Experimental therapies and ongoing clinical trials to slow down progression of ADPKD

Current Hypertension Reviews

Volumn 9, Issue 1, 2013, Pages 44-59

  Irazabal, Maria V ^a   Torres, Vicente E ^a  

^a MAYO CLINIC   (United States)

Author keywords

AMP activated protein kinase (AMPK) activators; Autosomal dominant polycystic kidney disease; Cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors; Mammalian target of rapamycin (mTOR) inhibitors; Somatostatin analogues; Src inhibitors

Indexed keywords

ANGIOPEPTIN; BETA CATENIN; COPEPTIN; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIN D1; EPIDERMAL GROWTH FACTOR RECEPTOR; EVEROLIMUS; HISTONE DEACETYLASE 1; HISTONE DEACETYLASE 2; HISTONE DEACETYLASE 3; HISTONE DEACETYLASE 4; HISTONE DEACETYLASE 5; HISTONE DEACETYLASE 6; HISTONE DEACETYLASE 7; HISTONE DEACETYLASE 8; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; MYOCYTE ENHANCER FACTOR 2; OCTREOTIDE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; POLYCYSTIN; POLYCYSTIN 1; POLYCYSTIN 2; RAPAMYCIN; ROSIGLITAZONE; TOLVAPTAN; TUBERIN; UNINDEXED DRUG; VASOPRESSIN V2 RECEPTOR;

ARTICLE; CALCIUM HOMEOSTASIS; CELL PROLIFERATION; CLINICAL TRIAL (TOPIC); DISEASE COURSE; DISEASE SEVERITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; ENDOPLASMIC RETICULUM; ENVIRONMENTAL FACTOR; EXON; GENE REPLACEMENT THERAPY; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; HUMAN; IN VITRO STUDY; KIDNEY POLYCYSTIC DISEASE; MISSENSE MUTATION; MULTICENTER STUDY (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); SEX DIFFERENCE; SIGNAL TRANSDUCTION; SMOKING; WNT SIGNALING PATHWAY;

CLINICAL TRIALS AS TOPIC; DISEASE PROGRESSION; GENETIC THERAPY; HUMANS; POLYCYSTIC KIDNEY, AUTOSOMAL DOMINANT; SIGNAL TRANSDUCTION; THERAPIES, INVESTIGATIONAL; TREATMENT OUTCOME;

EID: 84875333002     PISSN: 15734021     EISSN: 18756506     Source Type: Journal    
DOI: 10.2174/1573402111309010008     Document Type: Article

References (151)

1. Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354(20): 2122-2130.
2. Grantham JJ, Cook LT, Torres VE, et al. Determinants of renal volume in autosomal-dominant polycystic kidney disease. Kidney Int 2008; 73(1): 108-116.
3. Torres VE, King BF, Chapman AB, et al. Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2007; 2(1): 112-120.
4. Torres VE, Grantham JJ, Chapman AB, et al. Potentially modifiable factors affecting the progression of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2011; 6(3): 640-647.
5. Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clinical journal of the American Society of Nephrology: CJASN. [Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. 2012; 7(3): 479-486.
6. Harris PC, Bae KT, Rossetti S, et al. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2006; 17(11): 3013-3019.
7. Rossetti S, Adeva M, Kubly V, Consugar MB, Torres VE, Harris PC. An Olmsted County population-based study indicates that PKD2 is more common than previously described. J Am Soc Nephrol 2007; 18: 365A.
8. Dicks E, Ravani P, Langman D, Davidson WS, Pei Y, Parfrey PS. Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population and family-based cohort followed for 22 years. Clin J Am Soc Nephrol 2006; 1(4): 710-717.
9. Rossetti S, Kubly V, Consugar M, et al. Incompletely penetrant PKD1 alleles associated with mild, homozygous and in utero onset polycystic kidney disease. Kidney Int 2009;75(8): 848-855.
10. Pereira T V, Nunes AC, Rudnicki M, et al. Influence of ACE I/D gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease: a meta-analysis. Nephrol Dial Transplant 2006; 21(11): 3155-3163.
11. Gumprecht J, Zychma MJ, Karasek D, Grzeszczak W. ACE gene I/D polymorphism and the presence of renal failure or hypertension in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant 2007; 22(5): 1483.
12. Stefanakis N, Ziroyiannis P, Trygonis S, Lamnissou K. Modifier effect of the Glu298Asp polymorphism of endothelial nitric oxide synthase gene in autosomal-dominant polycystic kidney disease. Nephron Clin Pract 2008;110(2): c101-c106.
13. Courtney AE, McNamee PT, Heggarty S, Middleton D, Maxwell A P. Association of functional haem oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy. Nephrol Dial Transplant 2008; 23(2): 608-611.
14. Tazon-Vega B, Vilardell M, Perez-Oller L, et al. Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1. Nephrol Dial Transplant 2007; 22(6):1567-1577.
15. Reiterova J, Merta M, Stekrova J, et al. The influence of endothelin-A receptor gene polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy. Folia Biol (Praha) 2007; 53(4):134-137.
16. Reiterova J, Obeidova H, Lenicek M, et al. Influence of VEGF polymorphism on progression of autosomal dominant polycystic kidney disease. Kidney Blood Press Res 2008; 31(6): 398-403.
17. Reed BY, McFann K, Bekheirnia MR, et al. Variation in age at ESRD in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2008; 51(2): 173-183.
18. Paterson AD, Magistroni R, He N, et al. Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2005;16(3): 755-762.
19. Orth SR, Stockmann A, Conradt C, et al. Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney international. [Multicenter Study]. 1998; 54(3): 926-931.
20. Torres VE, Bankir L, Grantham JJ. A case for water in the treatment of polycystic kidney disease. Clin J Am Soc Nephrol 2009; 4(6): 1140-1150.
21. Torres VE. Vasopressin in chronic kidney disease: an elephant in the room? Kidney Int 2009; 76(9): 925-928.
22. Meijer E, Bakker SJ, van der Jagt EJ, 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): 361-368.
23. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. The International Polycystic Kidney Disease Consortium. Cell 1995; 81(2): 289-298.
24. Hughes J, Ward CJ, Peral B, et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 1995; 10(2): 151-160.
25. Mochizuki T, Wu G, Hayashi T, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996; 272(5266): 1339-1342.
26. Paterson AD, Wang KR, Lupea D, St George-Hyslop P, Pei Y. Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease. Am J Kidney Dis 2002; 40(1): 16-20.
27. Hayashi T, Mochizuki T, Reynolds DM, Wu G, Cai Y, Somlo S. Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). Genomics. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. 1997; 44(1):131-136.
28. Kottgen M. TRPP2 and autosomal dominant polycystic kidney disease. Biochim Biophys Acta 2007; 1772(8):836-850.
29. Cai Y, Maeda Y, Cedzich A, et al. Identification and characterization of polycystin-2, the PKD2 gene product. The Journal of biological chemistry. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. 1999; 274(40): 28557-28565.
30. Yoder BK, Richards WG, Sommardahl C, et al. Functional correction of renal defects in a mouse model for ARPKD through expression of the cloned wild-type Tg737 cDNA. Kidney international. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.]. 1996; 50(4):1240-1248.
31. Pritchard L, Sloane-Stanley JA, Sharpe JA, et al. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Human molecular genetics. [Research Support, Non-U.S. Gov't]. 2000; 9(18): 2617-2627.
32. Hammond SM, Wood MJ. Genetic therapies for RNA mis-splicing diseases. Trends Genet [Research Support, Non-U.S. Gov't Review]. 2011; 27(5): 196-205.
33. Verhaart IE, Aartsma-Rus A. Gene therapy for Duchenne muscular dystrophy. Curr Opin Neurol 2012.
34. Hoffman EP, Bronson A, Levin AA, et al. Restoring dystrophin expression in duchenne muscular dystrophy muscle progress in exon skipping and stop codon read through. The American journal of pathology. [Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Review]. 2011; 179(1): 12-22.
35. Lantinga-van Leeuwen I. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 2004; 13(24): 3069-3077.
36. Jiang ST, Chiou Y Y, Wang E, et al. Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am J Pathol 2006; 168(1): 205-220.
37. Hopp K, Ward CJ, Hommerding CJ, et al. In vivo modeling of a clinical PKD1 variant validates a dosage dependent disease mechanism in autosomal dominant polycystic kidney disease. JCI. 2012;in press.
38. Hopkins C, Li J, Rae F, Little MH. Stem cell options for kidney disease. J Pathol [Research Support, Non-U.S. Gov't Review]. 2009; 217(2): 265-281.
39. Koulen P, Cai Y, Geng L, Maeda Y, et al. Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 2002; 4(3):191-197.
40. Li Y, Wright JM, Qian F, Germino GG, Guggino WB. Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling. J Biol Chem 2005; 280(50): 41298-41306.
41. Anyatonwu GI, Estrada M, Tian X, Somlo S, Ehrlich BE. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc Natl Acad Sci USA 2007; 104(15): 6454-6459.
42. Xu C, Rossetti S, Jiang L, Harris PC, et al. Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling. Am J Physiol Renal Physiol 2007; 292(3): F930-F945.
43. Leuenroth SJ, Okuhara D, Shotwell JD, et al. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc Natl Acad Sci USA 2007; 104(11): 4389-4394.
44. Leuenroth SJ, Bencivenga N, Igarashi P, Somlo S, Crews CM. Triptolide reduces cystogenesis in a model of ADPKD. J Am Soc Nephrol 2008;19(9):1659-1662.
45. Leuenroth SJ, Bencivenga N, Chahboune H, Hyder F, Crews CM. Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. [Research Support, N.I.H., Extramural]. 2010; 25(7): 2187-2194.
46. Gradilone SA, Masyuk TV, Huang BQ, et al. Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD. Gastroenterology. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. 2010;139(1): 304-314 e2.
47. Gattone VH, 2nd, Chen NX, Sinders RM, et al. Calcimimetic inhibits late-stage cyst growth in ADPKD. Journal of the American Society of Nephrology: JASN 2009; 20(7): 1527-1532.
48. Chen NX, Moe SM, Eggleston-Gulyas T, et al. Calcimimetics inhibit renal pathology in rodent nephronophthisis. Kidney Int 2011; 80(6): 612-619.
49. Wang X, Harris PC, Somlo S, Batlle D, Torres VE. Effect of calcium-sensing receptor activation in models of autosomal recessive or dominant polycystic kidney disease. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2009; 24(2): 526-534.
50. Torres VE. Type II calcimimetics and polycystic kidney disease: unanswered questions. Journal of the American Society of Nephrology: JASN 2009; 20(7):1421-1425.
51. Boertien WE ME, Jie L, Bost JE, et al. Copeptin, a surrogate marker for vasopressin, is associated with change in kidney volume and rate of GFR loss in ADPKD: Results from the CRISP cohort. Am J Kidney Dis 2012.
52. 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): 309-318.
53. 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):1323-1326.
54. 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): 363-364.
55. 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): 846-851.
56. Meijer E, Gansevoort RT, de Jong PE, 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): 2445-2453.
57. Nagao S, Nishii K, Katsuyama M, et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol 2006;17(8): 2220-2227.
58. 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):102-108.
59. Romaker D, Puetz M, Teschner S, et al. Increased expression of secreted frizzled-related protein 4 in polycystic kidneys. Journal of the American Society of Nephrology: JASN 2009; 20(1): 48-56.
60. Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace D P. 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-F1013.
61. Irazabal MV, Torres VE, Hogan MC, 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.
62. Higashihara E, Torres VE, Chapman AB, et al. Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years' Experience. Clin J Am Soc Nephrol 2011; 6(10): 2499-2507.
63. Torres VE, Meijer E, Bae KT, 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): 692-699.
64. Masyuk TV, Masyuk AI, Torres VE, Harris PC, Larusso N F. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate. Gastroenterology 2007; 132(3):1104-1116.
65. Ruggenenti P, Remuzzi A, Ondei P, et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int 2005; 68(1): 206-216.
66. van Keimpema L, Nevens F, Vanslembrouck R, et al. Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2009; 137(5):1661-1668 e1-2.
67. Hogan MC, Masyuk TV, Page LJ, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol 2010; 21(6):1052-1061.
68. Caroli A, Antiga L, Cafaro M, et al. Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin J AmSoc Nephrol 2010; 5(5): 783-789.
69. Chrispijn M, Nevens F, Gevers TJ, et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther 2012; 35(2): 266-274.
70. Hogan MC, Masyuk TV, Page L, et al. Somatostatin analog therapy for severe polycystic liver disease: results after 2 years. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2012 Jul 6.
71. Elberg G, Elberg D, Lewis TV, et al. EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cells. Am J Physiol - Renal Physiol 2007; 293(5): F1622-F1632.
72. Tradtrantip L, Yangthara B, Padmawar P, Morrison C, Verkman AS. Thiophenecarboxylate suppressor of cyclic nucleotides discovered in a small-molecule screen blocks toxin-induced intestinal fluid secretion. Mol Pharmacol 2009; 75(1):134-142.
73. Sweeney WE, Jr., von Vigier RO, Frost P, Avner ED. Src inhibition ameliorates polycystic kidney disease. J Am Soc Nephrol 2008;19(7):1331-1341.
74. 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-C529.
75. Buchholz B, Klanke B, Schley G, et al. The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2011; 26(11): 3458-3465.
76. Yamaguchi T, Reif GA, Calvet JP, Wallace D P. 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-F951.
77. Spirli C, Morell CM, Locatelli L, et al. Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with Sorafenib. Hepatology 2012.
78. Omori S, Hida M, Fujita H, et al. Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease. J Am Soc Nephrol 2006; 17(6): 1604-1614.
79. Shibazaki S, Yu Z, Nishio S, et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Human Mol Genetics 2008; 17(11): 1505-1516.
80. Dere R, Wilson PD, Sandford RN, Walker CL. Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. PLoS One 2010; 5(2): e9239.
81. Distefano G, Boca M, Rowe I, 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. Molecular and cellular Biol 2009; 29(9): 2359-2371.
82. Spirli C, Okolicsanyi S, Fiorotto R, et al. Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology 2010; 51(5): 1778-1788.
83. Shillingford JM, Murcia NS, Larson CH, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA 2006;103(14): 5466-5471.
84. 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.
85. Wahl PR, Serra AL, Le Hir M, Molle KD, Hall MN, Wuthrich R P. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association -European Renal Association 2006; 21(3): 598-604.
86. Wu M, Wahl PR, Le Hir M, Wackerle-Men Y, Wuthrich R P, Serra AL. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease. Kidney & blood Pressure Research 2007; 30(4): 253-259.
87. Wu M, Arcaro A, Varga Z, et al. Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease. Am J Physiol Renal Physiol 2009; 297(6): F1597-F1605.
88. Renken C, Fischer DC, Kundt G, Gretz N, Haffner D. Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2011; 26(1): 92-100.
89. Gattone VH, 2nd, Sinders RM, Hornberger TA, Robling AG. Late progression of renal pathology and cyst enlargement is reduced by rapamycin in a mouse model of nephronophthisis. Kidney Int 2009; 76(2): 178-182.
90. Shillingford JM, Piontek KB, Germino GG, Weimbs T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol 2010; 21(3): 489-497.
91. Novalic Z, van der Wal AM, Leonhard WN, et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J Am Soc Nephrol 2012; 23(5): 842-853.
92. Canaud G, Knebelmann B, Harris PC, et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level? Am J Transplant 2010; 10(7): 1701-1706.
93. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363(9): 820-829.
94. Perico N, Antiga L, Caroli A, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol 2010;21(6): 1031-1040.
95. Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363(9): 830-840.
96. Shillingford JM, Leamon C P, Vlahov IR, Weimbs T. Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease. J Am Soc Nephrol 2012.
97. Takiar V, Nishio S, Seo-Mayer P, et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci USA 2011; 108(6): 2462-2467.
98. Lancaster MA, Gleeson JG. Cystic kidney disease: the role of Wnt signaling. Trends Mol Med 2010; 16(8): 349-360.
99. Leonhard WN, van der Wal A, Novalic Z, 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-F1202.
100. Gao J, Zhou H, Lei T, et al. Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways. Eur J Pharmacol 2011; 654(1): 92-99.
101. Sankaran D, Bankovic-Calic N, Ogborn MR, Crow G, Aukema HM. Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease. Am J Physiol Renam Physiol 2007; 293(3): F821-F830.
102. Monjazeb AM, Clay CE, High K P, Chilton FH. Antineoplastic properties of arachidonic acid and its metabolites. Prostaglandins Leukot Essent Fatty Acids 2002; 66(1): 5-12.
103. Altiok S, Xu M, Spiegelman BM. PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes & development 1997; 11(15): 1987-1998.
104. Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci USA 1997; 94(1): 237-241.
105. Demetri GD, Fletcher CD, Mueller E, et al. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci USA 1999; 96(7): 3951-3956.
106. Shimada T, Kojima K, Yoshiura K, Hiraishi H, Terano A. Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells. Gut 2002; 50(5): 658-664.
107. Qin C, Burghardt R, Smith R, Wormke M, Stewart J, Safe S. Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast cancer cells. Cancer Res 2003; 63(5): 958-964.
108. Nitschmann E B-CN, Aukema HM, Ogborn MR. Dietary supplementation with conjugated linoleic acid (CLA) attenuates fibrous and inflammation in the Han-SPRD-cy rat. J Am Soc Nephrol 2001;12:541A.
109. Muto S, Aiba A, Saito Y, et al. Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Human Mol Gen 2002;11(15):1731-1742.
110. Dai B, Liu Y, Mei C, et al. Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats. Clin Sci (Lond) 2010; 119(8): 323-333.
111. Blazer-Yost BL, Haydon J, Eggleston-Gulyas T, et al. Pioglitazone Attenuates Cystic Burden in the PCK Rodent Model of Polycystic Kidney Disease. PPAR Res 2010; 2010: 274376.
112. Yoshihara D, Kurahashi H, Morita M, et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am Jl Physiol Renal Physiol 2011; 300(2): F465-F474.
113. Raphael KL, Strait KA, Stricklett PK, et al. Effect of pioglitazone on survival and renal function in a mouse model of polycystic kidney disease. Am J Nephrol 2009; 30(5): 468-473.
114. Van Bodegom D, Saifudeen Z, Dipp S, et al. The polycystic kidney disease-1 gene is a target for p53-mediated transcriptional repression. J Biol Chem 2006; 281(42): 31234-31244.
115. Xia S, Li X, Johnson T, Seidel C, Wallace D P, Li R. Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts. Development 2010; 137(7): 1075-1084.
116. Li X. Epigenetics and autosomal dominant polycystic kidney disease. Biochim Biophys Acta 2011;1812(10): 1213-1218.
117. Cao Y, Semanchik N, Lee SH, et al. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc Natl Acad Sci USA 2009;106(51): 21819-21824.
118. Fan LX, Li X, Magenheimer B, Calvet J P. Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. Kidney Int 2012; 81(1): 76-85.
119. Bhunia AK, Piontek K, Boletta A, 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): 157-168.
120. 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. Nature cell biology 2005; 7(12): 1202-1212.
121. 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): 949-952.
122. Park J Y, Schutzer WE, Lindsley JN, et al. p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels. BMC Nephrol 2007; 8: 12.
123. Masyuk TV BJM, Gradilone SA, Stroope AJ, et al. Vitamin K3 inhibits hepatic cystogenesis in vitro and in vivo: a new therapeutic approach for treatment of polycystic liver diseases. Hepatology 2008; 48(4): 657A-658A.
124. Li X, Magenheimer BS, Xia S, et al. A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease. Nat Med 2008; 14(8): 863-868.
125. Lee DF, Kuo H P, Chen CT, et al. IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance. Int J Mol Med 2008; 22(5): 633-638.
126. Dell KM, Nemo R, Sweeney WE, Jr., Levin JI, Frost P, Avner ED. A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease. Kidney Int 2001; 60(4): 1240-1248.
127. Nemo R, Murcia N, Dell KM. Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease. Pediatric research. [Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.]. 2005 May;57(5 Pt 1):732-737.
128. Takakura A, Nelson EA, Haque N, et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Human molecular genetics 2011; 20(21): 4143-4154.
129. Sweeney WE, Jr., Avner ED. Functional activity of epidermal growth factor receptors in autosomal recessive polycystic kidney disease. Am J Physiol 1998; 275(3 Pt 2): F387-F394.
130. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 2000; 57(1): 33-40.
131. Torres VE, Sweeney WE, Jr., Wang X, et al. Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats. Kidney Int 2004; 66(5): 1766-1773.
132. Tao Y, Kim J, Yin Y, et al. VEGF receptor inhibition slows the progression of polycystic kidney disease. Kidney Int 2007; 72(11):1358-1366.
133. Amura CR, Brodsky KS, Groff R, Gattone VH, Voelkel NF, Doctor RB. VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice. Am J Physiol Cell Physiol 2007; 293(1): C419-C428.
134. Spirli C, Okolicsanyi S, Fiorotto R, et al. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology 2010; 138(1): 360-371 e7.
135. Raina S, Honer M, Kramer SD, et al. Anti-VEGF antibody treatment accelerates polycystic kidney disease. Am J Physiol y Renal Physiol 2011; 301(4): F773-F783.
136. McGrath-Morrow S, Cho C, Molls R, et al. VEGF receptor 2 blockade leads to renal cyst formation in mice. Kidney international 2006; 69(10):1741-1748.
137. Qin S, Taglienti M, Nauli SM, et al. Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J Clin Invest 2010; 120(10): 3617-3628.
138. Aukema HM, Housini I. Dietary soy protein effects on disease and IGF-I in male and female Han:SPRD-cy rats. Kidney Int 2001; 59(1): 52-61.
139. Nakamura T, Ebihara I, Nagaoka I, et al. Growth factor gene expression in kidney of murine polycystic kidney disease. J Am Soc Nephrol 1993; 3(7):1378-1386.
140. Park F, Sweeney WE, Jia G, Roman RJ, Avner ED. 20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease. J Am Soc Nephrol 2008;19(10): 1929-1939.
141. Edelstein CL. Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease. Clin J Am Soc Nephrol 2008; 3(4): 1219-1226.
142. Tao Y, Zafar I, Kim J, Schrier RW, Edelstein CL. Caspase-3 gene deletion prolongs survival in polycystic kidney disease. J Am Soc Nephrol 2008;19(4): 749-755.
143. Albaqumi M, Srivastava S, Li Z, 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): 740-749.
144. Alper SL. Let's look at cysts from both sides now. Kidney Int 2008; 74(6): 699-702.
145. Yu AS, Kanzawa SA, Usorov A, Lantinga-van Leeuwen IS, Peters DJ. Tight junction composition is altered in the epithelium of polycystic kidneys. J Pathol 2008; 216(1):120-128.
146. Magenheimer BS, St John PL, Isom KS, et al. Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na(+),K(+),2Cl(-) Co-transporter-dependent cystic dilation. J Am Soc Nephrol 2006;17(12): 3424-3437.
147. 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(7): 1300-1310.
148. 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): 529-534.
149. Grgic I, Kiss E, Kaistha B P, et al. Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proc Natl Acad Sci USA 2009;106(34):14518-14523.
150. Ataga KI, Smith WR, De Castro LM, et al. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 2008; 111(8): 3991-3997.
151. Nofziger C, Brown KK, Smith CD, et al. PPARgamma agonists inhibit vasopressin-mediated anion transport in the MDCK-C7 cell line. Am J Physiol Renal Physiol 2009; 297(1): F55-F62.