck G, Missiaen L, De Smedt H (2013) Polycystins and cellular Ca2+ signaling. Cell Mol Life Sci 70(15):2697–2712. https://doi.org/10.1007/s00018-012-1188-x

    Article  CAS  PubMed  Google Scholar 

  97. 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(6):1983–1994. https://doi.org/10.1046/j.1523-1755.2003.00023.x

    Article  CAS  PubMed  Google Scholar 

  98. 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(3):964–973. https://doi.org/10.1111/j.1523-1755.2004.00843.x

    Article  CAS  PubMed  Google Scholar 

  99. 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(4):1460–1471. https://doi.org/10.1046/j.1523-1755.2000.00991.x

    Article  CAS  PubMed  Google Scholar 

  100. Neufeld 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(5):1222–1236

    Article  CAS  PubMed  Google Scholar 

  101. Yamaguchi T, Nagao S, Kasahara M, Takahashi H, Grantham JJ (1997) Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am J Kidney Dis 30(5):703–709

    Article  CAS  PubMed  Google Scholar 

  102. 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(4):1242–1249

    CAS  PubMed  Google Scholar 

  103. 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(4):984–994

    CAS  PubMed  Google Scholar 

  104. Putnam WC, Swenson SM, Reif GA, Wallace DP, Helmkamp GM Jr, Grantham JJ (2007) Identification of a forskolin-like molecule in human renal cysts. J Am Soc Nephrol 18(3):934–943. https://doi.org/10.1681/ASN.2006111218

    Article  CAS  PubMed  Google Scholar 

  105. Nagao S, Nishii K, Yoshihara D, Kurahashi H, Nagaoka K, Yamashita T, Takahashi H, Yamaguchi T, Calvet JP, Wallace DP (2008) Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat. Kidney Int 73(3):269–277. https://doi.org/10.1038/sj.ki.5002629

    Article  CAS  PubMed  Google Scholar 

  106. Chen NX, Moe SM, Eggleston-Gulyas T, Chen X, Hoffmeyer WD, Bacallao RL, Herbert BS, Gattone VH 2nd (2011) Calcimimetics inhibit renal pathology in rodent nephronophthisis. Kidney Int 80(6):612–619. https://doi.org/10.1038/ki.2011.139

    Article  CAS  PubMed  Google Scholar 

  107. Janssens P, Weydert C, De Rechter S, Wissing KM, Liebau MC, Mekahli D (2018) Expanding the role of vasopressin antagonism in polycystic kidney diseases: from adults to children? Pediatr Nephrol 33(3):395–408. https://doi.org/10.1007/s00467-017-3672-x

    Article  PubMed  Google Scholar 

  108. Pinto CS, Reif GA, Nivens E, White C, Wallace DP (2012) Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl− secretion by human autosomal dominant polycystic kidney cells. Am J Physiol Renal Physiol 303(10):F1412–F1424. https://doi.org/10.1152/ajprenal.00692.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tao Y, Kim J, Schrier RW, Edelstein CL (2005) Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 16(1):46–51. https://doi.org/10.1681/ASN.2004080660

    Article  CAS  PubMed  Google Scholar 

  110. Shillingford JM, Piontek KB, Germino GG, Weimbs T (2010) Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol 21(3):489–497. https://doi.org/10.1681/ASN.2009040421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, Flask CA, Novick AC, Goldfarb DA, Kramer-Zucker A, Walz G, Piontek KB, Germino GG, Weimbs T (2006) 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 103(14):5466–5471. https://doi.org/10.1073/pnas.0509694103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. de Stephanis L, Bonon A, Varani K, Lanza G, Gafa R, Pinton P, Pema M, Somlo S, Boletta A, Aguiari G (2017) Double inhibition of cAMP and mTOR signalling may potentiate the reduction of cell growth in ADPKD cells. Clin Exp Nephrol 21(2):203–211. https://doi.org/10.1007/s10157-016-1289-1

    Article  CAS  PubMed  Google Scholar 

  113. Bonon A, Mangolini A, Pinton P, Del Senno L, Aguiari G (2013) Berberine slows cell growth in autosomal dominant polycystic kidney disease cells. Biochem Biophys Res Commun 441(3):668–674. https://doi.org/10.1016/j.bbrc.2013.10.076

    Article  CAS  PubMed  Google Scholar 

  114. Forbes TA, Howden SE, Lawlor K, Phipson B, Maksimovic J, Hale L, Wilson S, Quinlan C, Ho G, Holman K, Bennetts B, Crawford J, Trnka P, Oshlack A, Patel C, Mallett A, Simons C, Little MH (2018) Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. Am J Hum Genet 102(5):816–831. https://doi.org/10.1016/j.ajhg.2018.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Our research is supported by VLAIO and the Clinical Research Fund of UZ Leuven.

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Authors and Affiliations

  1. PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, GPURE, KU Leuven, Leuven, Belgium

    Caroline Weydert, Jean-Paul Decuypere, Peter Janssens & Djalila Mekahli

  2. Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    Humbert De Smedt

  3. Department of Nephrology, University Hospitals Brussels, Brussels, Belgium

    Peter Janssens

  4. VIB Center for Brain and Disease Research, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    Rudi Vennekens

  5. Department of Pediatric Nephrology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Djalila Mekahli

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  1. Caroline Weydert
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  2. Jean-Paul Decuypere
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  3. Humbert De Smedt
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  4. Peter Janssens
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  6. Djalila Mekahli
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Correspondence to Djalila Mekahli.

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1. d; 2. b: 3. e; 4. c; 5. a

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Weydert, C., Decuypere, JP., De Smedt, H. et al. Fundamental insights into autosomal dominant polycystic kidney disease from human-based cell models. Pediatr Nephrol 34, 1697–1715 (2019). https://doi.org/10.1007/s00467-018-4057-5

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  • DOI: https://doi.org/10.1007/s00467-018-4057-5

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