MTOR signaling in polycystic kidney disease

Trends in Molecular Medicine

Volumn 17, Issue 11, 2011, Pages 625-633

  Ibraghimov Beskrovnaya, Oxana ^a   Natoli, Thomas A ^a  

^a GENZYME CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOSPORIN; EVEROLIMUS; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PLACEBO; POLYCYSTIN 1; POLYCYSTIN 2; RAPAMYCIN; TACROLIMUS;

CHRONIC KIDNEY DISEASE; DISEASE COURSE; DRUG MECHANISM; ENZYME ACTIVATION; ENZYME INHIBITION; GENE MUTATION; HUMAN; KIDNEY POLYCYSTIC DISEASE; NONHUMAN; PATHOGENESIS; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CILIA; CLINICAL TRIALS AS TOPIC; HUMANS; KIDNEY; MUTATION; POLYCYSTIC KIDNEY DISEASES; PROTEIN KINASES; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; TRPP CATION CHANNELS;

EID: 80755139525     PISSN: 14714914     EISSN: 1471499X     Source Type: Journal    
DOI: 10.1016/j.molmed.2011.06.003     Document Type: Review

References (121)

1. Harris P.C., Torres V.E. Polycystic kidney disease. Annu. Rev. Med. 2009, 60:321-337.
2. Torres V.E., Harris P.C. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009, 76:149-168.
3. Ecder T., Schrier R.W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol. 2009, 5:221-228.
4. Sweeney W.E., Avner E.D. Diagnosis and management of childhood polycystic kidney disease. Pediatr. Nephrol. 2011, 26:675-692.
5. Menezes L.F., Onuchic L.F. Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease. Braz. J. Med. Biol. Res. 2006, 39:1537-1548.
6. Hildebrandt F., et al. Nephronophthisis: disease mechanisms of a ciliopathy. J. Am. Soc. Nephrol. 2009, 20:23-35.
7. Torres V.E. Treatment strategies and clinical trial design in ADPKD. Adv. Chronic Kidney Dis. 2010, 17:190-204.
8. Patel V., et al. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr. Opin. Nephrol. Hypertens. 2009, 18:99-106.
9. Hurd T.W., Hildebrandt F. Mechanisms of nephronophthisis and related ciliopathies. Nephron. Exp. Nephrol. 2011, 118:e9-e14.
10. Rosenbaum J.L., Witman G.B. Intraflagellar transport. Nat. Rev. Mol. Cell Biol. 2002, 3:813-825.
11. Satir P., et al. The primary cilium at a glance. J. Cell Sci. 2011, 123:499-503.
12. Goetz S.C., Anderson K.V. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 2010, 11:331-344.
13. Gascue C., et al. Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms. Pediatr. Nephrol. 2011, 26:1181-1195.
14. Gallagher A.R., et al. Molecular advances in autosomal dominant polycystic kidney disease. Adv. Chronic Kidney Dis. 2010, 17:118-130.
15. Pazour G.J., et al. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr. Biol. 2002, 12:R378-R380.
16. Yoder B.K., et al. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 2002, 13:2508-2516.
17. Ward C.J., et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum. Mol. Genet. 2003, 12:2703-2710.
18. Hildebrandt F., Otto E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?. Nat. Rev. Genet. 2005, 6:928-940.
19. Lin F., et al. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:5286-5291.
20. Pazour G.J., et al. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J. Cell Biol. 2000, 151:709-718.
21. Smith L.A., et al. 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. 2006, 17:2821-2831.
22. Praetorius H.A., Spring K.R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol. 2001, 184:71-79.
23. Nauli S.M., et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 2003, 33:129-137.
24. Simons M., et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 2005, 37:537-543.
25. Ross A.J., et al. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat. Genet. 2005, 37:1135-1140.
26. Tran P.V., et al. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat. Genet. 2008, 40:403-410.
27. Wong S.Y., Reiter J.F. The primary cilium at the crossroads of mammalian hedgehog signaling. Curr. Top. Dev. Biol. 2008, 85:225-260.
28. Christensen S.T., et al. The primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair. Curr. Top. Dev. Biol. 2008, 85:261-301.
29. Masyuk A.I., et al. Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 295:G725-G734.
30. Boehlke C., et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 2010, 12:1115-1122.
31. Tao Y., et al. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J. Am. Soc. Nephrol. 2005, 16:46-51.
32. Wahl P.R., et al. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol. Dial. Transplant. 2006, 21:598-604.
33. Brook-Carter P.T., et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease - a contiguous gene syndrome. Nat. Genet. 1994, 8:328-332.
34. Bonnet C.S., et al. Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Hum. Mol. Genet. 2009, 18:2166-2176.
35. Cai S.L., Walker C.L. TSC2, a key player in tumor suppression and cystic kidney disease. Nephrol. Ther. 2006, 2(Suppl. 2):S119-S122.
36. Kleymenova E., et al. Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol. Cell 2001, 7:823-832.
37. Hartman T.R., et al. The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum. Mol. Genet. 2009, 18:151-163.
38. Canaud G., et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?. Am. J. Transplant. 2010, 10:1701-1706.
39. Shillingford J.M., 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, 103:5466-5471.
40. Zafar I., et al. Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int. 2010, 78:754-761.
41. Gattone V.H., IInd, et al. Late progression of renal pathology and cyst enlargement is reduced by rapamycin in a mouse model of nephronophthisis. Kidney Int. 2009, 76:178-182.
42. Natoli T.A., et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med. 2010, 16:788-792.
43. Dere R., et al. Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. PLoS ONE 2010, 5:e9239.
44. Qin S., 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, 120:3617-3628.
45. Shillingford J.M., et al. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J. Am. Soc. Nephrol. 2010, 21:489-497.
46. Wahl P.R., et al. Mitotic activation of Akt signalling pathway in Han:SPRD rats with polycystic kidney disease. Nephrology (Carlton) 2007, 12:357-363.
47. Belibi F., et al. mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease. Am. J. Physiol. Renal Physiol. 2011, 300:F236-F244.
48. Renken C., et al. Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrol. Dial. Transplant. 2011, 26:92-100.
49. Wu M., 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:F1597-F1605.
50. Foster D.A., Toschi A. Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle 2009, 8:1026-1029.
51. Distefano G., 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, 29:2359-2371.
52. Zheng R., et al. Inhibition of PKHD1 may cause S-phase entry via mTOR signaling pathway. Cell Biol. Int. 2009, 33:926-933.
53. Toschi A., et al. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol. Cell. Biol. 2009, 29:1411-1420.
54. Reichardt W., et al. Monitoring kidney and renal cyst volumes applying MR approaches on a rapamycin treated mouse model of ADPKD. MAGMA 2009, 22:143-149.
55. Wu M., et al. Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease. Kidney Blood Press. Res. 2007, 30:253-259.
56. Zhang T., et al. Mycophenolate mofetil versus rapamycin in Han: SPRD rats with polycystic kidney disease. Biol. Res. 2009, 42:437-444.
57. Grantham J.J., et al. Volume progression in polycystic kidney disease. N. Engl. J. Med. 2006, 354:2122-2130.
58. Grantham J.J. Polycystic kidney disease. Sci. Med. 2003, 9:128-138.
59. Torres V.E., et al. Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. Clin. J. Am. Soc. Nephrol. 2010, 5:1312-1329.
60. Qian Q., et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J. Am. Soc. Nephrol. 2008, 19:631-638.
61. Serra A.L., et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 2010, 363:820-829.
62. Walz G., et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 2010, 363:830-840.
63. Huber T.B., et al. mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression. Kidney Int. 2010, 79:502-511.
64. Perico N., et al. Sirolimus therapy to halt the progression of ADPKD. J. Am. Soc. Nephrol. 2010, 21:1031-1040.
65. Ponticelli C., Locatelli F. Autosomal dominant polycystic kidney disease and mTOR inhibitors: the narrow road between hope and disappointment. Nephrol. Dial. Transplant. 2010, 25:3809-3812.
66. Roychowdhury A., et al. Recent advances in the discovery of small molecule mTOR inhibitors. Future Med. Chem. 2010, 2:1577-1589.
67. McCarty M.F., et al. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease. Med. Hypotheses 2009, 73:1008-1010.
68. Takiar V., et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:2462-2467.
69. Leuenroth S.J., et al. Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD. Nephrol. Dial. Transplant. 2010, 25:2187-2194.
70. Gattone V.H., IInd, et al. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 2003, 9:1323-1326.
71. Torres V.E., et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 2004, 10:363-364.
72. Ruggenenti P., et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005, 68:206-216.
73. Hogan M.C., et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J. Am. Soc. Nephrol. 2010, 21:1052-1061.
74. Li H., Sheppard D.N. Therapeutic potential of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors in polycystic kidney disease. BioDrugs 2009, 23:203-216.
75. Bukanov N.O., et al. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 2006, 444:949-952.
76. Ibraghimov-Beskrovnaya O. Targeting dysregulated cell cycle and apoptosis for polycystic kidney disease therapy. Cell Cycle 2007, 6:776-779.
77. Sweeney W.E., et al. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int. 2000, 57:33-40.
78. Sweeney W.E., et al. Src inhibition ameliorates polycystic kidney disease. J. Am. Soc. Nephrol. 2008, 19:1331-1341.
79. Omori S., et al. Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease. J. Am. Soc. Nephrol. 2006, 17:1604-1614.
80. Park F., et al. 20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease. J. Am. Soc. Nephrol. 2008, 19:1929-1939.
81. Li X., et al. A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease. Nat. Med. 2008, 14:863-868.
82. Wang S., et al. Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia. Mol. Cell. Biol. 2007, 27:3241-3252.
83. Xu C., 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:F930-F945.
84. Yamaguchi T., et al. Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J. Biol. Chem. 2004, 279:40419-40430.
85. Low S.H., et al. Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev. Cell 2006, 10:57-69.
86. Qian C.N., et al. Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium. J. Biol. Chem. 2005, 280:3938-3945.
87. Saadi-Kheddouci S., et al. Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 2001, 20:5972-5981.
88. Kim E., et al. The polycystic kidney disease 1 gene product modulates Wnt signaling. J. Biol. Chem. 1999, 274:4947-4953.
89. Lancaster M.A., et al. Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat. Med. 2009, 15:1046-1054.
90. Bhunia A.K., 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, 109:157-168.
91. Li X., et al. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat. Cell Biol. 2005, 7:1202-1212.
92. Schneider L., et al. PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts. Curr. Biol. 2005, 15:1861-1866.
93. Liu A., et al. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 2005, 132:3103-3111.
94. Fejes-Toth G., et al. Epithelial Na+ channel activation and processing in mice lacking SGK1. Am. J. Physiol. Renal Physiol. 2008, 294:F1298-F1305.
95. Strutz-Seebohm N., et al. Serum- and glucocorticoid-inducible kinases (SGK) regulate KCNQ1/KCNE potassium channels. Channels (Austin) 2009, 3:88-90.
96. Ullrich S., et al. Dexamethasone increases Na+/K+ ATPase activity in insulin secreting cells through SGK1. Biochem. Biophys. Res. Commun. 2007, 352:662-667.
97. Bertuccio C.A., et al. Polycystin-1 C-terminal cleavage is modulated by polycystin-2 expression. J. Biol. Chem. 2009, 284:21011-21026.
98. Chapin H.C., Caplan M.J. The cell biology of polycystic kidney disease. J. Cell Biol. 2010, 191:701-710.
99. Chauvet V., et al. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1C terminus. J. Clin. Invest. 2004, 114:1433-1443.
100. Mochizuki T., et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996, 272:1339-1342.
101. Tsiokas L., et al. Cell biology of polycystin-2. Cell. Signal. 2007, 19:444-453.
102. Hanaoka K., et al. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature 2000, 408:990-994.
103. Babich V., et al. The N-terminal extracellular domain is required for polycystin-1-dependent channel activity. J. Biol. Chem. 2004, 279:25582-25589.
104. Koulen P., et al. Polycystin-2 is an intracellular calcium release channel. Nat. Cell. Biol. 2002, 4:191-197.
105. Ward C.J., et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat. Genet. 2002, 30:259-269.
106. Onuchic L.F., et al. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am. J. Hum. Genet. 2002, 70:1305-1317.
107. Kaimori J.Y., et al. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum. Mol. Genet. 2007, 16:942-956.
108. Kim I., et al. Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J. Am. Soc. Nephrol. 2008, 19:455-468.
109. Sengupta S., et al. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 2010, 40:310-322.
110. Duvel K., et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 2010, 39:171-183.
111. Fingar D.C., et al. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002, 16:1472-1487.
112. Wullschleger S., et al. TOR signaling in growth and metabolism. Cell 2006, 124:471-484.
113. Nicklin P., et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009, 136:521-534.
114. Alessi D.R., et al. New insights into mTOR signaling: mTORC2 and beyond. Sci. Signal. 2009, 2:pe27.
115. Huang J., et al. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell. Biol. 2008, 28:4104-4115.
116. Huang J., et al. Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res. 2009, 69:6107-6114.
117. Cai S.L., et al. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J. Cell Biol. 2006, 173:279-289.
118. Kovacina K.S., et al. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J. Biol. Chem. 2003, 278:10189-10194.
119. Nascimento E.B., et al. Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1. Cell. Signal. 2010, 22:961-967.
120. Fang Y., et al. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 2001, 294:1942-1945.
121. Yip C.K., et al. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 2010, 38:768-774.