Novel Therapeutic Strategies Targeting Molecular Pathways of Cystogenesis in Autosomal Polycystic Kidney Disease
Main Article Content
Keywords
adult autosomal polycystic kidney disease, cystogenesis, mTOR signaling, somatostatin analogues, vasopressin 2 receptors
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that results from mutations in PKD1 or PKD2. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that destroy the architecture of the renal parenchyma and lead to kidney failure. Until recently, the causes and the molecular pathways that lead to cystogenesis remained obscure. In the last decade, enormous progress has been made in understanding the pathogenesis of ADPKD and the development of new therapies. The purpose of this review is to update on the promising therapies that are being developed and tested based on knowledge of recent advances in molecular and cellular targets involved in cystogenesis.
References
1. Chebib FT, Torres VE. Autosomal dominant polycystic kidney disease: core curriculum 2016. Am J Kidney Dis. 2016;67(5):792–810. http://dx.doi.org/10.1053/j.ajkd.2015.07.037
2. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76(2):149–68. http://dx.doi.org/10.1038/ki.2009.128
3. Rysz J, Gluba-Brzózka A, Franczyk B, Banach M, Bartnicki P. Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Pharmacother. 2016;17(15):2049–56. http://dx.doi.org/10.1080/14656566.2016.1232394
4. Vassilev PM, Guo L, Chen XZ, Segal Y, Peng JB, Basora N, et al. Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(21) homeostasis in polycystic kidney disease. Biochem Biophys Res Commun. 2001;282(1):341–50. http://dx.doi.org/10.1006/bbrc.2001.4554
5. Anyatonwu GI, Ehrlich BE. Organic cation permeation through the channel formed by polycystin-2. J Biol Chem. 2005;280(33):29488–93. http://dx.doi.org/10.1074/jbc.M504359200
6. LaRiviere WB, Irazabal MV, Torres VE. Novel therapeutic approaches to autosomal dominant polycystic kidney disease. Transl Res. 2015;165(4):488–98. https://dx.doi.org/10.1016/j.trsl.2014.11.003
7. Belibi FA, Edelstein CL. Novel targets for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Investig Drugs. 2010;19(3):315–28. http://dx.doi.org/10.1517/13543781003588491
8. Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996;87(6):979–87. http://dx.doi.org/10.1016/S0092-8674(00)81793-6
9. Brasier JL, Henske EP. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J Clin Invest. 1997;99(2):194–9. http://dx.doi.org/10.1172/JCI119147
10. Saigusa T, Bell PD. Molecular pathways and therapies in autosomal-dominant polycystic kidney disease. Physiology (Bethesda). 2015;30(3):195–207. http://dx.doi.org/10.1152/physiol.00032.2014
11. Mochizuki T, Tsuchiya K, Nitta K. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies. Clin Exp Nephrol. 2013;17(3):317–26. http://dx.doi.org/10.1007/s10157-012-0741-0
12. Torres VE, Harris PC. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol. 2014;25(1):18–32. http://dx.doi.org/10.1681/ASN.2013040398
13. Yamaguchi T, Hempson SJ, Reif GA, Hedge AM, Wallace DP. Calcium restores a normal proliferation phenotype in human polycystic kidney disease epithelial cells. J Am Soc Nephrol. 2006;17(1):178–87. http://dx.doi.org/10.1681/ASN.2005060645
14. Paavola J, Schliffke S, Rossetti S, Kuo IY, Yuan S, Sun Z, et al. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol. 2013;58:199–208. http://dx.doi.org/10.1016/j.yjmcc.2013.01.015
15. Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, et al. Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort: renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003;64(3):1035–45. http://dx.doi.org/10.1046/j.1523-1755.2003.00185.x
16. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. Clin J Am Soc Nephrol. 2006;1(1):148–57. http://dx.doi.org/10.2215/CJN.00330705
17. Brill SR, Ross KE, Davidow CJ, Ye M, Grantham JJ, Caplan MJ. Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells. Proc Natl Acad Sci U S A. 1996;93(19):10206–11. http://dx.doi.org/10.1073/pnas.93.19.10206
18. Hanaoka K, Devuyst O, Schwiebert EM, Wilson PD, Guggino WB. A role for CFTR in human autosomal dominant polycystic kidney disease. Am J Physiol. 1996;270(1 pt 1): C389–99.
19. Yamaguchi T, Pelling JC, Ramaswamy NT, Eppler JW, Wallace DP, Nagao S, et al. cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal regulated kinase pathway. Kidney Int. 2000;57(4):1460–71. http://dx.doi.org/10.1046/j.1523-1755.2000.00991.x
20. Hanaoka K, Guggino WB. cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol. 2000;11(7):1179–87.
21. Sweeney WE Jr, von Vigier RO, Frost P, Avner ED. Src inhibition ameliorates polycystic kidney disease. J Am Soc Nephrol. 2008;19(7):1331–41. http://dx.doi.org/10.1681/ASN.2007060665
22. Aguiari G, Bizzarri F, Bonon A, Mangolini A, Magri E, Pedriali M, et al. Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation. J Mol Med (Berl). 2012;90(11):1267–82. http://dx.doi.org/10.1007/s00109-012-0902-3
23. Distefano G, Boca M, Rowe I, Wodarczyk C, Ma L, Piontek KB, et al. Polycystin-1 regulates extracellular signal regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Mol Cell Biol. 2009;29(9):2359–71. http://dx.doi.org/10.1128/MCB.01259-08
24. Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, et al. Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology. 2010;51(5):1778–88. http://dx.doi.org/10.1002/hep.23511
25. Li M, Wang X, Meintzer MK, Laessig T, Birnbaum MJ, Heidenreich KA. Cyclic AMP promotes neuronal survival by phosphorylation of GSK3beta. Mol Cell Biol. 2000;20(24):9356–63. http://dx.doi.org/10.1128/MCB.20.24.9356-9363.2000
26. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem. 2006;281(15):9971–6. http://dx.doi.org/10.1074/jbc.M508778200
27. Qin S, Taglienti M, Cai L, Zhou J, Kreidberg JA. c-Met and NF-kB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol. 2012;23(8):1309–18. http://dx.doi.org/10.1681/ASN.2011030277
28. Talbot JJ, Shillingford JM, Vasanth S, Doerr N, Mukherjee S, Kinter MT, et al. Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci U S A. 2011;108(19):7985–90. http://dx.doi.org/10.1073/pnas.1103816108
29. Leonhard WN, van der Wal A, Novalic Z, Kunnen SJ, Gansevoort RT, Breuning MH, 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. 2011;300(5): F1193–202. http://dx.doi.org/10.1152/ajprenal.00419.2010
30. Takakura A, Nelson EA, Haque N, Humphreys BD, Zandi-Nejad K, Frank DA, et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet. 2011;20(21):4143–54. http://dx.doi.org/10.1093/hmg/ddr338
31. Knepper MA, Kwon TH, Nielsen S. Molecular physiology of water balance. N Engl J Med. 2015;372(14):1349–58. http://dx.doi.org/10.1056/NEJMra1404726
32. Meijer E, Bakker SJL, van der Jagt EJ, Navis G, de Jong PE, Struck J, et al. Copeptin, a surrogate marker of vasopressin, is associated with disease severity in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011;6(2):361–8. http://dx.doi.org/10.2215/CJN.04560510
33. Meijer E, Boertien WE, Zietse R, Gansevoort RT. Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease. Kidney Blood Press Res. 2011;34(4):235–44. http://dx.doi.org/10.1159/000326902
34. Boertien WE, Meijer E, Zittema D, van Dijk MA, Rabelink TJ, Breuning MH, et al. Copeptin, a surrogate marker for vasopressin, is associated with kidney function decline in subjects with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2012;27(11):4131–7. http://dx.doi.org/10.1093/ndt/gfs070
35. Zittema D, Boertien WE, van Beek AP, Dullaart RPF, Franssen CFM, de Jong PE, et al. Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. Clin J Am Soc Nephrol. 2012;7(6):906–13. http://dx.doi.org/10.2215/CJN.11311111
36. Ahrabi AK, Terryn S, Valenti G, Caron N, Serradeil-Le Gal C, Raufaste D, et al. PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. J Am Soc Nephrol. 2007;18(6):1740–53. http://dx.doi.org/10.1681/ASN.2006010052
37. Ho TA, Godefroid N, Gruzon D, Haymann J-P, Maréchal C, Wang X, et al. Autosomal dominant polycystic kidney disease is associated with central and nephrogenic defects in osmoregulation. Kidney Int. 2012;82(10):1121–9. http://dx.doi.org/10.1038/ki.2012.225
38. Yasuda G, Jeffries WB. Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int. 1998;54(1):80–6. http://dx.doi.org/10.1046/j.1523-1755.1998.00990.x
39. Nagao S, Nishii K, Katsuyama M, Kurahashi H, Marunouchi T, Takahashi H, et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol. 2006;17(8):2220–7. http://dx.doi.org/10.1681/ASN.2006030251
40. Gattone VH 2nd, Maser RL, Tian C, Rosenberg JM, Branden MG. Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet. 1999;24(3–4):309–18. http://dx.doi.org/10.1002/(SICI)1520-6408(1999)24:3/4%3C309::AID-DVG14%3E3.0.CO;2-5
41. Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003;9(10):1323–6. http://dx.doi.org/10.1038/nm935
42. Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH II. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004;10(4):363–4. http://dx.doi.org/10.1038/nm1004
43. Meijer E, Gansevoort RT, de Jong PE, van der Wal AM, Leonhard WN, de Krey SR, et al. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug. Nephrol Dial Transplant. 2011;26(8):2445–53. http://dx.doi.org/10.1093/ndt/gfr069
44. Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998;287(3):860–7.
45. Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat, J Am Soc Nephrol. 2005;16(4):846–51. http://dx.doi.org/10.1681/ASN.2004121090
46. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. 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. 2011;301(5): F1005–13. http://dx.doi.org/10.1152/ajprenal.00243.2011
47. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2008;19(1):102–8. http://dx.doi.org/10.1681/ASN.2007060688
48. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, et al. TEMPO 3:4 Trial Investigators: tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18. https://dx.doi.org/10.1056/NEJMoa1205511
49. Irazabal MV, Torres VE, Hogan MC, Glockner J, King BF, Ofstie TG, et al. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2011;80(3):295–301. http://dx.doi.org/10.1038/ki.2011.119
50. Boertien WE, Meijer E, de Jong PE, ter Horst GJ, Renken RJ, van der Jagt EJ, et al. Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis. 2015;65(6):833–41. http://dx.doi.org/10.1053/j.ajkd.2014.11.010
51. Boertien WE, Meijer E, de Jong PE, Bakker SJ, Czerwiec FS, Struck J, et al. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84(6):1278–86. http://dx.doi.org/10.1038/ki.2013.285
52. Gansevoort RT, Meijer E, Chapman AB, Czerwiec FS, Devuyst O, Grantham JJ, et al. TEMPO 3:4 Investigators. Nephrol Dial Transplant. 2016;31(11):1887–94. http://dx.doi.org/10.1093/ndt/gfv422
53. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, et al. Rationale and design of the TEMPO (tolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes) 3–4 study. Am J Kidney Dis. 2011;57(5):692–9. http://dx.doi.org/10.1053/j.ajkd.2010.11.029
54. Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, et al. Tolvaptan in autosomal dominant polycystic kidney disease: three years’ experience. Clin J Am Soc Nephrol. 2011;6(10):2499–507. http://dx.doi.org/10.2215/CJN.03530411
55. Gansevoort RT, Arici M, Benzing T, Birn H, Capasso G, Covic A, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transplant. 2016;31(3):337–48. http://dx.doi.org/10.1093/ndt/gfv456
56. Renal Association Working Group on Tolvaptan in ADPKD. http://www.renal.org/docs/default-source/guidelines-resources/other-guidlines/tolvaptan_in_adpkd-rawg2015_commentary-060516clean.pdf?sfvrsn=0
57. Devuyst O, Chapman AB, Boklage S. Tolerability of aquaretic-related symptoms: results from the TEMPO 3:4 trial [abstract plus poster]. World Congress of Nephrology; 2015. http://www.wcn2015.org/
58. European Medicines Agency. Tolvaptan (Jinarc): summary of product characteristics; 2015. http://www.ema.europa.eu/ [Accessed 18 Sep 2015].
59. Otsuka Pharmaceutical Development and Commercialization. Open-label trial to evaluate the long term safety of titrated immediate-release tolvaptan in subjects with autosomal dominant polycystic kidney disease. 2014. http://www.clinicaltrials.gov/ct2/show/NCT02251275 [Accessed 12 Feb 2017]
60. Otsuka Pharmaceutical Development and Commercialization. Efficacy and safety of tolvaptan in subjects with chronic kidney disease between late stage 2 to early stage 4 due to autosomal dominant polycystic kidney disease. 2014. http://www.clinicaltrials.gov/ct2/show/NCT02160145 [Accessed 12 Feb 2017]
61. Rai U, Thrimawithana TR, Valery C, Young SA. Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmacol Ther. 2015;152:98–110. http://dx.doi.org/10.1016/j.pharmthera.2015.05.007
62. Balster DA, O’Dorisio MS, Summers MA, Turman MA. Segmental expression of somatostatin receptor subtypes sst(1) and sst(2) in tubules and glomeruli of human kidney. Am J Physiol Renal Physiol. 2001;280(3): F457–65.
63. Bates CM, Kegg H, Grady S. Expression of somatostatin in the adult and developing mouse kidney. Kidney Int. 2004;66(5):1785–93. http://dx.doi.org/10.1111/j.1523-1755.2004.00953.x
64. Bates CM, Kegg H, Grady S. Expression of somatostatin receptors 1 and 2 in the adult mouse kidney. Regul Pept. 2004;119(1–2):11–20. http://dx.doi.org/10.1016/j.regpep.2003.12.015
65. Bhandari S, Watson N, Long E, Sharpe S, Zhong W, Xu SZ, et al. Expression of somatostatin and somatostatin receptor subtypes 1–5 in human normal and diseased kidney. J Histochem Cytochem. 2008;56(8):733–43. https://dx.doi.org/10.1369/jhc.2008.950998
66. Friedlander G, Amiel C. Somatostatin and alpha 2-adrenergic agonists selectively inhibit vasopressin-induced cyclic AMP accumulation in MDCK cells. FEBS Lett. 1986;198(1):38–42. http://dx.doi.org/10.1016/0014-5793(86)81180-2
67. Winkler SN, Torikai S, Levine BS, Kurokawa K. Effect of somatostatin on vasopressin-induced antidiuresis and renal cyclic AMP of rats. Miner Electrolyte Metab. 1982;7(1):8–14.
68. Tan CK, Podila PV, Taylor JE, Nagorney DM, Wiseman GA, Gores GJ, et al. Human cholangiocarcinomas express somatostatin receptors and respond to somatostatin with growth inhibition. Gastroenterology. 1995;108(6):1908–16. http://dx.doi.org/10.1016/0016-5085(95)90157-4
69. Irazabal MV, Torres VE. Experimental therapies and ongoing clinical trials to slow down progression of ADPKD. Curr Hypertens Rev. 2013;9(1):44–59. http://dx.doi.org/10.2174/1573402111309010008
70. Ruggenenti P, Remuzzi A, Ondei P, Fasolini G, Antiga L, Ene-Iordache B, et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68(1):206–16. http://dx.doi.org/10.1111/j.1523-1755.2005.00395.x
71. Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A, Remuzzi G, et al. Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin J Am Soc Nephrol. 2010;5(5):783–9. http://dx.doi.org/10.2215/CJN.05380709
72. Tietz Bogert PS, Huang BQ, Gradilone SA, Masyuk TV, Moulder GL, Ekker SC, et al. The zebrafish as a model to study polycystic liver disease. Zebrafish. 2013;10(2):211–17. http://dx.doi.org/10.1089/zeb.2012.0825
73. Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol. 2015;26(1):39–47. http://dx.doi.org/10.1681/ASN.2013121312
74. van Keimpema L, Nevens F, Vanslembrouck R, van Oijen MG, Hoffmann AL, Dekker HM, et al. Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2009;137(5):1661-8.e1-2.
75. Chrispijn M, Nevens F, Gevers TJ, Vanslembrouck R, van Oijen MG, Coudyzer W. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35(2):266–74. http://dx.doi.org/10.1111/j.1365-2036.2011.04923.x
76. Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010;21(6):1052–61. http://dx.doi.org/10.1681/ASN.2009121291
77. Hogan MC, Masyuk TV, Page L, Holmes DR 3rd, Li X, Bergstralh EJ, et al. Somatostatin analog therapy for severe polycystic liver disease: results after 2 years. Nephrol Dial Transplant. 2012;27(9):3532–9. http://dx.doi.org/10.1093/ndt/gfs152
78. Caroli A, Perico N, Perna A, Antiga L, Brambilla P, Pisani A, et al. Effect of long acting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet (London, England). 2013;382(9903):1485–95. http://dx.doi.org/10.1016/S0140-6736(13)61407-5
79. Gevers TJ, Hol JC, Monshouwer R, Dekker HM, Wetzels JF, Drenth JP. Effect of lanreotide on polycystic liver and kidneys in autosomal dominant polycystic kidney disease: an observational trial. Liver Int. 2015;35(5):1607–14. http://doi.org/10.1111/liv.12726
80. Myint TM, Rangan GK, Webster AC. Treatments to slow progression of autosomal dominant polycystic kidney disease: systematic review and meta-analysis of randomized trials. Nephrology (Carlton). 2014;19(4):217–26. http://dx.doi.org/10.1111/nep.12211
81. Lantinga MA, D’Agnolo HM, Casteleijn NF, de Fijter JW, Meijer E, Messchendorp AL, et al. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: an Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study. Drug Saf. 2017; 40(2):153–167.
82. Ibraghimov-Beskrovnaya O, Natoli TA. mTOR signaling in polycystic kidney disease. Trends Mol Med. 2011;17(11):625–33. http://dx.doi.org/10.1016/j.molmed.2011.06.003
83. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – A contiguous gene syndrome. Nat Genet. 1994;8(4):328–32. http://dx.doi.org/10.1038/ng1294-328
84. Cai SL, Walker CL. TSC2, a key player in tumor suppression and cystic kidney disease. Nephrol Ther. 2006;2 Suppl 2:S119–22.
85. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell Biol. 2012;47(4):535–46. http://dx.doi.org/10.1016/j.molcel.2012.06.009
86. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103(14):5466–71. http://dx.doi.org/10.1073/pnas.0509694103
87. Shillingford JM, Piontek KB, Germino GG, Weimbs T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol. 2010;21(3):489–97. http://dx.doi.org/10.1681/ASN.2009040421
88. Wahl PR, Serra AL, Le Hir M, Molle KD, Hall MN, Wüthrich RP. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2006;21(3):598–604. http://dx.doi.org/10.1093/ndt/gfi181
89. Wu M, Wahl PR, Le Hir M, Wackerle-Men Y, Wuthrich RP, Serra AL, et al. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease. Kidney Blood Press Res. 2007;30(4):253–9. http://dx.doi.org/10.1159/000104818
90. Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-Mtor activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst. 2008;100(2):140–54. http://dx.doi.org/10.1093/jnci/djm288
91. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol. 2005;16(1):46–51. http://dx.doi.org/10.1681/ASN.2004080660
92. Zafar I, Belibi FA, He Z, Edelstein CL. Long-term rapamycin therapy in the Han: SPRD rat model of polycystic kidney disease (PKD). Nephrol Dial Transplant. 2009;24(8):2349–53. http://dx.doi.org/10.1093/ndt/gfp129
93. Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):830–40. http://dx.doi.org/10.1056/NEJMoa1003491
94. Serra AL, Poster D, Kistler AD, Krauer F, Raina S, Young J, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820–9. http://dx.doi.org/10.1056/NEJMoa0907419
95. Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol. 2010;21(6):1031–40. http://dx.doi.org/10.1681/ASN.2009121302
96. Stallone G, Infante B, Grandaliano G, Bristogiannis C, Macarini L, Mezzopane D, et al. Rapamycin for treatment of type I autosomal dominant polycystic kidney disease (RAPYD-study): a randomized, controlled study. Nephrol Dial Transplant. 2012;27(9):3560–7. http://dx.doi.org/10.1093/ndt/gfs264
97. Braun WE, Schold JD, Stephany BR, Spirko RA, Herts BR. Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized controlled pilot study. Clin J Am Soc Nephrol. 2014;9(5):881–8. http://dx.doi.org/10.2215/CJN.02650313
98. Moes DJ, Guchelaar HJ, de Fijter JW. Sirolimus and everolimus in kidney transplantation. Drug Discov Today. 2015;20(10):1243–9. http://dx.doi.org/10.1016/j.drudis.2015.05.006
99. Musumeci F, Schenone S, Brullo C, Botta M. An update on dual Src/Abl inhibitors. Future Med Chem. 2012;4(6):799–822. http://dx.doi.org/10.4155/fmc.12.29
100. Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP. Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem. 2004;279(39):40419–30. http://dx.doi.org/10.1074/jbc.M405079200
101. Elliott J, Zheleznova NN, Wilson PD. c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation. Am J Physiol Cell Physiol. 2011;301(2): C522–9. http://dx.doi.org/10.1152/ajpcell.00163.2010
102. Leuenroth SJ, Okuhara D, Shotwell JD, Markowitz GS, Yu Z, Somlo S, et al. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc Natl Acad Sci U S A. 2007;104(11):4389–94. http://dx.doi.org/10.1073/pnas.0700499104
103. Leuenroth SJ, Bencivenga N, Chahboune H, Hyder F, Crews CM. Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD. Nephrol Dial Transplant. 2010;25(7):2187–94. http://dx.doi.org/10.1093/ndt/gfp777
104. Chen D, Ma Y, Wang X, Yu S, Li L, Dai B, et al. Triptolide-containing formulation in patients with autosomal dominant polycystic kidney disease and proteinuria: an uncontrolled trial. Am J Kidney Dis. 2014;63(6):1070–2. http://dx.doi.org/10.1053/j.ajkd.2014.01.418
105. Yamaguchi T, Reif GA, Calvet JP, Wallace DP. Sorafenib inhibits cAMP-dependent ERK activation, cell proliferation, and in vitro cyst growth of human ADPKD cyst epithelial cells. Am J Physiol Renal Physiol. 2010;299(5): F944–51. http://dx.doi.org/10.1152/ajprenal.00387.2010
106. Spirli C, Morell CM, Locatelli L, Okolicsanyi S, Ferrero C, Kim AK, et al. Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with sorafenib. Hepatology. 2012;56(6):2363–74. http://dx.doi.org/10.1002/hep.25872
107. Buchholz B, Klanke B, Schley G, Bollag G, Tsai J, Kroening S. The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis. Nephrol Dial Transplant. 2011;26(11):3458–65. http://dx.doi.org/10.1093/ndt/gfr432
108. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell. 2002;109(2):157–68. http://dx.doi.org/10.1016/S0092-8674(02)00716-X
109. Li X, Luo Y, Starremans PG, McNamara CA, Pei Y, Zhou J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat Cell Biol. 2005;7(12):1202–12. http://dx.doi.org/10.1038/ncb1326
110. Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature. 2006;444(7121):949–52. http://dx.doi.org/10.1038/nature05348
111. Bukanov NO, Moreno SE, Natoli TA, Rogers KA, Smith LA, Ledbetter SR, et al. CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. Cell Cycle. 2012;11(21):4040–6. http://dx.doi.org/10.4161/cc.22375
112. Chen HP, Zhao YT, Zhao TC. Histone deacetylases and mechanisms of regulation of gene expression. Crit Rev Oncog. 2015;20(1–2):35–47. http://dx.doi.org/10.1615/CritRevOncog.2015012997
113. Cao Y, Semanchik N, Lee SH, Somlo S, Barbano PE, Coifman R, et al. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc Natl Acad Sci U S A. 2009;106(51):21819–24. http://dx.doi.org/10.1073/pnas.0911987106
114. Xia S, Li X, Johnson T, Seidel C, Wallace DP, Li R. Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts. Development. 2010;137(7):1075–84. http://dx.doi.org/10.1242/dev.049437
115. Fan LX, Li X, Magenheimer B, Calvet JP, Li X. Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. Kidney Int. 2012;81(1):76–85. http://dx.doi.org/10.1038/ki.2011.296
116. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25(3):138–45. http://dx.doi.org/10.1016/j.tem.2013.12.001
117. Zhou X, Fan LX, Sweeney WE Jr, Denu JM, Avner ED, Li X. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J Clin Invest. 2013;123(7):3084–98. http://dx.doi.org/10.1172/JCI64401
118. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066–73. http://dx.doi.org/10.1126/science.2475911
119. Akabas MH. Cystic fibrosis transmembrane conductance regulator. Structure and function of an epithelial chloride channel. J Biol Chem. 2000;275(6):3729–32. http://dx.doi.org/10.1074/jbc.275.6.3729
120. Morales MM, Falkenstein D, Lopes AG. The cystic fibrosis transmembrane regulator (CFTR) in the kidney. An Acad Bras Cienc. 2000;72(3):399–406. http://dx.doi.org/10.1590/S0001-37652000000300013
121. O’Sullivan DA, Torres VE, Gabow PA, Thibodeau SN, King BF, Bergstralh EJ. Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease. Am J Kidney Dis. 1998;32(6):976–83. http://doi.org/10.1016/S0272-6386(98)70072-1
122. Persu A, Devuyst O, Lannoy N, Materne R, Brosnahan G, Gabow PA, et al. CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2000;11(12):2285–96.
123. Xu N, Glockner JF, Rossetti S, Babovich-Vuksanovic D, Harris PC, Torres VE. Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. J Nephrol. 2006;19(4):529–34.
124. Yang B, Sonawane ND, Zhao D, Somlo S, Verkman AS. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2008;19:1300–10. http://dx.doi.org/10.1681/ASN.2007070828
125. Tradtrantip L, Sonawane ND, Namkung W, Verkman AS. Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model. J Med Chem. 2009;52(20):6447–55. http://dx.doi.org/10.1021/jm9009873
126. Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS. Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem. 2011;54(15):5468–77. http://dx.doi.org/10.1021/jm200505e
127. Albaqumi M, Srivastava S, Li Z, Zhdnova O, Wulff H, Itani O, et al. KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease. Kidney Int. 2008;74(6):740–9. http://dx.doi.org/10.1038/ki.2008.246
128. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;26;115(5):577–90. http://dx.doi.org/10.1016/S0092-8674(03)00929-2
129. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–26. http://dx.doi.org/10.1016/j.molcel.2008.03.003
130. Hallows KR, Raghuram V, Kemp BE, Witters LA, Foskett JK. Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase. J Clin Invest. 2000;105(12):1711–21. http://dx.doi.org/10.1172/JCI9622
131. King JD Jr, Fitch AC, Lee JK, McCane JE, Mak DO, Foskett JK. AMP-activated protein kinase phosphorylation of the R domain inhibits PKA stimulation of CFTR. Am J Physiol Cell Physiol. 2009;297(1): C94–101. http://dx.doi.org/10.1152/ajpcell.00677.2008
132. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74. http://dx.doi.org/10.1172/JCI13505
133. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–6. http://dx.doi.org/10.1126/science.1120781
134. Takiar V, Nishio S, Seo-Mayer P, King JD Jr, Li H, Zhang L, et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A. 2011;108(6):2462–7. http://dx.doi.org/10.1073/pnas.1011498108
135. Blazer-Yost BL, Haydon J, Eggleston-Gulyas T, Chen JH, Wang X, Gattone V, et al. Pioglitazone attenuates cystic burden in the PCK rodent model of polycystic kidney disease. PPAR Res. 2010;2010:274376. http://dx.doi.org/10.1155/2010/274376
136. Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am J Physiol Renal Physiol. 2011;300(2): F465–74. http://dx.doi.org/10.1152/ajprenal.00460.2010
137. Muto S, Aiba A, Saito Y, Nakao K, Nakamura K, Tomita K, et al. Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Hum Mol Genet. 2002;11(15):1731–42. http://dx.doi.org/10.1093/hmg/11.15.1731
138. Dai B, Liu Y, Mei C, Fu L, Xiong X, Zhang Y, et al. Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han: SPRD rats. Clin Sci (Lond). 2010;119(8):323–33. http://doi.org/10.1042/CS20100113
139. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med. 2010;16(7):788–92. http://dx.doi.org/10.1038/nm.2171
140. Natoli TA, Husson H, Rogers KA, Smith LA, Wang B, Budman Y, et al. Loss of GM3 synthase gene, but not sphingosine kinase 1, is protective against murine nephronophthisis-related polycystic kidney disease. Hum Mol Genet. 2012;21(15):3397–407. http://dx.doi.org/10.1093/hmg/dds172
141. Turner CM, Ramesh B, Srai SK, Burnstock G, Unwin RJ. Altered ATP-sensitive P2 receptor subtype expression in the Han: SPRD cy/+ rat, a model of autosomal dominant polycystic kidney disease. Cells Tissues Organs. 2004;178(3):168–79. http://dx.doi.org/10.1159/000082247
142. Xu C, Shmukler BE, Nishimura K, Kaczmarek E, Rossetti S, Harris PC, et al. 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. 2009;296(6): F1464–76. http://dx.doi.org/10.1152/ajprenal.90542.2008
143. Chang MY, Lu JK, Tian YC, Chen YC, Hung CC, Huang YH. Inhibition of the P2X7 receptor reduces cystogenesis in PKD. J Am Soc Nephrol. 2011;22(9):1696–706. http://dx.doi.org/10.1681/ASN.2010070728
2. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76(2):149–68. http://dx.doi.org/10.1038/ki.2009.128
3. Rysz J, Gluba-Brzózka A, Franczyk B, Banach M, Bartnicki P. Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Pharmacother. 2016;17(15):2049–56. http://dx.doi.org/10.1080/14656566.2016.1232394
4. Vassilev PM, Guo L, Chen XZ, Segal Y, Peng JB, Basora N, et al. Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(21) homeostasis in polycystic kidney disease. Biochem Biophys Res Commun. 2001;282(1):341–50. http://dx.doi.org/10.1006/bbrc.2001.4554
5. Anyatonwu GI, Ehrlich BE. Organic cation permeation through the channel formed by polycystin-2. J Biol Chem. 2005;280(33):29488–93. http://dx.doi.org/10.1074/jbc.M504359200
6. LaRiviere WB, Irazabal MV, Torres VE. Novel therapeutic approaches to autosomal dominant polycystic kidney disease. Transl Res. 2015;165(4):488–98. https://dx.doi.org/10.1016/j.trsl.2014.11.003
7. Belibi FA, Edelstein CL. Novel targets for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Investig Drugs. 2010;19(3):315–28. http://dx.doi.org/10.1517/13543781003588491
8. Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996;87(6):979–87. http://dx.doi.org/10.1016/S0092-8674(00)81793-6
9. Brasier JL, Henske EP. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J Clin Invest. 1997;99(2):194–9. http://dx.doi.org/10.1172/JCI119147
10. Saigusa T, Bell PD. Molecular pathways and therapies in autosomal-dominant polycystic kidney disease. Physiology (Bethesda). 2015;30(3):195–207. http://dx.doi.org/10.1152/physiol.00032.2014
11. Mochizuki T, Tsuchiya K, Nitta K. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies. Clin Exp Nephrol. 2013;17(3):317–26. http://dx.doi.org/10.1007/s10157-012-0741-0
12. Torres VE, Harris PC. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol. 2014;25(1):18–32. http://dx.doi.org/10.1681/ASN.2013040398
13. Yamaguchi T, Hempson SJ, Reif GA, Hedge AM, Wallace DP. Calcium restores a normal proliferation phenotype in human polycystic kidney disease epithelial cells. J Am Soc Nephrol. 2006;17(1):178–87. http://dx.doi.org/10.1681/ASN.2005060645
14. Paavola J, Schliffke S, Rossetti S, Kuo IY, Yuan S, Sun Z, et al. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol. 2013;58:199–208. http://dx.doi.org/10.1016/j.yjmcc.2013.01.015
15. Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, et al. Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort: renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003;64(3):1035–45. http://dx.doi.org/10.1046/j.1523-1755.2003.00185.x
16. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. Clin J Am Soc Nephrol. 2006;1(1):148–57. http://dx.doi.org/10.2215/CJN.00330705
17. Brill SR, Ross KE, Davidow CJ, Ye M, Grantham JJ, Caplan MJ. Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells. Proc Natl Acad Sci U S A. 1996;93(19):10206–11. http://dx.doi.org/10.1073/pnas.93.19.10206
18. Hanaoka K, Devuyst O, Schwiebert EM, Wilson PD, Guggino WB. A role for CFTR in human autosomal dominant polycystic kidney disease. Am J Physiol. 1996;270(1 pt 1): C389–99.
19. Yamaguchi T, Pelling JC, Ramaswamy NT, Eppler JW, Wallace DP, Nagao S, et al. cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal regulated kinase pathway. Kidney Int. 2000;57(4):1460–71. http://dx.doi.org/10.1046/j.1523-1755.2000.00991.x
20. Hanaoka K, Guggino WB. cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol. 2000;11(7):1179–87.
21. Sweeney WE Jr, von Vigier RO, Frost P, Avner ED. Src inhibition ameliorates polycystic kidney disease. J Am Soc Nephrol. 2008;19(7):1331–41. http://dx.doi.org/10.1681/ASN.2007060665
22. Aguiari G, Bizzarri F, Bonon A, Mangolini A, Magri E, Pedriali M, et al. Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation. J Mol Med (Berl). 2012;90(11):1267–82. http://dx.doi.org/10.1007/s00109-012-0902-3
23. Distefano G, Boca M, Rowe I, Wodarczyk C, Ma L, Piontek KB, et al. Polycystin-1 regulates extracellular signal regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Mol Cell Biol. 2009;29(9):2359–71. http://dx.doi.org/10.1128/MCB.01259-08
24. Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, et al. Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology. 2010;51(5):1778–88. http://dx.doi.org/10.1002/hep.23511
25. Li M, Wang X, Meintzer MK, Laessig T, Birnbaum MJ, Heidenreich KA. Cyclic AMP promotes neuronal survival by phosphorylation of GSK3beta. Mol Cell Biol. 2000;20(24):9356–63. http://dx.doi.org/10.1128/MCB.20.24.9356-9363.2000
26. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem. 2006;281(15):9971–6. http://dx.doi.org/10.1074/jbc.M508778200
27. Qin S, Taglienti M, Cai L, Zhou J, Kreidberg JA. c-Met and NF-kB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol. 2012;23(8):1309–18. http://dx.doi.org/10.1681/ASN.2011030277
28. Talbot JJ, Shillingford JM, Vasanth S, Doerr N, Mukherjee S, Kinter MT, et al. Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci U S A. 2011;108(19):7985–90. http://dx.doi.org/10.1073/pnas.1103816108
29. Leonhard WN, van der Wal A, Novalic Z, Kunnen SJ, Gansevoort RT, Breuning MH, 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. 2011;300(5): F1193–202. http://dx.doi.org/10.1152/ajprenal.00419.2010
30. Takakura A, Nelson EA, Haque N, Humphreys BD, Zandi-Nejad K, Frank DA, et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet. 2011;20(21):4143–54. http://dx.doi.org/10.1093/hmg/ddr338
31. Knepper MA, Kwon TH, Nielsen S. Molecular physiology of water balance. N Engl J Med. 2015;372(14):1349–58. http://dx.doi.org/10.1056/NEJMra1404726
32. Meijer E, Bakker SJL, van der Jagt EJ, Navis G, de Jong PE, Struck J, et al. Copeptin, a surrogate marker of vasopressin, is associated with disease severity in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011;6(2):361–8. http://dx.doi.org/10.2215/CJN.04560510
33. Meijer E, Boertien WE, Zietse R, Gansevoort RT. Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease. Kidney Blood Press Res. 2011;34(4):235–44. http://dx.doi.org/10.1159/000326902
34. Boertien WE, Meijer E, Zittema D, van Dijk MA, Rabelink TJ, Breuning MH, et al. Copeptin, a surrogate marker for vasopressin, is associated with kidney function decline in subjects with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2012;27(11):4131–7. http://dx.doi.org/10.1093/ndt/gfs070
35. Zittema D, Boertien WE, van Beek AP, Dullaart RPF, Franssen CFM, de Jong PE, et al. Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. Clin J Am Soc Nephrol. 2012;7(6):906–13. http://dx.doi.org/10.2215/CJN.11311111
36. Ahrabi AK, Terryn S, Valenti G, Caron N, Serradeil-Le Gal C, Raufaste D, et al. PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. J Am Soc Nephrol. 2007;18(6):1740–53. http://dx.doi.org/10.1681/ASN.2006010052
37. Ho TA, Godefroid N, Gruzon D, Haymann J-P, Maréchal C, Wang X, et al. Autosomal dominant polycystic kidney disease is associated with central and nephrogenic defects in osmoregulation. Kidney Int. 2012;82(10):1121–9. http://dx.doi.org/10.1038/ki.2012.225
38. Yasuda G, Jeffries WB. Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int. 1998;54(1):80–6. http://dx.doi.org/10.1046/j.1523-1755.1998.00990.x
39. Nagao S, Nishii K, Katsuyama M, Kurahashi H, Marunouchi T, Takahashi H, et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol. 2006;17(8):2220–7. http://dx.doi.org/10.1681/ASN.2006030251
40. Gattone VH 2nd, Maser RL, Tian C, Rosenberg JM, Branden MG. Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet. 1999;24(3–4):309–18. http://dx.doi.org/10.1002/(SICI)1520-6408(1999)24:3/4%3C309::AID-DVG14%3E3.0.CO;2-5
41. Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003;9(10):1323–6. http://dx.doi.org/10.1038/nm935
42. Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH II. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004;10(4):363–4. http://dx.doi.org/10.1038/nm1004
43. Meijer E, Gansevoort RT, de Jong PE, van der Wal AM, Leonhard WN, de Krey SR, et al. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug. Nephrol Dial Transplant. 2011;26(8):2445–53. http://dx.doi.org/10.1093/ndt/gfr069
44. Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998;287(3):860–7.
45. Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat, J Am Soc Nephrol. 2005;16(4):846–51. http://dx.doi.org/10.1681/ASN.2004121090
46. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. 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. 2011;301(5): F1005–13. http://dx.doi.org/10.1152/ajprenal.00243.2011
47. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2008;19(1):102–8. http://dx.doi.org/10.1681/ASN.2007060688
48. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, et al. TEMPO 3:4 Trial Investigators: tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18. https://dx.doi.org/10.1056/NEJMoa1205511
49. Irazabal MV, Torres VE, Hogan MC, Glockner J, King BF, Ofstie TG, et al. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2011;80(3):295–301. http://dx.doi.org/10.1038/ki.2011.119
50. Boertien WE, Meijer E, de Jong PE, ter Horst GJ, Renken RJ, van der Jagt EJ, et al. Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis. 2015;65(6):833–41. http://dx.doi.org/10.1053/j.ajkd.2014.11.010
51. Boertien WE, Meijer E, de Jong PE, Bakker SJ, Czerwiec FS, Struck J, et al. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84(6):1278–86. http://dx.doi.org/10.1038/ki.2013.285
52. Gansevoort RT, Meijer E, Chapman AB, Czerwiec FS, Devuyst O, Grantham JJ, et al. TEMPO 3:4 Investigators. Nephrol Dial Transplant. 2016;31(11):1887–94. http://dx.doi.org/10.1093/ndt/gfv422
53. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, et al. Rationale and design of the TEMPO (tolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes) 3–4 study. Am J Kidney Dis. 2011;57(5):692–9. http://dx.doi.org/10.1053/j.ajkd.2010.11.029
54. Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, et al. Tolvaptan in autosomal dominant polycystic kidney disease: three years’ experience. Clin J Am Soc Nephrol. 2011;6(10):2499–507. http://dx.doi.org/10.2215/CJN.03530411
55. Gansevoort RT, Arici M, Benzing T, Birn H, Capasso G, Covic A, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transplant. 2016;31(3):337–48. http://dx.doi.org/10.1093/ndt/gfv456
56. Renal Association Working Group on Tolvaptan in ADPKD. http://www.renal.org/docs/default-source/guidelines-resources/other-guidlines/tolvaptan_in_adpkd-rawg2015_commentary-060516clean.pdf?sfvrsn=0
57. Devuyst O, Chapman AB, Boklage S. Tolerability of aquaretic-related symptoms: results from the TEMPO 3:4 trial [abstract plus poster]. World Congress of Nephrology; 2015. http://www.wcn2015.org/
58. European Medicines Agency. Tolvaptan (Jinarc): summary of product characteristics; 2015. http://www.ema.europa.eu/ [Accessed 18 Sep 2015].
59. Otsuka Pharmaceutical Development and Commercialization. Open-label trial to evaluate the long term safety of titrated immediate-release tolvaptan in subjects with autosomal dominant polycystic kidney disease. 2014. http://www.clinicaltrials.gov/ct2/show/NCT02251275 [Accessed 12 Feb 2017]
60. Otsuka Pharmaceutical Development and Commercialization. Efficacy and safety of tolvaptan in subjects with chronic kidney disease between late stage 2 to early stage 4 due to autosomal dominant polycystic kidney disease. 2014. http://www.clinicaltrials.gov/ct2/show/NCT02160145 [Accessed 12 Feb 2017]
61. Rai U, Thrimawithana TR, Valery C, Young SA. Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmacol Ther. 2015;152:98–110. http://dx.doi.org/10.1016/j.pharmthera.2015.05.007
62. Balster DA, O’Dorisio MS, Summers MA, Turman MA. Segmental expression of somatostatin receptor subtypes sst(1) and sst(2) in tubules and glomeruli of human kidney. Am J Physiol Renal Physiol. 2001;280(3): F457–65.
63. Bates CM, Kegg H, Grady S. Expression of somatostatin in the adult and developing mouse kidney. Kidney Int. 2004;66(5):1785–93. http://dx.doi.org/10.1111/j.1523-1755.2004.00953.x
64. Bates CM, Kegg H, Grady S. Expression of somatostatin receptors 1 and 2 in the adult mouse kidney. Regul Pept. 2004;119(1–2):11–20. http://dx.doi.org/10.1016/j.regpep.2003.12.015
65. Bhandari S, Watson N, Long E, Sharpe S, Zhong W, Xu SZ, et al. Expression of somatostatin and somatostatin receptor subtypes 1–5 in human normal and diseased kidney. J Histochem Cytochem. 2008;56(8):733–43. https://dx.doi.org/10.1369/jhc.2008.950998
66. Friedlander G, Amiel C. Somatostatin and alpha 2-adrenergic agonists selectively inhibit vasopressin-induced cyclic AMP accumulation in MDCK cells. FEBS Lett. 1986;198(1):38–42. http://dx.doi.org/10.1016/0014-5793(86)81180-2
67. Winkler SN, Torikai S, Levine BS, Kurokawa K. Effect of somatostatin on vasopressin-induced antidiuresis and renal cyclic AMP of rats. Miner Electrolyte Metab. 1982;7(1):8–14.
68. Tan CK, Podila PV, Taylor JE, Nagorney DM, Wiseman GA, Gores GJ, et al. Human cholangiocarcinomas express somatostatin receptors and respond to somatostatin with growth inhibition. Gastroenterology. 1995;108(6):1908–16. http://dx.doi.org/10.1016/0016-5085(95)90157-4
69. Irazabal MV, Torres VE. Experimental therapies and ongoing clinical trials to slow down progression of ADPKD. Curr Hypertens Rev. 2013;9(1):44–59. http://dx.doi.org/10.2174/1573402111309010008
70. Ruggenenti P, Remuzzi A, Ondei P, Fasolini G, Antiga L, Ene-Iordache B, et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68(1):206–16. http://dx.doi.org/10.1111/j.1523-1755.2005.00395.x
71. Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A, Remuzzi G, et al. Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin J Am Soc Nephrol. 2010;5(5):783–9. http://dx.doi.org/10.2215/CJN.05380709
72. Tietz Bogert PS, Huang BQ, Gradilone SA, Masyuk TV, Moulder GL, Ekker SC, et al. The zebrafish as a model to study polycystic liver disease. Zebrafish. 2013;10(2):211–17. http://dx.doi.org/10.1089/zeb.2012.0825
73. Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol. 2015;26(1):39–47. http://dx.doi.org/10.1681/ASN.2013121312
74. van Keimpema L, Nevens F, Vanslembrouck R, van Oijen MG, Hoffmann AL, Dekker HM, et al. Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2009;137(5):1661-8.e1-2.
75. Chrispijn M, Nevens F, Gevers TJ, Vanslembrouck R, van Oijen MG, Coudyzer W. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35(2):266–74. http://dx.doi.org/10.1111/j.1365-2036.2011.04923.x
76. Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010;21(6):1052–61. http://dx.doi.org/10.1681/ASN.2009121291
77. Hogan MC, Masyuk TV, Page L, Holmes DR 3rd, Li X, Bergstralh EJ, et al. Somatostatin analog therapy for severe polycystic liver disease: results after 2 years. Nephrol Dial Transplant. 2012;27(9):3532–9. http://dx.doi.org/10.1093/ndt/gfs152
78. Caroli A, Perico N, Perna A, Antiga L, Brambilla P, Pisani A, et al. Effect of long acting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet (London, England). 2013;382(9903):1485–95. http://dx.doi.org/10.1016/S0140-6736(13)61407-5
79. Gevers TJ, Hol JC, Monshouwer R, Dekker HM, Wetzels JF, Drenth JP. Effect of lanreotide on polycystic liver and kidneys in autosomal dominant polycystic kidney disease: an observational trial. Liver Int. 2015;35(5):1607–14. http://doi.org/10.1111/liv.12726
80. Myint TM, Rangan GK, Webster AC. Treatments to slow progression of autosomal dominant polycystic kidney disease: systematic review and meta-analysis of randomized trials. Nephrology (Carlton). 2014;19(4):217–26. http://dx.doi.org/10.1111/nep.12211
81. Lantinga MA, D’Agnolo HM, Casteleijn NF, de Fijter JW, Meijer E, Messchendorp AL, et al. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: an Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study. Drug Saf. 2017; 40(2):153–167.
82. Ibraghimov-Beskrovnaya O, Natoli TA. mTOR signaling in polycystic kidney disease. Trends Mol Med. 2011;17(11):625–33. http://dx.doi.org/10.1016/j.molmed.2011.06.003
83. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – A contiguous gene syndrome. Nat Genet. 1994;8(4):328–32. http://dx.doi.org/10.1038/ng1294-328
84. Cai SL, Walker CL. TSC2, a key player in tumor suppression and cystic kidney disease. Nephrol Ther. 2006;2 Suppl 2:S119–22.
85. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell Biol. 2012;47(4):535–46. http://dx.doi.org/10.1016/j.molcel.2012.06.009
86. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103(14):5466–71. http://dx.doi.org/10.1073/pnas.0509694103
87. Shillingford JM, Piontek KB, Germino GG, Weimbs T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol. 2010;21(3):489–97. http://dx.doi.org/10.1681/ASN.2009040421
88. Wahl PR, Serra AL, Le Hir M, Molle KD, Hall MN, Wüthrich RP. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2006;21(3):598–604. http://dx.doi.org/10.1093/ndt/gfi181
89. Wu M, Wahl PR, Le Hir M, Wackerle-Men Y, Wuthrich RP, Serra AL, et al. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease. Kidney Blood Press Res. 2007;30(4):253–9. http://dx.doi.org/10.1159/000104818
90. Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-Mtor activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst. 2008;100(2):140–54. http://dx.doi.org/10.1093/jnci/djm288
91. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol. 2005;16(1):46–51. http://dx.doi.org/10.1681/ASN.2004080660
92. Zafar I, Belibi FA, He Z, Edelstein CL. Long-term rapamycin therapy in the Han: SPRD rat model of polycystic kidney disease (PKD). Nephrol Dial Transplant. 2009;24(8):2349–53. http://dx.doi.org/10.1093/ndt/gfp129
93. Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):830–40. http://dx.doi.org/10.1056/NEJMoa1003491
94. Serra AL, Poster D, Kistler AD, Krauer F, Raina S, Young J, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820–9. http://dx.doi.org/10.1056/NEJMoa0907419
95. Perico N, Antiga L, Caroli A, Ruggenenti P, Fasolini G, Cafaro M, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol. 2010;21(6):1031–40. http://dx.doi.org/10.1681/ASN.2009121302
96. Stallone G, Infante B, Grandaliano G, Bristogiannis C, Macarini L, Mezzopane D, et al. Rapamycin for treatment of type I autosomal dominant polycystic kidney disease (RAPYD-study): a randomized, controlled study. Nephrol Dial Transplant. 2012;27(9):3560–7. http://dx.doi.org/10.1093/ndt/gfs264
97. Braun WE, Schold JD, Stephany BR, Spirko RA, Herts BR. Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized controlled pilot study. Clin J Am Soc Nephrol. 2014;9(5):881–8. http://dx.doi.org/10.2215/CJN.02650313
98. Moes DJ, Guchelaar HJ, de Fijter JW. Sirolimus and everolimus in kidney transplantation. Drug Discov Today. 2015;20(10):1243–9. http://dx.doi.org/10.1016/j.drudis.2015.05.006
99. Musumeci F, Schenone S, Brullo C, Botta M. An update on dual Src/Abl inhibitors. Future Med Chem. 2012;4(6):799–822. http://dx.doi.org/10.4155/fmc.12.29
100. Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP. Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem. 2004;279(39):40419–30. http://dx.doi.org/10.1074/jbc.M405079200
101. Elliott J, Zheleznova NN, Wilson PD. c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation. Am J Physiol Cell Physiol. 2011;301(2): C522–9. http://dx.doi.org/10.1152/ajpcell.00163.2010
102. Leuenroth SJ, Okuhara D, Shotwell JD, Markowitz GS, Yu Z, Somlo S, et al. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc Natl Acad Sci U S A. 2007;104(11):4389–94. http://dx.doi.org/10.1073/pnas.0700499104
103. Leuenroth SJ, Bencivenga N, Chahboune H, Hyder F, Crews CM. Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD. Nephrol Dial Transplant. 2010;25(7):2187–94. http://dx.doi.org/10.1093/ndt/gfp777
104. Chen D, Ma Y, Wang X, Yu S, Li L, Dai B, et al. Triptolide-containing formulation in patients with autosomal dominant polycystic kidney disease and proteinuria: an uncontrolled trial. Am J Kidney Dis. 2014;63(6):1070–2. http://dx.doi.org/10.1053/j.ajkd.2014.01.418
105. Yamaguchi T, Reif GA, Calvet JP, Wallace DP. Sorafenib inhibits cAMP-dependent ERK activation, cell proliferation, and in vitro cyst growth of human ADPKD cyst epithelial cells. Am J Physiol Renal Physiol. 2010;299(5): F944–51. http://dx.doi.org/10.1152/ajprenal.00387.2010
106. Spirli C, Morell CM, Locatelli L, Okolicsanyi S, Ferrero C, Kim AK, et al. Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with sorafenib. Hepatology. 2012;56(6):2363–74. http://dx.doi.org/10.1002/hep.25872
107. Buchholz B, Klanke B, Schley G, Bollag G, Tsai J, Kroening S. The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis. Nephrol Dial Transplant. 2011;26(11):3458–65. http://dx.doi.org/10.1093/ndt/gfr432
108. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell. 2002;109(2):157–68. http://dx.doi.org/10.1016/S0092-8674(02)00716-X
109. Li X, Luo Y, Starremans PG, McNamara CA, Pei Y, Zhou J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat Cell Biol. 2005;7(12):1202–12. http://dx.doi.org/10.1038/ncb1326
110. Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature. 2006;444(7121):949–52. http://dx.doi.org/10.1038/nature05348
111. Bukanov NO, Moreno SE, Natoli TA, Rogers KA, Smith LA, Ledbetter SR, et al. CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. Cell Cycle. 2012;11(21):4040–6. http://dx.doi.org/10.4161/cc.22375
112. Chen HP, Zhao YT, Zhao TC. Histone deacetylases and mechanisms of regulation of gene expression. Crit Rev Oncog. 2015;20(1–2):35–47. http://dx.doi.org/10.1615/CritRevOncog.2015012997
113. Cao Y, Semanchik N, Lee SH, Somlo S, Barbano PE, Coifman R, et al. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc Natl Acad Sci U S A. 2009;106(51):21819–24. http://dx.doi.org/10.1073/pnas.0911987106
114. Xia S, Li X, Johnson T, Seidel C, Wallace DP, Li R. Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts. Development. 2010;137(7):1075–84. http://dx.doi.org/10.1242/dev.049437
115. Fan LX, Li X, Magenheimer B, Calvet JP, Li X. Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. Kidney Int. 2012;81(1):76–85. http://dx.doi.org/10.1038/ki.2011.296
116. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25(3):138–45. http://dx.doi.org/10.1016/j.tem.2013.12.001
117. Zhou X, Fan LX, Sweeney WE Jr, Denu JM, Avner ED, Li X. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J Clin Invest. 2013;123(7):3084–98. http://dx.doi.org/10.1172/JCI64401
118. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066–73. http://dx.doi.org/10.1126/science.2475911
119. Akabas MH. Cystic fibrosis transmembrane conductance regulator. Structure and function of an epithelial chloride channel. J Biol Chem. 2000;275(6):3729–32. http://dx.doi.org/10.1074/jbc.275.6.3729
120. Morales MM, Falkenstein D, Lopes AG. The cystic fibrosis transmembrane regulator (CFTR) in the kidney. An Acad Bras Cienc. 2000;72(3):399–406. http://dx.doi.org/10.1590/S0001-37652000000300013
121. O’Sullivan DA, Torres VE, Gabow PA, Thibodeau SN, King BF, Bergstralh EJ. Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease. Am J Kidney Dis. 1998;32(6):976–83. http://doi.org/10.1016/S0272-6386(98)70072-1
122. Persu A, Devuyst O, Lannoy N, Materne R, Brosnahan G, Gabow PA, et al. CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2000;11(12):2285–96.
123. Xu N, Glockner JF, Rossetti S, Babovich-Vuksanovic D, Harris PC, Torres VE. Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. J Nephrol. 2006;19(4):529–34.
124. Yang B, Sonawane ND, Zhao D, Somlo S, Verkman AS. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2008;19:1300–10. http://dx.doi.org/10.1681/ASN.2007070828
125. Tradtrantip L, Sonawane ND, Namkung W, Verkman AS. Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model. J Med Chem. 2009;52(20):6447–55. http://dx.doi.org/10.1021/jm9009873
126. Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS. Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem. 2011;54(15):5468–77. http://dx.doi.org/10.1021/jm200505e
127. Albaqumi M, Srivastava S, Li Z, Zhdnova O, Wulff H, Itani O, et al. KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease. Kidney Int. 2008;74(6):740–9. http://dx.doi.org/10.1038/ki.2008.246
128. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;26;115(5):577–90. http://dx.doi.org/10.1016/S0092-8674(03)00929-2
129. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–26. http://dx.doi.org/10.1016/j.molcel.2008.03.003
130. Hallows KR, Raghuram V, Kemp BE, Witters LA, Foskett JK. Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase. J Clin Invest. 2000;105(12):1711–21. http://dx.doi.org/10.1172/JCI9622
131. King JD Jr, Fitch AC, Lee JK, McCane JE, Mak DO, Foskett JK. AMP-activated protein kinase phosphorylation of the R domain inhibits PKA stimulation of CFTR. Am J Physiol Cell Physiol. 2009;297(1): C94–101. http://dx.doi.org/10.1152/ajpcell.00677.2008
132. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74. http://dx.doi.org/10.1172/JCI13505
133. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–6. http://dx.doi.org/10.1126/science.1120781
134. Takiar V, Nishio S, Seo-Mayer P, King JD Jr, Li H, Zhang L, et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A. 2011;108(6):2462–7. http://dx.doi.org/10.1073/pnas.1011498108
135. Blazer-Yost BL, Haydon J, Eggleston-Gulyas T, Chen JH, Wang X, Gattone V, et al. Pioglitazone attenuates cystic burden in the PCK rodent model of polycystic kidney disease. PPAR Res. 2010;2010:274376. http://dx.doi.org/10.1155/2010/274376
136. Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am J Physiol Renal Physiol. 2011;300(2): F465–74. http://dx.doi.org/10.1152/ajprenal.00460.2010
137. Muto S, Aiba A, Saito Y, Nakao K, Nakamura K, Tomita K, et al. Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Hum Mol Genet. 2002;11(15):1731–42. http://dx.doi.org/10.1093/hmg/11.15.1731
138. Dai B, Liu Y, Mei C, Fu L, Xiong X, Zhang Y, et al. Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han: SPRD rats. Clin Sci (Lond). 2010;119(8):323–33. http://doi.org/10.1042/CS20100113
139. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med. 2010;16(7):788–92. http://dx.doi.org/10.1038/nm.2171
140. Natoli TA, Husson H, Rogers KA, Smith LA, Wang B, Budman Y, et al. Loss of GM3 synthase gene, but not sphingosine kinase 1, is protective against murine nephronophthisis-related polycystic kidney disease. Hum Mol Genet. 2012;21(15):3397–407. http://dx.doi.org/10.1093/hmg/dds172
141. Turner CM, Ramesh B, Srai SK, Burnstock G, Unwin RJ. Altered ATP-sensitive P2 receptor subtype expression in the Han: SPRD cy/+ rat, a model of autosomal dominant polycystic kidney disease. Cells Tissues Organs. 2004;178(3):168–79. http://dx.doi.org/10.1159/000082247
142. Xu C, Shmukler BE, Nishimura K, Kaczmarek E, Rossetti S, Harris PC, et al. 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. 2009;296(6): F1464–76. http://dx.doi.org/10.1152/ajprenal.90542.2008
143. Chang MY, Lu JK, Tian YC, Chen YC, Hung CC, Huang YH. Inhibition of the P2X7 receptor reduces cystogenesis in PKD. J Am Soc Nephrol. 2011;22(9):1696–706. http://dx.doi.org/10.1681/ASN.2010070728
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Published
Mar 15, 2017
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How to Cite
Novel Therapeutic Strategies Targeting Molecular Pathways of Cystogenesis in Autosomal Polycystic Kidney Disease. (2017). Journal of Renal and Hepatic Disorders, 1(1), 35-49. https://doi.org/10.15586/jrenhep.2017.10
Section
Review Nephrology
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