Clinical and Molecular Insights into Tuberous Sclerosis Complex Renal Disease

Pediatric Nephrology volume 26, pages839–852(2011)Cite this article

Abstract

Patients with tuberous sclerosis complex are at great risk of developing renal lesions as part of their disease. These lesions include renal cysts and tumors. Significant advances in understanding the cell biology of these renal lesions has already led to clinical trials demonstrating that pharmacological interventions are likely possible. This review focuses on the pathology of these renal lesions, their underlying cell biology, and the possible therapeutic strategies that may prove to significantly improve care for these patients.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Gomez M, Sampson J, Whittemore V (1999) Tuberous sclerosis. Oxford University Press, New York

    Google Scholar 

  2. 2.

    Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66:792–796

    CAS  PubMed  Google Scholar 

  3. 3.

    Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, Choy YS, Reeve MP, Thiele E, Egelhoff JC, Kasprzyk-Obara J, Domanska-Pakiela D, Kwiatkowski DJ (2001) Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 68:64–80

    CAS  PubMed  Google Scholar 

  4. 4.

    Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES (1998) Renal lesion growth in children with tuberous sclerosis complex. J Urol 160:141–145

    CAS  PubMed  Google Scholar 

  5. 5.

    Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA (2006) Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors. Kidney Int 70:1777–1782

    CAS  PubMed  Google Scholar 

  6. 6.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    de Chadarevian JP, Legido A, Miles DK, Katsetos CD (2003) Epilepsy, atherosclerosis, myocardial infarction, and carbamazepine. J Child Neurol 18:150–151

    PubMed  Google Scholar 

  8. 8.

    Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, Nellist M, Gamble V, Harris PC, Sampson JR (1994) Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease–a contiguous gene syndrome. Nat Genet 8:328–332

    CAS  PubMed  Google Scholar 

  9. 9.

    Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J, Northrup H, Au KS, Lazarus R, Domanska-Pakiela D, Kotulska K, Jozwiak S, Kwiatkowski DJ (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 121:389–400

    CAS  PubMed  Google Scholar 

  10. 10.

    Sampson JR, Maheshwar MM, Aspinwall R, Thompson P, Cheadle JP, Ravine D, Roy S, Haan E, Berstein J, Harris PC (1997) Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet 61:843–851

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Valero Puerta JA, Medina Perez M, Valpuesta Fernandez I, Sanchez Gonzalez M (1999) A simple renal cyst, the origin of Wunderlich's syndrome. Arch Esp Urol 52:794–797

    CAS  PubMed  Google Scholar 

  12. 12.

    Bernstein J, Meyer R (1967) Parenchymal maldevelopment of the kidney. In: Kelley V (ed) Brennemann-Kelley practice of pediatrics. Harper, New York, pp 1–30

    Google Scholar 

  13. 13.

    Potter E (1952) Pathology of the fetus and the newborn. Year Book Medical Publishers, Chicago

    Google Scholar 

  14. 14.

    Ferrus A, Garcia-Bellido A (1976) Morphogenetic mutants detected in mitotic recombination clones. Nature 260:425–426

    CAS  PubMed  Google Scholar 

  15. 15.

    Siroky BJ, Czyzyk-Krzeska MF, Bissler JJ (2009) Renal involvement in tuberous sclerosis complex and von Hippel-Lindau disease: shared disease mechanisms? Nat Clin Pract Nephrol 5:143–156

    CAS  PubMed  Google Scholar 

  16. 16.

    Orskov B, Romming Sorensen V, Feldt-Rasmussen B, Strandgaard S (2010) Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark. Clin J Am Soc Nephrol. doi:https://doi.org/10.2215/CJN.01460210

  17. 17.

    Masoumi A, Reed-Gitomer B, Kelleher C, Bekheirnia MR, Schrier RW (2008) Developments in the management of autosomal dominant polycystic kidney disease. Ther Clin Risk Manag 4:393–407

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Jones AC, Daniells CE, Snell RG, Tachataki M, Idziaszczyk SA, Krawczak M, Sampson JR, Cheadle JP (1997) Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet 6:2155–2216

    CAS  PubMed  Google Scholar 

  19. 19.

    Bernstein J (1993) Renal cystic disease in the tuberous sclerosis complex. Pediatr Nephrol 7:490–495

    CAS  PubMed  Google Scholar 

  20. 20.

    Bissler JJ, Siroky BJ, Yin H (2010) Glomerulocystic kidney disease. Pediatr Nephrol 25:2049–2059

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Sarnat HB, Flores-Sarnat L (2005) Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J Child Neurol 20:637–643

    PubMed  Google Scholar 

  22. 22.

    Hao Z, Guo C, Jiang X, Krueger S, Pietri T, Dufour S, Cone RE, O'Rourke J (2006) New transgenic evidence for a system of sympathetic axons able to express tissue plasminogen activator (t-PA) within arterial/arteriolar walls. Blood 108:200–202

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Henske EP (2005) Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr Nephrol 20:854–857

    PubMed  Google Scholar 

  24. 24.

    Lin F, Yang W, Betten M, The BT, Yang XJ, French Kidney Cancer Study Group (2006) Expression of S-100 protein in renal cell neoplasms. Hum Pathol 37:462–470

    CAS  PubMed  Google Scholar 

  25. 25.

    Martignoni G, Pea M, Cossu Rocca P, Bonetti F (2003) Renal pathology in the tuberous sclerosis complex. Pathology 35:505–512

    PubMed  Google Scholar 

  26. 26.

    Bonetti F, Pea M, Martignoni G, Doglioni C, Zamboni G, Capelli P, Rimondi P, Andrion A (1994) Clear cell ("sugar") tumor of the lung is a lesion strictly related to angiomyolipoma–the concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC). Pathology 26:230–236

    CAS  PubMed  Google Scholar 

  27. 27.

    El-Hashemite N, Walker V, Zhang H, Kwiatkowski DJ (2003) Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res 63:5173–5177

    CAS  PubMed  Google Scholar 

  28. 28.

    Karbowniczek M, Yu J, Henske EP (2003) Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non-neoplastic vascular structures. Am J Pathol 162:491–500

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    O'Callaghan FJ, Harris T, Joinson C, Bolton P, Noakes M, Presdee D, Renowden S, Shiell A, Martyn CN, Osborne JP (2004) The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 89:530–533

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    McCullough DL, Scott R Jr, Seybold HM (1971) Renal angiomyolipoma (hamartoma): review of the literature and report of 7 cases. J Urol 105:32–44

    CAS  PubMed  Google Scholar 

  31. 31.

    Stillwell TJ, Gomez MR, Kelalis PP (1987) Renal lesions in tuberous sclerosis. J Urol 138:477–481

    CAS  PubMed  Google Scholar 

  32. 32.

    Bernstein J, Robbins TO (1991) Renal involvement in tuberous sclerosis. Ann NY Acad Sci 615:36–49

    CAS  PubMed  Google Scholar 

  33. 33.

    Kennelly MJ, Grossman HB, Cho KJ (1994) Outcome analysis of 42 cases of renal angiomyolipoma [see comments]. J Urol 152:1988–1991

    CAS  PubMed  Google Scholar 

  34. 34.

    Lemaitre L, Robert Y, Dubrulle F, Claudon M, Duhamel A, Danjou P, Mazeman E (1995) Renal angiomyolipoma: growth followed up with CT and/or US [see comments]. Radiology 197:598–602

    CAS  PubMed  Google Scholar 

  35. 35.

    Steiner MS, Goldman SM, Fishman EK, Marshall FF (1993) The natural history of renal angiomyolipoma. J Urol 150:1782–1786

    CAS  PubMed  Google Scholar 

  36. 36.

    Pacheco-Rodriguez G, Moss J (2010) The role of chemokines in migration of metastatic-like lymphangioleiomyomatosis cells. Crit Rev Immunol 30:387–394

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Ou YC, Wu HC, Yang CR, Chang CL, Hwang TI, Chang CH (1991) Renal angiomyolipoma: experience of 23 patients. Chung Hua I Hsueh Tsa Chih Taipei 48:217–223

    CAS  PubMed  Google Scholar 

  38. 38.

    Bissler JJ, Racadio J, Donnelly LF, Johnson MD (2002) Reduction of postembolization syndrome after ablation of renal angiomyolipoma. Am J Kidney Dis 39:966–971

    PubMed  Google Scholar 

  39. 39.

    Casper KA, Donnelly LF, Chen B, Bissler JJ (2002) Tuberous sclerosis complex: renal imaging findings. Radiology 225:451–456

    PubMed  Google Scholar 

  40. 40.

    Adler J, Greweldinger J, Litzky G (1984) "Macro" aneurysm in renal angiomyolipoma: two cases, with therapeutic embolization in one patient. Urol Radiol 6:201–203

    CAS  PubMed  Google Scholar 

  41. 41.

    Kessler OJ, Gillon G, Neuman M, Engelstein D, Winkler H, Baniel J (1998) Management of renal angiomyolipoma: analysis of 15 cases. Eur Urol 33:572–575

    CAS  PubMed  Google Scholar 

  42. 42.

    Mouded IM, Tolia BM, Bernie JE, Newman HR (1978) Symptomatic renal angiomyolipoma: report of 8 cases, 2 with spontaneous rupture. J Urol 119:684–688

    CAS  PubMed  Google Scholar 

  43. 43.

    Pode D, Meretik S, Shapiro A, Caine M (1985) Diagnosis and management of renal angiomyolipoma. Urology 25:461–467

    CAS  PubMed  Google Scholar 

  44. 44.

    Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225:78–82

    PubMed  Google Scholar 

  45. 45.

    Clarke A, Hancock E, Kingswood C, Osborne JP (1999) End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant 14:988–991

    CAS  PubMed  Google Scholar 

  46. 46.

    Schillinger F, Montagnac R (1996) Chronic renal failure and its treatment in tuberous sclerosis. Nephrol Dial Transplant 11:481–485

    CAS  PubMed  Google Scholar 

  47. 47.

    Fox CH, Voleti V, Khan LS, Murray B, Vassalotti J (2008) A quick guide to evidence-based chronic kidney disease care for the primary care physician. Postgrad Med 120:E01–E06

    PubMed  Google Scholar 

  48. 48.

    Patel U, Simpson E, Kingswood JC, Saggar-Malik AK (2005) Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma. Clin Radiol 60:665–673, discussion 663-664

    CAS  PubMed  Google Scholar 

  49. 49.

    Eble JN, Amin MB, Young RH (1997) Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 21:1123–1130

    CAS  PubMed  Google Scholar 

  50. 50.

    Mai KT, Perkins DG, Collins JP (1996) Epithelioid cell variant of renal angiomyolipoma [see comments]. Histopathology 28:277–280

    CAS  PubMed  Google Scholar 

  51. 51.

    Lin CN, Chiang HS, Hsu SI, Huang AH, Chuang SS (1994) Renal angiomyolipoma with a prominent angiomatous component and extramedullary hematopoiesis: a case report. Chung Hua I Hsueh Tsa Chih Taipei 53:185–187

    CAS  PubMed  Google Scholar 

  52. 52.

    Tweeddale DN, Dawe CJ, McDonald JR (1955) Angiolipoleiomyoma of the kidney:report of a case with observations on histogenesis. Cancer 8:764–770

    CAS  PubMed  Google Scholar 

  53. 53.

    Obuz F, Karabay N, Secil M, Igci E, Kovanlikaya A, Yorukoglu K (2000) Various radiological appearances of angiomyolipomas in the same kidney. Eur Radiol 10:897–899

    CAS  PubMed  Google Scholar 

  54. 54.

    Wong AL, McGeorge A, Clark AH (1981) Renal angiomyolipoma: a review of the literature and a report of 4 cases. Br J Urol 53:406–411

    CAS  PubMed  Google Scholar 

  55. 55.

    Farrow GM, Harrison EG Jr, Utz DC, Jones DR (1968) Renal angiomyolipoma. A clinicopathologic study of 32 cases. Cancer 22:564–570

    CAS  PubMed  Google Scholar 

  56. 56.

    Eble JN (1998) Angiomyolipoma of kidney. Semin Diagn Pathol 15:21–40

    CAS  PubMed  Google Scholar 

  57. 57.

    Bjornsson J, Short MP, Kwiatkowski DJ, Henske EP (1996) Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol 149:1201–1208

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Hardman JA, McNicholas TA, Kirkham N, Fletcher MS (1993) Recurrent renal angiomyolipoma associated with renal carcinoma in a patient with tuberous sclerosis. Br J Urol 72:983–984

    CAS  PubMed  Google Scholar 

  59. 59.

    Aydin H, Magi-Galluzzi C, Lane BR, Sercia L, Lopez JL, Rini BL, Zhou M (2009) Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. Am J Surg Pathol 33:289–297

    PubMed  Google Scholar 

  60. 60.

    Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW (2005) Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 29:1558–1575

    PubMed  Google Scholar 

  61. 61.

    Jimenez RE, Eble JN, Reuter VE, Epstein JI, Folpe AL, de Peralta-Venturina M, Tamboli P, Ansell ID, Grignon DJ, Young RH, Amin MB (2001) Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases. Mod Pathol 14:157–163

    CAS  PubMed  Google Scholar 

  62. 62.

    Amin MB, Crotty TB, Tickoo SK, Farrow GM (1997) Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 21:1–12

    CAS  PubMed  Google Scholar 

  63. 63.

    Eble JN, Hull MT (1984) Morphologic features of renal oncocytoma: a light and electron microscopic study. Hum Pathol 15:1054–1061

    CAS  PubMed  Google Scholar 

  64. 64.

    Zerban H, Nogueira E, Riedasch G, Bannasch P (1987) Renal oncocytoma: origin from the collecting duct. Virchows Arch B Cell Pathol Incl Mol Pathol 52:375–387

    CAS  PubMed  Google Scholar 

  65. 65.

    Siracusano S, Zanon M, D'Aloia G, Plaino F, Trombetta C, Bussani R (1998) Rare association of renal angiomyolipoma and oncocytoma. Urology 51:837–839

    CAS  PubMed  Google Scholar 

  66. 66.

    Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ, Fujikawa K, Bjornsson J, Bernstein J, Henske EP (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208–2216

    CAS  PubMed  Google Scholar 

  67. 67.

    Breysem L, Nijs E, Proesmans W, Smet MH (2002) Tuberous sclerosis with cystic renal disease and multifocal renal cell carcinoma in a baby girl. Pediatr Radiol 32:677–680

    PubMed  Google Scholar 

  68. 68.

    Robertson FM, Cendron M, Klauber GT, Harris BH (1996) Renal cell carcinoma in association with tuberous sclerosis in children. J Pediatr Surg 31:729–730

    CAS  PubMed  Google Scholar 

  69. 69.

    Lane BR, Aydin H, Danforth TL, Zhou M, Remer EM, Novick AC, Campell SC (2008) Clinical correlates of renal angiomyolipoma subtypes in 209 patients: classic, fat poor, tuberous sclerosis associated and epithelioid. J Urol 180:836–843

    PubMed  Google Scholar 

  70. 70.

    Saito K, Fujii Y, Kasahara I, Kasuga T, Kihara K (2002) Malignant clear cell "sugar" tumor of the kidney: clear cell variant of epithelioid angiomyolipoma. J Urol 168:2533–2534

    PubMed  Google Scholar 

  71. 71.

    Pea M, Bonetti F, Martignoni G, Henske EP, Manfrin E, Colato C, Bernstein J (1998) Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 22:180–187

    CAS  PubMed  Google Scholar 

  72. 72.

    Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20:267–275

    CAS  PubMed  Google Scholar 

  73. 73.

    Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102:8204–8209

    CAS  PubMed  Google Scholar 

  74. 74.

    Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293

    CAS  PubMed  Google Scholar 

  75. 75.

    Nakamura T, Sakamoto K (2008) Forkhead transcription factor FOXO subfamily is essential for reactive oxygen species-induced apoptosis. Mol Cell Endocrinol 281:47–55

    CAS  PubMed  Google Scholar 

  76. 76.

    Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unteman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458–470

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonar JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140–151

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Shillingford JM, Piontek KB, Germino GG, Weimbs T (2010) Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol 21:489–497

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Carelli S, Lesma E, Paratore S, Grande V, Zadra G, Bosari S, Di Giulio AM, Gorio A (2007) Survivin expression in tuberous sclerosis complex cells. Mol Med 13:166–177

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Juul A, Dalgaard P, Blum WF, Bang P, Hall K, MichaelsenKF MJ, Skakkebaek NE (1995) Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 80:2534–2542

    CAS  PubMed  Google Scholar 

  81. 81.

    Maggio M, Ble A, Ceda GP, Metter EJ (2006) Decline in insulin-like growth factor-I levels across adult life span in two large population studies. J Gerontol A Biol Sci Med Sci 61:182–183

    PubMed  Google Scholar 

  82. 82.

    Lesma E, Grande V, Ancona S, Carelli S, Di Giulio AM, Gorio A (2008) Anti-EGFR antibody efficiently and specifically inhibits human TSC2/ smooth muscle cell proliferation. Possible treatment options for TSC and LAM. PLoS one 3:e3558

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Pazour GJ, Witman GB (2003) The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol 15:105–110

    CAS  PubMed  Google Scholar 

  84. 84.

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

    CAS  PubMed  Google Scholar 

  85. 85.

    Hou X, Mrug M, Yoder BK, Lefkowitz EJ, Kremmidiotis G, D'Eustachio P, BeierDR Guay-Woodford LM (2002) Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J Clin Invest 109:533–540

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100:5286–5291

    CAS  PubMed  Google Scholar 

  87. 87.

    Cardenas-Rodriguez M, Badano JL (2009) Ciliary biology: understanding the cellular and genetic basis of human ciliopathies. Am J Med Genet C Semin Med Genet 151C:263–280

    CAS  PubMed  Google Scholar 

  88. 88.

    Astrinidis A, Senapedis W, Henske EP (2006) Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet 15:287–297

    CAS  PubMed  Google Scholar 

  89. 89.

    Distefano G, Boca M, Rowe I, Wodarczyk C, Ma L, Piontek KB, Germino GG, Pandolfi PP, Boletta A (2009) 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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kleymenova E, Ibraghimov-Beskrovnaya O, Kugoh H, Everitt J, Xu H, Kiguchi K, Landes G, Harris P, Walker C (2001) Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell 7:823–832

    CAS  PubMed  Google Scholar 

  91. 91.

    Praetorius HA, Spring KR (2001) Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184:71–79

    CAS  PubMed  Google Scholar 

  92. 92.

    Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137

    CAS  PubMed  Google Scholar 

  93. 93.

    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 (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37:537–543

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Bonnet CS, Aldred M, von Ruhland C, Harris R, Sandford R, Cheadle JP (2009) Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Hum Mol Genet 18:2166–2176

    CAS  PubMed  Google Scholar 

  95. 95.

    Christensen ST, Pedersen LB, Schneider L, Satir P (2007) Sensory cilia and integration of signal transduction in human health and disease. Traffic 8:97–109

    CAS  PubMed  Google Scholar 

  96. 96.

    Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL, Griffin JD, Kwiatkowski DJ (2007) PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117:730–738

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Neugebauer JM, Amack JD, Peterson AG, Bisgrove BW, Yost HJ (2009) FGF signalling during embryo development regulates cilia length in diverse epithelia. Nature 458:651–654

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Meyers EN, Martin GR (1999) Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285:403–406

    CAS  PubMed  Google Scholar 

  99. 99.

    Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1:e53

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Satir P, Christensen ST (2007) Overview of structure and function of mammalian cilia. Annu Rev Physiol 69:377–400

    CAS  PubMed  Google Scholar 

  101. 101.

    Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22

    CAS  PubMed  Google Scholar 

  102. 102.

    Manning BD (2004) Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 167:399–403

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Jaeschke A, Hartkamp J, Saitoh M, Roworth W, Nobukuni T, Hodges A, Sampson J, Thomas G, Lamb R (2002) Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol 159:217–224

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda H (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11:525–534

    CAS  PubMed  Google Scholar 

  105. 105.

    Kenerson H, Aicher L, True L, Yeung R (2002) Activated mTOR pathway in the pathogenesis of tuberous sclerosis. In: Whittemore V (ed) New perspectives in tuberous sclerosis complex. TS Alliance, Chantilly

    Google Scholar 

  106. 106.

    Kenerson HL, Aicher LD, True LD, Yeung RS (2002) Activated Mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 62:5645–5650

    CAS  PubMed  Google Scholar 

  107. 107.

    Ito N, Rubin GM (1999) Gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96:529–539

    CAS  PubMed  Google Scholar 

  108. 108.

    Klionsky DJ, Meijer AJ, Codogno P (2005) Autophagy and p70S6 kinase. Autophagy 1:59–60, discussion 60-61

    CAS  PubMed  Google Scholar 

  109. 109.

    Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273:3963–3966

    CAS  PubMed  Google Scholar 

  110. 110.

    Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6:304–312

    CAS  PubMed  Google Scholar 

  111. 111.

    Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348

    CAS  PubMed  Google Scholar 

  112. 112.

    Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN (2002) Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291–7297

    CAS  PubMed  Google Scholar 

  113. 113.

    Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, Domingo D, Yahalom J (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439–444

    CAS  PubMed  Google Scholar 

  114. 114.

    Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 11:448–457

    CAS  PubMed  Google Scholar 

  115. 115.

    Opipari AW Jr, Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR (2004) Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res 64:696–703

    CAS  PubMed  Google Scholar 

  116. 116.

    Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5:726–734

    CAS  PubMed  Google Scholar 

  117. 117.

    Lefranc F, Kiss R (2006) Autophagy, the Trojan horse to combat glioblastomas. Neurosurg Focus 20:E7

    PubMed  Google Scholar 

  118. 118.

    Iwamaru A, Kondo Y, Iwado E, Aoki H, Fujiwara K, Yokoyama T, Mills GB, Kondo S (2007) Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene 26:1840–1851

    CAS  PubMed  Google Scholar 

  119. 119.

    Lefranc F, Facchini V, Kiss R (2007) Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 12:1395–1403

    CAS  PubMed  Google Scholar 

  120. 120.

    Schweichel JU, Merker HJ (1973) The morphology of various types of cell death in prenatal tissues. Teratology 7:253–266

    CAS  PubMed  Google Scholar 

  121. 121.

    Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Kianchi K, Fehrenbacher N, Elling F, Rizzuto R, Mathiasen IS, Jaattela M (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25:193–205

    PubMed  Google Scholar 

  122. 122.

    Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14:1576–1582

    CAS  PubMed  Google Scholar 

  123. 123.

    Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29:541–551

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Department of Defense (TS050008).

Author information

Affiliations

  1. Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, MLC 7022, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Brian J. Siroky & John J. Bissler

  2. Division of Pathology, Cincinnati Children’s Hospital Medical Center, MLC 7022, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Hong Yin

Authors
  1. Brian J. Siroky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John J. Bissler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John J. Bissler.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Siroky, B.J., Yin, H. & Bissler, J.J. Clinical and Molecular Insights into Tuberous Sclerosis Complex Renal Disease. Pediatr Nephrol 26, 839–852 (2011). https://doi.org/10.1007/s00467-010-1689-5

Download citation

Keywords

  • Rapamycin
  • mTORC1
  • Oncocytoma
  • Renal cyst
  • Angiomyolipoma
  • Tuberous sclerosis complex
  • Endoplasmic reticulum stress
  • Autophagy