Strategies targeting cAMP signaling in the treatment of polycystic kidney disease

Journal of the American Society of Nephrology

Volumn 25, Issue 1, 2014, Pages 18-32

  Torres, Vicente E ^a   Harris, Peter C ^a  

^a MAYO CLINIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTEGRIN; ANGIOPEPTIN; BETA CATENIN; BETA INTEGRIN; CALCIUM; CYCLIC AMP; FIBROCYSTIN; GLYCOGEN SYNTHASE KINASE 3BETA; LAMININ; LAMININ 10; LAMININ 322; MOZAVAPTAN; OCTREOTIDE; POLYCYSTIN 1; POLYCYSTIN 2; SOMATOSTATIN DERIVATIVE; TOLVAPTAN; UNCLASSIFIED DRUG; VASOPRESSIN V2 RECEPTOR;

CALCIUM HOMEOSTASIS; CELL DIVISION; CELL PROLIFERATION; ENZYME PHOSPHORYLATION; EXTRACELLULAR MATRIX; FLUID INTAKE; FOCAL ADHESION; GLOMERULUS BASEMENT MEMBRANE; KIDNEY FIBROSIS; KIDNEY INTERSTITIUM; KIDNEY POLYCYSTIC DISEASE; KIDNEY TUBULE; KIDNEY TUBULE EXCRETION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN CONTENT; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; TISSUE LEVEL;

EID: 84891818486     PISSN: 10466673     EISSN: 15333450     Source Type: Journal    
DOI: 10.1681/ASN.2013040398     Document Type: Review

References (170)

1. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AEH, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J: Polycystins 1 and 2 mediate mechanosensation in the primary ciliumof kidney cells. NatGenet 33: 129-137, 2003
2. Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, Ingber DE, Loghman-Adham M, Zhou J: Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J AmSocNephrol 17: 1015-1025, 2006
3. Wang S, Zhang J,Nauli SM, Li X, Starremans PG, Luo Y, Roberts KA, Zhou J: Fibrocystin/ polyductin, found in the same protein complex with polycystin-2, regulates calciumresponses in kidney epithelia. Mol Cell Biol 27: 3241-3252, 2007
4. Pisitkun T, Shen RF, Knepper MA: Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101: 13368-13373, 2004
5. Hogan MC, Manganelli L, Woollard JR, Masyuk AI, Masyuk TV, Tammachote R, Huang BQ, Leontovich AA, Beito TG, Madden BJ, Charlesworth MC, Torres VE, LaRusso NF, Harris PC, Ward CJ: Characterization of PKD protein-positive exosomelike vesicles. J Am Soc Nephrol 20: 278-288, 2009
6. Scheffers MS, van der Bent P, Prins F, Spruit L, Breuning MH, Litvinov SV, de Heer E, Peters DJM: Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells. Hum Mol Genet 9: 2743-2750, 2000
7. Boletta A, Qian F, Onuchic LF, Bragonzi A, CorteseM, Deen PM, Courtoy PJ, SoriaMR, Devuyst O, Monaco L, Germino GG: Biochemical characterization of bona fide polycystin-1 in vitro and in vivo. Am J Kidney Dis 38: 1421-1429, 2001
8. Newby LJ, Streets AJ, Zhao Y, Harris PC, Ward CJ, Ong ACM: Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex. J Biol Chem 277: 20763-20773, 2002
9. Li Y, Santoso NG, Yu S, Woodward OM, Qian F, Guggino WB: Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling with implications for polycystic kidney disease. J Biol Chem284: 36431-36441, 2009
10. Santoso NG, Cebotaru L, Guggino WB: Polycystin-1, 2, and STIM1 interactwith IP(3) R to modulate ER Ca release through the PI3K/Akt pathway. Cell Physiol Biochem27: 715-726, 2011
11. Koulen P, Cai Y, Geng L, Maeda Y, NishimuraS,WitzgallR, EhrlichBE, SomloS: Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4: 191-197, 2002
12. Witzgall R: Polycystin-2-an intracellular or plasma membrane channel? Naunyn Schmiedebergs Arch Pharmacol 371: 342-347, 2005
13. Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG: PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet 16: 179-183, 1997
14. Wu Y, Dai XQ, Li Q, Chen CX, Mai W, Hussain Z, Long W, Montalbetti N, Li G, Glynne R, Wang S, Cantiello HF, Wu G, Chen XZ: Kinesin-2 mediates physical and functional interactions between polycystin-2andfibrocystin.HumMol Genet 15: 3280-3292, 2006
15. Kim I, Li C, Liang D,Chen XZ, Coffy RJ,Ma J, Zhao P, Wu G: Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. J Biol Chem 283: 31559-31566, 2008
16. 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 Chem280: 41298-41306, 2005
17. Anyatonwu GI, Estrada M, Tian X, Somlo S, Ehrlich BE: Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc Natl Acad Sci U S A 104: 6454-6459, 2007
18. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP: Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci U S A 96: 3934-3939, 1999
19. Bai CX, Giamarchi A, Rodat-Despoix L, Padilla F, Downs T, Tsiokas L, Delmas P: Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO Rep 9: 472-479, 2008
20. Du J, Ding M, Sours-Brothers S, Graham S, Ma R: Mediation of angiotensin II-induced Ca2+ signaling by polycystin 2 in glomerular mesangial cells. Am J Physiol Renal Physiol 294: F909-F918, 2008
21. Köttgen M, Buchholz B, Garcia-Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T, Nitschke R, Suzuki M, Kramer-Zucker A, Germino GG, Watnick T, Prenen J, Nilius B, Kuehn EW, Walz G: TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol 182: 437-447, 2008
22. Mekahli D,SammelsE, LuytenT,Welkenhuyzen K, van den Heuvel LP, Levtchenko EN, Gijsbers R, Bultynck G, Parys JB, De Smedt H, Missiaen L: Polycystin-1 and polycystin-2 are both required to amplify inositol-trisphosphate-induced Ca2+ release. Cell Calcium 51: 452-458, 2012
23. Morel N, Vandenberg G, Ahrabi AK, Caron N, Desjardins F, Balligand JL, Horie S, Devuyst O: PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta. Pflugers Arch 457: 845-856, 2009
24. Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Somlo S, Harris PC, Torres VE, Sieck GC: Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum Mol Genet 12: 1875-1880, 2003
25. 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 17: 178-187, 2006
26. Geng L, Boehmerle W, Maeda Y, Okuhara DY, Tian X, Yu Z, Choe CU, Anyatonwu GI, Ehrlich BE, Somlo S: Syntaxin 5 regulates the endoplasmic reticulum channel-release properties of polycystin-2. Proc Natl Acad Sci U S A 105: 15920-15925, 2008
27. Xu C, Rossetti S, Jiang L, Harris PC, Brown-Glaberman U, Wandinger-Ness A, Bacallao R, Alper SL: Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling. Am J Physiol Renal Physiol 292: F930-F945, 2007
28. Ahrabi AK, Terryn S, Valenti G, Caron N, Serradeil-Le Gal C, Raufaste D, Nielsen S, Horie S, Verbavatz JM, Devuyst O: PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis inmice.JAmSoc Nephrol 18: 1740-1753, 2007
29. Banales JM, Masyuk TV, Gradilone SA, Masyuk AI, Medina JF, LaRusso NF: The cAMP effectors Epac and protein kinase a (PKA) are involvedin the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD). Hepatology 49: 160-174, 2009
30. Spirli C, Locatelli L, Fiorotto R, Morell CM, Fabris L, Pozzan T, Strazzabosco M: Altered store operated calcium entry increases cyclic 39,59-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes. Hepatology 55: 856-868, 2012
31. Zaika O,MamenkoM, Berrout J, Boukelmoune N, O'Neil RG, Pochynyuk O: TRPV4 dysfunction promotes renal cystogenesis in autosomal recessive polycystic kidney disease. J Am Soc Nephrol 24: 604-616, 2013
32. Yamaguchi T, Nagao S, Kasahara M, Takahashi H, Grantham JJ: Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. AmJ Kidney Dis 30: 703-709, 1997
33. 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 9: 1323-1326, 2003
34. Smith LA, BukanovNO,HussonH, Russo RJ, Barry TC, Taylor AL, Beier DR, Ibraghimov-Beskrovnaya O: Development of polycystic kidney disease in juvenile cystic kidney mice: Insights into pathogenesis, ciliary abnormalities, and common features with human disease. J Am Soc Nephrol 17: 2821-2831, 2006
35. Starremans PG, Li X, Finnerty PE, Guo L, Takakura A, Neilson EG, Zhou J: A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 59 end of Pkd1. Kidney Int 73: 1394-1405, 2008
36. Hopp K,Ward CJ, Hommerding CJ, Nasr SH, Tuan HF, Gainullin VG, Rossetti S, Torres VE, Harris PC: Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Invest 122: 4257-4273, 2012
37. Masyuk TV,Masyuk AI, Torres VE, Harris PC, Larusso NF: Octreotide inhibits hepatic cystogenesis in a rodentmodel ofpolycystic liver disease by reducing cholangiocyte adenosine 39,59-cyclic monophosphate. Gastroenterology 132: 1104-1116, 2007
38. Kip SN,Hunter LW, RenQ, Harris PC, Somlo S, Torres VE, Sieck GC, Qian Q: [Ca2+]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: Relevance to the ADPKD phenotype. Circ Res 96: 873-880, 2005
39. Banizs B, Komlosi P, Bevensee MO, Schwiebert EM, Bell PD, Yoder BK: Altered pH(i) regulation and Na(+)/HCO3 (-) transporter activity in choroid plexus of ciliadefective Tg737(orpk) mutant mouse. Am J Physiol Cell Physiol 292: C1409-C1416, 2007
40. Wang X, Ward CJ, Harris PC, Torres VE: Cyclic nucleotide signaling in polycystic kidney disease. Kidney Int 77: 129-140, 2010
41. Choi YH, Suzuki A, Hajarnis S, Ma Z, Chapin HC, Caplan MJ, Pontoglio M, Somlo S, Igarashi P: Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. Proc Natl Acad Sci U S A 108: 10679-10684, 2011
42. Parnell SC, Magenheimer BS, Maser RL, Rankin CA, Smine A, Okamoto T, Calvet JP: The polycystic kidney disease-1 protein, polycystin-1, binds and activates heterotrimeric G-proteins in vitro. Biochem Biophys Res Commun 251: 625-631, 1998
43. PutnamWC, Swenson SM, Reif GA, Wallace DP, Helmkamp GM Jr., Grantham JJ: Identification of a forskolin-like molecule in human renal cysts. J AmSoc Nephrol 18: 934-943, 2007
44. Hovater MB, Olteanu D, Welty EA, Schwiebert EM: Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts. Purinergic Signal 4: 109-124, 2008
45. Blazer-Yost BL, Haydon J, Eggleston-Gulyas T, Chen JH, Wang X, Gattone V, Torres VE: Pioglitazone attenuates cystic burden in the PCK rodent model of polycystic kidney disease. PPAR Res 2010: 274376, 2010
46. Buchholz B, Klanke B, Schley G, Bollag G, Tsai J, Kroening S, YoshiharaD,Wallace DP, Kraenzlin B, Gretz N, Hirth P, Eckardt KU, Bernhardt WM: The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis. Nephrol Dial Transplant 26: 3458-3465, 2011
47. Rees S, Kittikulsuth W, Roos K, Strait KA, Van Hoek A, Kohan DE: Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease [published ahead of print October 24, 2013]. J Am Soc Nephrol doi:10.1681/ ASN.2013010077
48. Sussman C, Ward C, Leightner A, Harris P, Torres V: Regulation of renal cyst formation by phosphodiesterase 1a in zebrafish [Abstract]. J Am Soc Nephrol 23: 1A, 2012
49. Hong Ye, Xiaofang Wang, Caroline R. Sussman, Peter C. Harris, Vincent C. Manganielo, Christopher James Ward, Vicente E. Torres: Genetic approach to evaluate the role of the PDE3 subfamilies in polycystic kidney disease (PKD). J Am Soc Nephrol 23: 239A, 2012
50. Cheng J, Thompson MA, Walker HJ, Gray CE, Warner GM, Zhou W, Grande JP: Lixazinone stimulates mitogenesis of Madin-Darby canine kidney cells. Exp Biol Med (Maywood) 231: 288-295, 2006
51. 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 75: 134-142, 2009
52. Carroll TJ, Das A: Planar cell polarity in kidney development and disease. Organogenesis 7: 180-190, 2011
53. Saadi-Kheddouci S, Berrebi D, Romagnolo B, Cluzeaud F, Peuchmaur M, Kahn A, Vandewalle A, Perret C: Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20: 5972-5981, 2001
54. Qian CN, Knol J, Igarashi P, Lin F, Zylstra U, Teh BT,Williams BO: Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium. J Biol Chem 280: 3938-3945, 2005
55. Saburi S, Hester I, Fischer E, Pontoglio M, Eremina V,GesslerM,Quaggin SE, Harrison R, Mount R,McNeill H: Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat Genet 40: 1010-1015, 2008
56. Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Krönig C, Schermer B, Benzing T, Cabello OA, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G: Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37: 537-543, 2005
57. Li M, Wang X, Meintzer MK, Laessig T, Birnbaum MJ, Heidenreich KA: Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol Cell Biol 20: 9356-9363, 2000
58. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO: Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem281: 9971-9976, 2006
59. Gallegos TF, Kouznetsova V, Kudlicka K, Sweeney DE, Bush KT, Willert K, Farquhar MG,NigamSK: A protein kinase A andWntdependent network regulating an intermediate stage in epithelial tubulogenesis during kidney development. Dev Biol 364: 11-21, 2012
60. Song BH, Choi SC, Han JK: Local activation of protein kinase A inhibits morphogenetic movements during Xenopus gastrulation. Dev Dyn 227: 91-103, 2003
61. Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG: A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13: 1490-1495, 2007
62. Nadasdy T, Lajoie G, Laszik Z, Blick KE, Molnar-Nadasdy G, Silva FG: Cell proliferation in the developing human kidney. Pediatr Dev Pathol 1: 49-55, 1998
63. Nadasdy T, Laszik Z, Blick KE, Johnson LD, Silva FG: Proliferative activity of intrinsic cell populations in the normal human kidney. J Am Soc Nephrol 4: 2032-2039, 1994
64. Yamaguchi T, Pelling JC, Ramaswamy NT, Eppler JW,Wallace DP, Nagao S, Rome LA, Sullivan LP, Grantham JJ: cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int 57: 1460-1471, 2000
65. Hanaoka K, Guggino WB: cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol 11: 1179-1187, 2000
66. 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 279: 40419-40430, 2004
67. Distefano G, Boca M, Rowe I,Wodarczyk C, Ma L, Piontek KB, GerminoGG, Pandolfi PP, Boletta A: 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 29: 2359-2371, 2009
68. Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M: ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology 138: 360-371, 2010
69. Rowe I, Chiaravalli M, Mannella V, Ulisse V, Quilici G, Pema M, Song XW, Xu H, Mari S, Qian F, Pei Y,MuscoG, Boletta A:Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 19: 488-493, 2013
70. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD: Activation of a metabolic gene regulatory network downstream of mTOR complex. Mol Cell 39: 171-183, 2010
71. Yecies JL, Manning BD: Transcriptional control of cellular metabolism by mTOR signaling. Cancer Res 71: 2815-2820, 2011
72. Takiar V, Nishio S, Seo-Mayer P, King JD Jr., Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ: Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A 108: 2462-2467, 2011
73. Aguiari G, Bizzarri F, Bonon A, Mangolini A, Magri E, Pedriali M, Querzoli P, Somlo S, Harris PC, Catizone L, Del Senno L: Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: Implications in ADPKD cell proliferation.JMol Med (Berl) 90: 1267-1282, 2012
74. 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 AmSocNephrol 23: 1309-1318, 2012
75. Talbot JJ, Shillingford JM, Vasanth S, Doerr N, Mukherjee S, Kinter MT, Watnick T, Weimbs T: Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci U S A 108: 7985-7990, 2011
76. Leonhard WN, van der Wal A, Novalic Z, Kunnen SJ,Gansevoort RT, BreuningMH, de Heer E, Peters DJ: Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: In vivo evidence from a Pkd1-deletion model. Am J Physiol Renal Physiol 300: F1193-F1202, 2011
77. Takakura A, Nelson EA, Haque N, Humphreys BD, Zandi-Nejad K, Frank DA, Zhou J: Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet 20: 4143-4154, 2011
78. Stayner C, Iglesias DM, Goodyer PR, Ellis L, Germino G, Zhou J, Eccles MR: Pax2 gene dosage influences cystogenesis in autosomal dominant polycystic kidney disease. Hum Mol Genet 15: 3520-3528, 2006
79. Ostrom L, Tang MJ, Gruss P, Dressler GR: Reduced Pax2 gene dosage increases apoptosis and slows the progression of renal cystic disease. Dev Biol 219: 250-258, 2000
80. Metcalf D, Mifsud S, Di Rago L, Nicola NA, HiltonDJ, AlexanderWS: Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Proc Natl Acad Sci U S A 99: 943-948, 2002
81. Grantham JJ, Geiser JL, Evan AP: Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31: 1145-1152, 1987
82. Jacobsson L, Lindqvist B, Michaelson G, Bjerle P: Fluid turnover in renal cysts. Acta Med Scand 202: 327-329, 1977
83. Mangoo-Karim R, Uchic M, Lechene C, Grantham JJ: Renal epithelial cyst formation and enlargement in vitro: Dependence on cAMP. Proc Natl Acad Sci U S A 86: 6007-6011, 1989
84. YeM,Grantham JJ: The secretion of fluid by renal cysts from patients with autosomal dominant polycystic kidney disease.NEngl J Med 329: 310-313, 1993
85. Sullivan LP, Wallace DP, Grantham JJ: Epithelial transport in polycystic kidney disease. Physiol Rev 78: 1165-1191, 1998
86. Tradtrantip L, Sonawane ND, Namkung W, Verkman AS: Nanomolar potency pyrimidopyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model. J Med Chem52: 6447-6455, 2009
87. Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS: Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. JMed Chem54: 5468-5477, 2011
88. Li H, Findlay IA, Sheppard DN: The relationship between cell proliferation, Clsecretion, and renal cyst growth: A study using CFTR inhibitors. Kidney Int 66: 1926-1938, 2004
89. Magenheimer BS, St John PL, Isom KS, Abrahamson DR, De Lisle RC, Wallace DP, Maser RL, Grantham JJ, Calvet JP: 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 AmSocNephrol 17: 3424-3437, 2006
90. 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 19: 1300-1310, 2008
91. Hanaoka K, Devuyst O, Schwiebert EM, Wilson PD, Guggino WB: A role for CFTR in human autosomal dominant polycystic kidney disease. Am J Physiol 270: C389-C399, 1996
92. Davidow CJ,Maser RL, Rome LA, Calvet JP, Grantham JJ: The cystic fibrosis transmembrane conductance regulator mediates transepithelial fluid secretion by human autosomal dominant polycystic kidney disease epitheliumin vitro. Kidney Int 50: 208-218, 1996
93. 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. AmJ Kidney Dis 32: 976-983, 1998
94. Xu N, Glockner JF, Rossetti S, Babovich-Vuksanovic D, Harris PC, Torres VE: Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis. J Nephrol 19: 529-534, 2006
95. Persu A, Devuyst O, Lannoy N, Materne R, BrosnahanG,Gabow PA, Pirson Y, Verellen-Dumoulin C: CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 11: 2285-2296, 2000
96. Nakanishi K, Sweeney WE Jr., Macrae Dell K, Cotton CU, Avner ED: Role of CFTR in autosomal recessive polycystic kidney disease. J Am Soc Nephrol 12: 719-725, 2001
97. Wilson PD: Polycystin: New aspects of structure, function, and regulation. J Am Soc Nephrol 12: 834-845, 2001
98. Chen D, Roberts R, Pohl M, Nigam S, Kreidberg J, Wang Z, Heino J, Ivaska J, Coffa S, Harris RC, Pozzi A, Zent R: Differential expression of collagen-and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis. Am J Physiol Renal Physiol 287: F602-F611, 2004
99. Zent R, Bush KT, Pohl ML, Quaranta V, Koshikawa N, Wang Z, Kreidberg JA, Sakurai H, Stuart RO, Nigám SK: Involvement of laminin binding integrins and laminin-5 in branching morphogenesis of the ureteric bud during kidney development. Dev Biol 238: 289-302, 2001
100. van Adelsberg J: Murine polycystic kidney epithelial cell lines have increased integrinmediated adhesion to collagen. Am J Physiol 267: F1082-F1093, 1994
101. Joly D, Morel V, Hummel A, Ruello A, Nusbaum P, Patey N, Noël LH, Rousselle P, Knebelmann B: Beta4 integrin and laminin 5 are aberrantly expressed in polycystic kidney disease: Role in increased cell adhesion and migration. Am J Pathol 163: 1791-1800, 2003
102. Wallace DP, QuanteMT, Reif GA, Nivens E, Ahmed F, Hempson SJ, Blanco G, Yamaguchi T: Periostin induces proliferation of human autosomal dominant polycystic kidney cells through alphaV-integrin receptor. Am J Physiol Renal Physiol 295: F1463-F1471, 2008
103. Daïkha-Dahmane F, Narcy F, Dommergues M, Lacoste M, Beziau A, Gubler M-C: Distribution of alpha-integrin subunits in fetal polycystic kidney diseases. PediatrNephrol 11: 267-273, 1997
104. Joly D, Berissi S, Bertrand A, Strehl L, Patey N, Knebelmann B: Laminin 5 regulates polycystic kidney cell proliferation and cyst formation. J Biol Chem281: 29181-29189, 2006
105. Wu W, Kitamura S, Truong DM, Rieg T, Vallon V, Sakurai H, Bush KT, Vera DR, Ross RS,Nigam SK: Beta1-integrin is required for kidney collecting duct morphogenesis and maintenance of renal function. Am J Physiol Renal Physiol 297: F210-F217, 2009
106. Shannon MB, Patton BL, Harvey SJ, Miner JH: A hypomorphic mutation in the mouse laminin alpha5 gene causes polycystic kidney disease. J Am Soc Nephrol 17: 1913-1922, 2006
107. Howe AK: Regulation of actin-based cell migration by cAMP/PKA. Biochim Biophys Acta 1692: 159-174, 2004
108. Meyer CJ, Alenghat FJ, Rim P, Fong JH, Fabry B, Ingber DE: Mechanical control of cyclic AMP signalling and gene transcription through integrins. Nat Cell Biol 2: 666-668, 2000
109. Alenghat FJ, Tytell JD, Thodeti CK, Derrien A, Ingber DE: Mechanical control of cAMP signaling through integrins is mediated by the heterotrimeric Galphas protein. J Cell Biochem 106: 529-538, 2009
110. O'Connor KL, Shaw LM, Mercurio AM: Release of cAMP gating by the alpha6beta4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells. J Cell Biol 143: 1749-1760, 1998
111. Netherton SJ, Sutton JA, Wilson LS, Carter RL, Maurice DH: Both protein kinase A and exchange protein activated by cAMP coordinate adhesion of human vascular endothelial cells. Circ Res 101: 768-776, 2007
112. Eid AH: cAMP induces adhesion of microvascular smooth muscle cells to fibronectin via an Epac-mediated but PKA-independent mechanism. Cell Physiol Biochem 30: 247-258, 2012
113. Werder AA, Amos MA, Nielsen AH, Wolfe GH: Comparative effects of germfree and ambient environments on the development of cystic kidney disease in CFWwd mice. J Lab Clin Med 103: 399-407, 1984
114. Gardner KD Jr., Reed WP, Evan AP, Zedalis J, Hylarides MD, Leon AA: Endotoxin provocation of experimental renal cystic disease. Kidney Int 32: 329-334, 1987
115. Gardner KD Jr., Burnside JS, Elzinga LW, Locksley RM: Cytokines in fluids from polycystic kidneys. Kidney Int 39: 718-724, 1991
116. Karihaloo A, Koraishy F, Huen SC, Lee Y, MerrickD, CaplanMJ, Somlo S, Cantley LG: Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol 22: 1809-1814, 2011
117. Swenson-Fields KI, Vivian CJ, Salah SM, Peda JD, Davis BM, van Rooijen N, Wallace DP, Fields TA: Macrophages promote polycystic kidney disease progression. Kidney Int 83: 855-864, 2013
118. Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, Ruhrberg C, Cantley LG: Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 22: 317-326, 2011
119. Anders HJ, Ryu M: Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int 80: 915-925, 2011
120. Wang Y, Harris DC: Macrophages in renal disease. J AmSoc Nephrol 22: 21-27, 2011
121. Mantovani A, Sica A: Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr Opin Immunol 22: 231-237, 2010
122. Tang X, Mo C, Wang Y,Wei D, Xiao H: Antitumour strategies aiming to target tumourassociated macrophages. Immunology 138: 93-104, 2013
123. Yu H, Pardoll D, Jove R: STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer 9: 798-809, 2009
124. Liu AM, Lo RK,Wong CS, Morris C,Wise H, Wong YH: Activation of STAT3 byGalpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase. J Biol Chem 281: 35812-35825, 2006
125. Chun KS, Lao HC, Langenbach R: The prostaglandin E2 receptor, EP2, stimulates keratinocyte proliferation in mouse skin by G protein-dependent and betaarrestin1-dependent signaling pathways. J Biol Chem 285: 39672-39681, 2010
126. Nault JC, Fabre M, Couchy G, Pilati C, Jeannot E, Tran Van Nhieu J, Saint-PaulMC, De Muret A, Redon MJ, Buffet C, Salenave S, Balabaud C, Prevot S, Labrune P, Bioulac-Sage P, Scoazec JY, Chanson P, Zucman-Rossi J: GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation.JHepatol 56: 184-191, 2012
127. Pringle DR, Yin Z, Lee AA, Manchanda PK, Yu L, Parlow AF, Jarjoura D, La Perle KM, Kirschner LS: Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer. Endocr Relat Cancer 19: 435-446, 2012
128. Yasuda G, Jeffries WB: Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int 54: 80-86, 1998
129. Mutig K, Paliege A, Kahl T, Jöns T, Müller-Esterl WP, Bachmann S: Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL. Am J Physiol Renal Physiol 293: F1166-F1177, 2007
130. Carmosino M, Brooks HL, Cai Q, Davis LS, Opalenik S, Hao C, Breyer MD: Axial heterogeneity of vasopressin-receptor subtypes along thehuman andmouse collecting duct. Am J Physiol Renal Physiol 292: F351-F360, 2007
131. Verani RR, Silva FG: Histogenesis of the renal cysts in adult (autosomal dominant) polycystic kidney disease: A histochemical study. Mod Pathol 1: 457-463, 1988
132. Bankir L, Bichet DG: Polycystic kidney disease: An early urea-selective urine-concentrating defect in ADPKD. Nat Rev Nephrol 8: 437-439, 2012
133. 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 24: 309-318, 1999
134. Torres VE, Wang X, QianQ, Somlo S,Harris PC, Gattone VH 2nd: Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. NatMed 10: 363-364, 2004
135. 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 16: 846-851, 2005
136. Meijer E, Gansevoort RT, de Jong PE, van derWal AM, LeonhardWN, de Krey SR, van den Born J, Mulder GM, van Goor H, Struck J, de Heer E, Peters DJ: 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 26: 2445-2453, 2011
137. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE: Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 19: 102-108, 2008
138. Romaker D, Puetz M, Teschner S, Donauer J, Geyer M, Gerke P, Rumberger B, Dworniczak B, Pennekamp P, Buchholz B, Neumann HP, Kumar R, Gloy J, Eckardt KU, Walz G: Increased expression of secreted frizzled-related protein 4 in polycystic kidneys. J Am Soc Nephrol 20: 48-56, 2009
139. 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 301: F1005-F1013, 2011
140. Grantham JJ, Chapman AB, Torres VE, Ouyang J, Shoaf SE, Czerwiec FS: Acute and chronic osmostasis after vassopressin V2 receptor inhibiton with Tolvaptan in ADPKD [Abstract]. J Am Soc Nephrol 16: 361A, 2005
141. Chapman AB, Torres VE, Grantham JJ, Shoaf SS, Ouyang JJ, Czerwiec FS: A phase IIB pilot study of the safety and efficacy of tolvaptan, a vasopressin V2 receptor antagonist (V2RA) in paitents with ADPKD. J Am Soc Nephrol 16: 68A, 2005
142. Torres VE, Wang X, Ward CJ, Grantham JJ, Chapman AB, Ouyang J, Shoaf SE, Czerwiec FS: Urine aquaporin 2 and cyclic AMP responses to tolvaptan administration in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 16: 361A, 2005
143. Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, Horie S, Nutahara K, Ouyang J, Krasa HB, Czerwiec FS; TEMPOFormula and 156-05-002 Study Investigators: Tolvaptan in autosomal dominant polycystic kidney disease: Three years' experience. Clin J Am Soc Nephrol 6: 2499-2507, 2011
144. Irazabal MV, Torres VE, Hogan MC, Glockner J, King BF, Ofstie TG, Krasa HB, Ouyang J, Czerwiec FS: Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int 80: 295-301, 2011
145. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators: Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367: 2407-2418, 2012
146. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang JJ, Czerwiec FS: 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 57: 692-699, 2011
147. Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB: Somatostatin analogues in the control of neuroendocrine tumours: Efficacy and mechanisms. Endocr Relat Cancer 15: 701-720, 2008
148. Pyronnet S, Bousquet C, Najib S, Azar R, Laklai H, Susini C: Antitumor effects of somatostatin. Mol Cell Endocrinol 286: 230-237, 2008
149. 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 280: F457-F465, 2001
150. Bates CM, Kegg H, Grady S: Expression of somatostatin in the adult and developing mouse kidney. Kidney Int 66: 1785-1793, 2004
151. Bates CM, Kegg H, Grady S: Expression of somatostatin receptors 1 and 2 in the adult mouse kidney. Regul Pept 119: 11-20, 2004
152. Bhandari S, Watson N, Long E, Sharpe S, Zhong W, Xu SZ, Atkin SL:
153. Winkler SN, Torikai S, Levine BS, Kurokawa K: Effect of somatostatin on vasopressininduced antidiuresis and renal cyclicAMP of rats.Miner Electrolyte Metab 7: 8-14, 1982
154. Friedlander G, Amiel C: Somatostatin and alpha 2-adrenergic agonists selectively inhibit vasopressin-induced cyclic AMP accumulation in MDCK cells. FEBS Lett 198: 38-42, 1986
155. Forrest JN Jr., Reichlin S, Goodman DB: Somatostatin: An endogenous peptide in the toad urinary bladder inhibits vasopressin-stimulated water flow. Proc Natl Acad Sci U S A 77: 4984-4987, 1980
156. Mountokalakis T, Levy M: Effect of somatostatin on renal water handling in the dog. Can J Physiol Pharmacol 60: 655-664, 1982
157. Tan CK, Podila PV, Taylor JE, Nagorney DM, Wiseman GA, Gores GJ, LaRusso NF: Human cholangiocarcinomas express somatostatin receptors and respond to somatostatin with growth inhibition. Gastroenterology 108: 1908-1916, 1995
158. Tracy TF Jr., Tector AJ, GoerkeME, Kitchen S, Lagunoff D: Somatostatin analogue (octreotide) inhibits bile duct epithelial cell proliferation and fibrosis after extrahepatic biliary obstruction. Am J Pathol 143: 1574-1578, 1993
159. Masyuk TV, Radtke BN, Stroope AJ, Banales JM, Gradilone SA, Huang B, Masyuk AI, Hogan MC, Torres VE, Larusso NF: Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases. Hepatology 58: 409-421, 2013
160. Ruggenenti P, Remuzzi A, Ondei P, Fasolini G, Antiga L, Ene-Iordache B, Remuzzi G, Epstein FH: Safety and efficacy of longacting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int 68: 206-216, 2005
161. Caroli A, Antiga L, Cafaro M, Fasolini G, Remuzzi A, Remuzzi G, Ruggenenti P: Reducing polycystic liver volume in ADPKD: Effects of somatostatin analogue octreotide. Clin J Am Soc Nephrol 5: 783-789, 2010
162. van Keimpema L, Nevens F, Vanslembrouck R, vanOijenMG, Hoffmann AL, Dekker HM, de Man RA, Drenth JP: Lanreotide reduces the volume of polycystic liver: A randomized, double-blind, placebo-controlled trial. Gastroenterology 137: 1661-1668, 2009
163. Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X, KimB, King BF,Glockner J, Holmes DR 3rd, Rossetti S, Harris PC, LaRussoNF, Torres VE: Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J AmSocNephrol 21: 1052-1061, 2010
164. Chrispijn M, Nevens F, Gevers TJ, Vanslembrouck R, van Oijen MG, Coudyzer W, Hoffmann AL, Dekker HM, de Man RA, van Keimpema L, Drenth JP: The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther 35: 266-274, 2012
165. Hogan MC, Masyuk TV, Page L, Holmes DR 3rd, Li X, Bergstralh EJ, Irazabal MV, Kim B, King BF, Glockner JF, Larusso NF, Torres VE: Somatostatin analog therapy for severe polycystic liver disease: Results after 2 years. Nephrol Dial Transplant 27: 3532-3539, 2012
166. Schmid HA, Brueggen J: Effects of somatostatin analogs on glucose homeostasis in rats. J Endocrinol 212: 49-60, 2012
167. Torres VE, Bankir L, Grantham JJ: A case for water in the treatment of polycystic kidney disease. Clin J Am Soc Nephrol 4: 1140-1150, 2009
168. Nagao S, Nishii K, Katsuyama M, Kurahashi H, Marunouchi T, Takahashi H,Wallace DP: Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol 17: 2220-2227, 2006
169. Wang CJ, Creed C, Winklhofer FT, Grantham JJ: Water prescription in autosomal dominant polycystic kidney disease: Apilot study. Clin JAmSocNephrol 6: 192-197, 2011
170. ChrispijnM, Gevers TJ, Hol JC, Monshouwer R, Dekker HM, Drenth JP: Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: Results from a randomized controlled trial. J Hepatol 59: 153-159, 2013