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Clinical Nephrotoxins pp 223–249Cite as

Renal cell culture models: Contribution to the understanding of nephrotoxic mechanisms

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The kidney represents a major target for toxic xenobiotics due to its role in the control of body fluid and electrolyte homeostasis. The high blood perfusion rate (20% of cardiac output) and the capability to extract, metabolize, secrete and concentrate toxic compounds make the kidneys extremely vulnerable to a wide variety of toxins, many of which are yet to be identified. It is estimated that therapeutic agents cause 20% of all diagnosed end stage renal disease (ESRD) and that chemicals and drugs may play a significant role in at least 50% of ESRD cases of unknown etiology [1].

Because of the functional and biochemical heterogeneity of the nephron, the susceptibility to a particular nephrotoxic insult will vary among nephron segments. The epithelial cells of the proximal nephron are target sites for a wide variety of nephrotoxic chemicals due to a large number of transport systems [2] and the presence of xenobiotic metabolizing enzymes such as cytochrome P-450, NADPH-cytochrome c reductase, glucuronyl transferase, sulfotransferases, glutathione S-transferases, cysteine conjugate β-lyase, monooxygenases and prostaglandin H synthase [3]. Another factor is the intracellular concentration of glutathione (GSH ) and GSH dependent enzyme activity, which is highest in proximal tubule and decreases progressively down the nephron [4, 5]. Additionally the proximal tubule has a high requirement for oxygen which makes this area of the nepron especially sensitive to oxygen deprivation [6].

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References

  1. Commission of the European Communities/International Programme on Chemical Safety. Health signficance and early detection of nephrotoxicity. Proceedings of the joint CEC/IPCS Workshop. Commission of the European Communities/International Programme on Chemical Safety. Luxembourg, 26-29 April 1988. Toxicol Lett 46: 1-306, 1989.

    Google Scholar 

  2. Fanos V and Cataldi L. Renal transport of antibiotics and nephrotoxicity: a review. J Chemother 13: 461-472, 2001.

    PubMed  CAS  Google Scholar 

  3. Lohr JW, Willsky GR, and Acara MA. Renal drug metabolism. Pharmacol Rev 50: 107-141, 1998.

    PubMed  CAS  Google Scholar 

  4. Mohandas J, Marshall JJ, Duggin GG, Horvath JS, and Tiller DJ. Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney. Possible implications in analgesic nephropathy. Biochem Pharmacol 33: 1801-1807, 1984.

    PubMed  CAS  Google Scholar 

  5. Guder WG and Ross BD. Enzyme distribution along the nephron. Kidney Int 26: 101-111, 1984.

    PubMed  CAS  Google Scholar 

  6. Leonard MO, Kieran NE, Howell K, Burne MJ, Varadarajan R, Dhakshinamoorthy S, Porter AG, O’Farrelly C, Rabb H, and Taylor CT. Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. FASEB J 20: 2624-2626, 2006.

    PubMed  CAS  Google Scholar 

  7. European Economic Community. Council Directive 86/609/EEC of 24 November on the approximation of laws, regulations, and administrative provisions of the Member States regarding the protection of animals used for experimental and other purposes. Off J Eur Commun L352: 1-29, 1986.

    Google Scholar 

  8. Stokes WS and Marafante E. Introduction and summary of the 13th meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies. Environ Health Perspect 106 Suppl 2: 405-412, 1998.

    PubMed  Google Scholar 

  9. Webster WS, Brown-Woodman PD, and Ritchie HE. A review of the contribution of whole embryo culture to the determination of hazard and risk in teratogenicity testing. Int J Dev Biol 41: 329-335, 1997.

    PubMed  CAS  Google Scholar 

  10. Ashby J, Kier L, Wilson AG, Green T, Lefevre PA, Tinwell H, Willis GA, Heydens WF, and Clapp MJ. Evaluation of the potential carcinogenicity and genetic toxicity to humans of the herbicide acetochlor. Hum Exp Toxicol 15: 702-735, 1996.

    PubMed  CAS  Google Scholar 

  11. Green T, Lee R, Moore RB, Ashby J, Willis GA, Lund VJ, and Clapp MJ. Acetochlor-induced rat nasal tumors: further studies on the mode of action and relevance to humans. Regul Toxicol Pharmacol 32: 127-133, 2000.

    PubMed  CAS  Google Scholar 

  12. Dybing E and Huitfeldt HS. Species differences in carcinogen metabolism and interspecies extrapolation. IARC Sci Publ: 501-522, 1992.

    Google Scholar 

  13. Hengstler JG, Van der Burg B, Steinberg P, and Oesch F. Interspecies differences in cancer susceptibility and toxicity. Drug Metab Rev 31: 917-970, 1999.

    PubMed  CAS  Google Scholar 

  14. Hayes JD and Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30: 445-600, 1995.

    PubMed  CAS  Google Scholar 

  15. Pfaller W and Gstraunthaler G. Nephrotoxicity testing in vitro--what we know and what we need to know. Environ Health Perspect 106 Suppl 2: 559-569, 1998.

    Google Scholar 

  16. Green DF, Hwang KH, Ryan US, and Bourgoignie JJ. Culture of endothelial cells from baboon and human glomeruli. Kidney Int 41: 1506-1516, 1992.

    PubMed  CAS  Google Scholar 

  17. van Setten PA, van Hinsbergh VW, van der Velden TJ, van de Kar NC, Vermeer M, Mahan JD, Assmann KJ, van den Heuvel LP, and Monnens LA. Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int 51: 1245-1256, 1997.

    PubMed  CAS  Google Scholar 

  18. Haraldsen G, Kvale D, Lien B, Farstad IN, and Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J Immunol 156: 2558-2565, 1996.

    PubMed  CAS  Google Scholar 

  19. van Muijen GN, Ruiter DJ, and Warnaar SO. Coexpression of intermediate filament polypeptides in human fetal and adult tissues. Lab Invest 57: 359-369, 1987.

    PubMed  CAS  Google Scholar 

  20. Diaz-Flores L, Gutierrez R, Varela H, Rancel N, and Valladares F. Microvascular pericytes: a review of their morphological and functional characteristics. Histol Histopathol 6: 269-286, 1991.

    PubMed  CAS  Google Scholar 

  21. Herman IM and D’Amore PA. Microvascular pericytes contain muscle and nonmuscle actins. J Cell Biol 101: 43-52, 1985.

    PubMed  CAS  Google Scholar 

  22. Hewett PW and Murray JC. Human microvessel endothelial cells: isolation, culture and characterization. In vitro Cell Dev Biol Anim 29A: 823-830, 1993.

    PubMed  CAS  Google Scholar 

  23. Jennings P. Novel Approaches For In vitro Nephrotoxicity Testing. PhD thesis, University College Dublin Library, 2001.

    Google Scholar 

  24. Ronco P and Debiec H. Podocyte antigens and glomerular disease. Nephron Exp Nephrol 107: e41-46, 2007.

    PubMed  Google Scholar 

  25. Kerjaschki D, Sharkey DJ, and Farquhar MG. Identification and characterization of podocalyxin--the major sialoprotein of the renal glomerular epithelial cell. J Cell Biol 98: 1591-1596, 1984.

    PubMed  CAS  Google Scholar 

  26. Shankland SJ, Pippin JW, Reiser J, and Mundel P. Podocytes in culture: past, present, and future. Kidney Int 72: 26-36, 2007.

    PubMed  CAS  Google Scholar 

  27. Johnson RJ, Iida H, Alpers CE, Majesky MW, Schwartz SM, Pritzi P, Gordon K, and Gown AM. Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation. J Clin Invest 87: 847-858, 1991

    PubMed  CAS  Google Scholar 

  28. Stamenkovic I, Skalli O, and Gabbiani G. Distribution of intermediate filament proteins in normal and diseased human glomeruli. Am J Pathol 125: 465-475, 1986.

    PubMed  CAS  Google Scholar 

  29. Ishimura E, Sterzel RB, Morii H, and Kashgarian M. Extracellular matrix protein: gene expression and synthesis in cultured rat mesangial cells. Nippon Jinzo Gakkai Shi 34: 9-17, 1992.

    PubMed  CAS  Google Scholar 

  30. Potier M, L’Azou B, and Cambar J. Isolated glomeruli and cultured mesangial cells as in vitro models to study immunosuppressive agents. Cell Biol Toxicol 12: 263-270, 1996.

    PubMed  CAS  Google Scholar 

  31. Ardaillou R, Chansel D, Stefanovic V, and Ardaillou N. Cell surface receptors and ectoenzymes in mesangial cells. J Am Soc Nephrol 2: S107-115, 1992.

    PubMed  CAS  Google Scholar 

  32. Kriz W, Elger M, Lemley K, and Sakai T. Structure of the glomerular mesangium: a biomechanical interpretation. Kidney Int Suppl 30: S2-9, 1990.

    PubMed  CAS  Google Scholar 

  33. Gstraunthaler G and Pfaller W. Continuous renal cell lines as in vitro tools to study nephrotoxicity. In vitro Methods of Toxicology: 93-113, 1992.

    Google Scholar 

  34. Rabito CA. Occluding junctions in a renal cell line (LLC-PK1) with characteristics of proximal tubular cells. Am J Physiol 250: F734-743, 1986.

    PubMed  CAS  Google Scholar 

  35. Simmons NL. Tissue culture of established renal cell lines. Methods Enzymol 191: 426-436, 1990.

    PubMed  CAS  Google Scholar 

  36. Horster M. Primary culture of mammalian nephron epithelia: requirements for cell outgrowth and proliferation from defined explanted nephron segments. Pflugers Arch 382: 209-215, 1979.

    PubMed  CAS  Google Scholar 

  37. Morel F. Sites of hormone action in the mammalian nephron. Am J Physiol 240: F159-164, 1981.

    PubMed  CAS  Google Scholar 

  38. Blais A, Morvan-Baleynaud J, Friedlander G, and Le Grimellec C. Primary culture of rabbit proximal tubules as a cellular model to study nephrotoxicity of xenobiotics. Kidney Int 44: 13-18, 1993.

    PubMed  CAS  Google Scholar 

  39. Luhe A, Hildebrand H, Bach U, Dingermann T, and Ahr HJ. A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays. Toxicol Sci 73: 315-328, 2003.

    PubMed  Google Scholar 

  40. Schwerdt G, Holzinger H, Sauvant C, Konigs M, Humpf HU, and Gekle M. Long-term effects of ochratoxin A on fibrosis and cell death in human proximal tubule or fibroblast cells in primary culture. Toxicology 232: 57-67, 2007.

    PubMed  CAS  Google Scholar 

  41. Springate J and Taub M. Ifosfamide toxicity in cultured proximal renal tubule cells. Pediatr Nephrol 22: 358-365, 2007.

    PubMed  Google Scholar 

  42. Jennings P, Koppelstaetter C, Aydin S, Abberger T, Wolf AM, Mayer G, and Pfaller W. Cyclosporine A induces senescence in renal tubular epithelial cells. Am J Physiol Renal Physiol 293: F831-838, 2007.

    PubMed  CAS  Google Scholar 

  43. Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, and Wu JR. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A 85: 6622-6626, 1988.

    PubMed  CAS  Google Scholar 

  44. Hayflick L. The Limited In vitro Lifetime Of Human Diploid Cell Strains. Exp Cell Res 37: 614-636, 1965.

    PubMed  CAS  Google Scholar 

  45. Gstraunthaler G, Pfaller W, and Kotanko P. Lack of fructose-1,6-bisphosphatase activity in LLC-PK1 cells. Am J Physiol 248: C181-183, 1985.

    PubMed  CAS  Google Scholar 

  46. Hull RN, Cherry WR, and Weaver GW. The origin and characteristics of a pig kidney cell strain, LLC-PK. In vitro 12: 670-677, 1976.

    PubMed  CAS  Google Scholar 

  47. Takaoka T, Katsuta H, Endo M, Sato K, and Okumura H. Establishment of a cell strain, JTC-12, from cynomolgus monkey kidney tissue. Jpn J Exp Med 32: 351-368, 1962.

    PubMed  CAS  Google Scholar 

  48. Koyama H, Goodpasture C, Miller MM, Teplitz RL, and Riggs AD. Establishment and characterization of a cell line from the American opossum (Didelphys virginiana). In vitro 14: 239-246, 1978.

    PubMed  CAS  Google Scholar 

  49. Gstraunthaler G, Pfaller W, and Kotanko P. Biochemical characterization of renal epithelial cell cultures (LLC-PK1 and MDCK). Am J Physiol 248: F536-544, 1985.

    PubMed  CAS  Google Scholar 

  50. Gaush CR, Hard WL, and Smith TF. Characterization of an established line of canine kidney cells (MDCK). Proc Soc Exp Biol Med 122: 931-935, 1966.

    PubMed  CAS  Google Scholar 

  51. Handler JS, Preston AS, Perkins FM, Matsumura M, Johnson JP, and Watlington CO. The effect of adrenal steroid hormones on epithelia formed in culture by A6 cells. Ann N Y Acad Sci 372: 442-454, 1981.

    PubMed  CAS  Google Scholar 

  52. Saier MH, Jr. Growth and differentiated properties of a kidney epithelial cell line (MDCK). Am J Physiol 240: C106-109, 1981.

    PubMed  CAS  Google Scholar 

  53. Louvard D. Apical membrane aminopeptidase appears at site of cell-cell contact in cultured kidney epithelial cells. Proc Natl Acad Sci U S A 77: 4132-4136, 1980.

    PubMed  CAS  Google Scholar 

  54. Ausiello DA, Hall DH, and Dayer JM. Modulation of cyclic AMP-dependent protein kinase by vasopressin and calcitonin in cultured porcine renal LLC-PK1 cells. Biochem J 186: 773-780, 1980.

    PubMed  CAS  Google Scholar 

  55. Gstraunthaler GJ. Epithelial cells in tissue culture. Ren Physiol Biochem 11: 1-42, 1988.

    PubMed  CAS  Google Scholar 

  56. Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA, and Torok-Storb B. HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney Int 45: 48-57, 1994.

    PubMed  CAS  Google Scholar 

  57. Hong HX, Zhang YM, Xu H, Su ZY, and Sun P. Immortalization of swine umbilical vein endothelial cells with human telomerase reverse transcriptase. Mol Cells 24: 358-363, 2007.

    PubMed  CAS  Google Scholar 

  58. Shay JW and Wright WE. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26: 867-874, 2005.

    PubMed  CAS  Google Scholar 

  59. Satchell SC, Tasman CH, Singh A, Ni L, Geelen J, von Ruhland CJ, O’Hare MJ, Saleem MA, van den Heuvel LP, and Mathieson PW. Conditionally immortalized human glomerular endothelial cells expressing fenestrations in response to VEGF. Kidney Int 69: 1633-1640, 2006.

    PubMed  CAS  Google Scholar 

  60. Kowolik CM, Liang S, Yu Y, and Yee JK. Cre-mediated reversible immortalization of human renal proximal tubular epithelial cells. Oncogene 23: 5950-5957, 2004.

    PubMed  CAS  Google Scholar 

  61. Gstraunthaler G, Thurner B, Weirich-Schwaiger H, and Pfaller W. A novel gluconeogenic strain of OK cells with metabolic properties different from gluconegenic LLC-PK1 cells. Cell Physiol Biochem 3: 78-88, 1993.

    CAS  Google Scholar 

  62. Gstraunthaler G, Gersdorf E, Fischer WM, Joannidis M, and Pfaller W. Morphological and biochemical changes of LLC-PK1 cells during adaptation to glucose-free culture conditions. Ren Physiol Biochem 13: 137-153, 1990.

    PubMed  CAS  Google Scholar 

  63. Holcomb T, Curthoys NP, and Gstraunthaler G. Subcellular localization of PEPCK and metabolism of gluconeogenic substrains of renal cell lines. Am J Physiol 268: C449-457, 1995.

    PubMed  CAS  Google Scholar 

  64. Chung SD, Alavi N, Livingston D, Hiller S, and Taub M. Characterization of primary rabbit kidney cultures that express proximal tubule functions in a hormonally defined medium. J Cell Biol 95: 118-126, 1982.

    PubMed  CAS  Google Scholar 

  65. Pettersen EO, Larsen LH, Ramsing NB, and Ebbesen P. Pericellular oxygen depletion during ordinary tissue culturing, measured with oxygen microsensors. Cell Prolif 38: 257-267, 2005.

    PubMed  Google Scholar 

  66. Gstraunthaler G, Seppi T, and Pfaller W. Impact of culture conditions, culture media volumes, and glucose content on metabolic properties of renal epithelial cell cultures. Are renal cells in tissue culture hypoxic? Cell Physiol Biochem 9: 150-172, 1999.

    PubMed  CAS  Google Scholar 

  67. Handler JS, Preston AS, and Steele RE. Factors affecting the differentiation of epithelial transport and responsiveness to hormones. Fed Proc 43: 2221-2224, 1984.

    PubMed  CAS  Google Scholar 

  68. Cook JR, Crute BE, Patrone LM, Gabriels J, Lane ME, and Van Buskirk RG. Microporosity of the substratum regulates differentiation of MDCK cells in vitro. In vitro Cell Dev Biol 25: 914-922, 1989.

    PubMed  CAS  Google Scholar 

  69. Zlatkine P, Moll G, Blais A, Loiseau A, and Le Grimellec C. Transport of choline by Madin-Darby canine kidney cells. Biochim Biophys Acta 1153: 237-242, 1993.

    PubMed  CAS  Google Scholar 

  70. Lang MA, Muller J, Preston AS, and Handler JS. Complete response to vasopressin requires epithelial organization in A6 cells in culture. Am J Physiol 250: C138-145, 1986.

    PubMed  CAS  Google Scholar 

  71. Okuda M, Tsuda K, Masaki K, Hashimoto Y, and Inui K. Cisplatin-induced toxicity in LLC-PK1 kidney epithelial cells: role of basolateral membrane transport. Toxicol Lett 106: 229-235, 1999.

    PubMed  CAS  Google Scholar 

  72. Felder E, Jennings P, Seppi T, and Pfaller W. LLC-PK(1) cells maintained in a new perfusion cell culture system exhibit an improved oxidative metabolism. Cell Physiol Biochem 12: 153-162, 2002.

    PubMed  CAS  Google Scholar 

  73. Aydin S, Signorelli S, Lechleitner T, Joannidis M, Pleban C, Perco P, Pfaller W, and Jennings P. Influence of microvascular endothelial cells on transcriptional regulation of proximal tubular epithelial cells. Am J Physiol Cell Physiol 294: C543-554, 2008.

    PubMed  CAS  Google Scholar 

  74. Bijuklic K, Jennings P, Kountchev J, Hasslacher J, Aydin S, Sturn D, Pfaller W, Patsch JR, and Joannidis M. Migration of leukocytes across an endothelium-epithelium bilayer as a model of renal interstitial inflammation. Am J Physiol Cell Physiol 293: C486-492, 2007.

    PubMed  CAS  Google Scholar 

  75. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55-63, 1983.

    PubMed  CAS  Google Scholar 

  76. Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T, Goto T, Okuhara M, Kohsaka M, Aoki Het al., and FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40: 1256-1265, 1987.

    CAS  Google Scholar 

  77. Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, and Imanaka H. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40: 1249-1255, 1987.

    CAS  Google Scholar 

  78. Potier M, Wolf A, and Cambar J. Comparative study of cyclosporin A, cyclosporin G, and the novel cyclosporin derivative IMM 125 in isolated glomeruli and cultured rat mesangial cells: a morphometric analysis. Nephrol Dial Transplant 13: 1406-1411, 1998.

    PubMed  CAS  Google Scholar 

  79. L’Azou B, Medina J, Frieauff W, Cordier A, Cambar J, and Wolf A. In vitro models to study mechanisms involved in cyclosporine A-mediated glomerular contraction. Arch Toxicol 73: 337-345, 1999.

    PubMed  Google Scholar 

  80. Rodriguez-Puyol D, Lamas S, Olivera A, Lopez-Farre A, Ortega G, Hernando L, and Lopez-Novoa JM. Actions of cyclosporin A on cultured rat mesangial cells. Kidney Int 35: 632-637, 1989.

    PubMed  CAS  Google Scholar 

  81. L’Azou B, Lakhdar B, Potaux L, and Cambar J. Protective effect of verapamil in cyclosporin-incubated human and murine isolated glomeruli. Ren Fail 16: 665-672, 1994.

    PubMed  Google Scholar 

  82. Stahl RA, Adler S, Baker PJ, Johnson RJ, Chen YP, Pritzl P, and Couser WG. Cyclosporin A inhibits prostaglandin E2 formation by rat mesangial cells in culture. Kidney Int 35: 1161-1167, 1989.

    PubMed  CAS  Google Scholar 

  83. Han SY, Mun KC, Choi HJ, Kwak CS, Bae JH, Suh SI, Park SB, Kim HC, and Chang EJ. Effects of cyclosporine and tacrolimus on the oxidative stress in cultured mesangial cells. Transplant Proc 38: 2240-2241, 2006.

    PubMed  CAS  Google Scholar 

  84. Gagliardini E and Benigni A. Therapeutic potential of TGF-beta inhibition in chronic renal failure. Expert Opin Biol Ther 7: 293-304, 2007.

    PubMed  CAS  Google Scholar 

  85. Waiser J, Dell K, Bohler T, Dogu E, Gaedeke J, Budde K, and Neumayer HH. Cyclosporine A up-regulates the expression of TGF-beta1 and its receptors type I and type II in rat mesangial cells. Nephrol Dial Transplant 17: 1568-1577, 2002.

    PubMed  CAS  Google Scholar 

  86. Waiser J, Dell K, Kreutzkamp J, Bohler T, Budde K, Peters H, and Neumayer HH. FK506, transforming growth factor-beta1 andmesangial matrix synthesis: parallels and differences compared with cyclosporine A. Cytokine 33: 59-65, 2006.

    PubMed  CAS  Google Scholar 

  87. Fornoni A, Lenz O, Tack I, Potier M, Elliot SJ, Striker LJ, and Striker GE. Matrix accumulation in mesangial cells exposed to cyclosporine A requires a permissive genetic background. Transplantation 70: 587-593, 2000.

    PubMed  CAS  Google Scholar 

  88. Becker GM, Gandolfi AJ, and Nagle RB. Effects of cyclosporin A on a kidney epithelial cell line (LLC-PK1). Res Commun Chem Pathol Pharmacol 56: 277-280, 1987.

    PubMed  CAS  Google Scholar 

  89. Healy E, Dempsey M, Lally C, and Ryan MP. Apoptosis and necrosis: mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line. Kidney Int 54: 1955-1966, 1998.

    PubMed  CAS  Google Scholar 

  90. Lechner J, Malloth N, Seppi T, Beer B, Jennings P, and Pfaller W. IFN{alpha} induces barrier destabilization and apoptosis in renal proximal tubular epithelium. Am J Physiol Cell Physiol, 2007.

    Google Scholar 

  91. Lally C, Healy E, and Ryan MP. Cyclosporine A-induced cell cycle arrest and cell death in renal epithelial cells. Kidney Int 56: 1254-1257, 1999.

    PubMed  CAS  Google Scholar 

  92. Miyashita T and Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80: 293-299, 1995.

    PubMed  CAS  Google Scholar 

  93. Yang CW, Faulkner GR, Wahba IM, Christianson TA, Bagby GC, Jin DC, Abboud HE, Andoh TF, and Bennett WM. Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice. Am J Transplant 2: 391-399, 2002.

    PubMed  CAS  Google Scholar 

  94. Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, and Johnson RJ. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int 53: 897-908, 1998.

    PubMed  CAS  Google Scholar 

  95. Bakker RC, van Kooten C, van de Lagemaat-Paape ME, Daha MR, and Paul LC. Renal tubular epithelial cell death and cyclosporin A. Nephrol Dial Transplant 17: 1181-1188, 2002.

    PubMed  CAS  Google Scholar 

  96. Zhou X, Yang G, Davis CA, Doi SQ, Hirszel P, Wingo CS, and Agarwal A. Hydrogen peroxide mediates FK506-induced cytotoxicity in renal cells. Kidney Int 65: 139-147, 2004.

    PubMed  CAS  Google Scholar 

  97. Johnson DW, Saunders HJ, Johnson FJ, Huq SO, Field MJ, and Pollock CA. Fibrogenic effects of cyclosporin A on the tubulointerstitium: role of cytokines and growth factors. Exp Nephrol 7: 470-478, 1999.

    PubMed  CAS  Google Scholar 

  98. Slattery C, Campbell E, McMorrow T, and Ryan MP. Cyclosporine A-induced renal fibrosis: a role for epithelial-mesenchymal transition. Am J Pathol 167: 395-407, 2005.

    PubMed  CAS  Google Scholar 

  99. McMorrow T, Gaffney MM, Slattery C, Campbell E, and Ryan MP. Cyclosporine A induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. Nephrol Dial Transplant 20: 2215-2225, 2005.

    PubMed  CAS  Google Scholar 

  100. Qiu J, Tu Z, Shi Y, Zhang L, Li Q, Wang W, Ye F, Wang J, and Bu H. Interference of cyclosporine on glucose metabolism: potential role in chronic transplantation kidney fibrosis. Transplant Proc 38: 2065-2068, 2006.

    PubMed  CAS  Google Scholar 

  101. Massicot F, Martin C, Dutertre-Catella H, Ellouk-Achard S, Pham-Huy C, Thevenin M, Rucay P, Warnet JM, and Claude JR. Modulation of energy status and cytotoxicity induced by FK506 and cyclosporin A in a renal epithelial cell line. Arch Toxicol 71: 529-531, 1997.

    PubMed  CAS  Google Scholar 

  102. Dominguez JH, Soleimani M, and Batiuk T. Studies of renal injury IV: The GLUT1 gene protects renal cells from cyclosporine A toxicity. Kidney Int 62: 127-136, 2002.

    PubMed  CAS  Google Scholar 

  103. Strutz F, Zeisberg M, Renziehausen A, Raschke B, Becker V, van Kooten C, and Muller G. TGF-beta 1 induces proliferation in humanrenal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int 59: 579-592, 2001.

    PubMed  CAS  Google Scholar 

  104. Johnson DW, Saunders HJ, Vesey DA, Qi W, Field MJ, and Pollock CA. Enalaprilat directly ameliorates in vitro cyclosporin nephrotoxicity in human tubulo-interstitial cells. Nephron 86: 473-481, 2000.

    PubMed  CAS  Google Scholar 

  105. Nakahama H, Fukunaga M, Kakihara M, Horio M, Fujiwara Y, Fukuhara Y, Ueda N, Orita Y, and Kamada T. Comparative effects ofcyclosporine A and FK-506 on endothelin secretion by a cultured renal cell line, LLC-PK1. J Cardiovasc Pharmacol 17 Suppl 7: S172-173, 1991.

    PubMed  CAS  Google Scholar 

  106. Nakahama H. Stimulatory effect of cyclosporine A on endothelin secretion by a cultured renal epithelial cell line, LLC-PK1 cells. Eur J Pharmacol 180: 191-192, 1990.

    PubMed  CAS  Google Scholar 

  107. Saeki T, Ueda K, Tanigawara Y, Hori R, and Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem 268: 6077-6080, 1993.

    PubMed  CAS  Google Scholar 

  108. Hauser IA, Koziolek M, Hopfer U, and Thevenod F. Therapeutic concentrations of cyclosporine A, but not FK506, increase P-glycoprotein expression in endothelial and renal tubule cells. Kidney Int 54: 1139-1149, 1998.

    PubMed  CAS  Google Scholar 

  109. Yuan CM, Bohen EM, Musio F, and Carome MA. Sublethal heat shock and cyclosporine exposure produce tolerance against subsequent cyclosporine toxicity. Am J Physiol 271: F571-578, 1996.

    PubMed  CAS  Google Scholar 

  110. Hanigan MH and Devarajan P. Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 1: 47-61, 2003.

    PubMed  Google Scholar 

  111. Townsend DM, Deng M, Zhang L, Lapus MG, and Hanigan MH. Metabolism of Cisplatin to a nephrotoxin in proximal tubule cells. J Am Soc Nephrol 14: 1-10, 2003.

    PubMed  CAS  Google Scholar 

  112. Hanigan MH, Lykissa ED, Townsend DM, Ou CN, Barrios R, and Lieberman MW. Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin. Am J Pathol 159: 1889-1894, 2001.

    PubMed  CAS  Google Scholar 

  113. Endo T, Kimura O, and Sakata M. Carrier-mediated uptake of cisplatin by the OK renal epithelial cell line. Toxicology 146: 187-195, 2000.

    PubMed  CAS  Google Scholar 

  114. Kuo MT, Chen HH, Song IS, Savaraj N, and Ishikawa T. The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26: 71-83, 2007.

    PubMed  CAS  Google Scholar 

  115. Ishida S, Lee J, Thiele DJ, and Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci U S A 99: 14298-14302, 2002.

    PubMed  CAS  Google Scholar 

  116. Zimnicka AM, Maryon EB, and Kaplan JH. Human copper transporter hCTR1 mediates basolateral uptake of copper into enterocytes: implications for copper homeostasis. J Biol Chem 282: 26471-26480, 2007.

    PubMed  CAS  Google Scholar 

  117. Courjault F, Leroy D, Coquery L, and Toutain H. Platinum complex-induced dysfunction of cultured renal proximal tubule cells.A comparative study of carboplatin and transplatin with cisplatin. Arch Toxicol 67: 338-346, 1993.

    PubMed  CAS  Google Scholar 

  118. Montine TJ and Borch RF. Quiescent LLC-PK1 cells as a model for cis-diamminedichloroplatinum(II) nephrotoxicity and modulation by thiol rescue agents. Cancer Res 48: 6017-6024, 1988.

    PubMed  CAS  Google Scholar 

  119. Fukuishi N and Gemba M. Use of cultured renal epithelial cells for the study of cisplatin toxicity. Jpn J Pharmacol 50: 247-249, 1989.

    PubMed  CAS  Google Scholar 

  120. Lieberthal W, Triaca V, and Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs.necrosis. Am J Physiol 270: F700-708, 1996.

    PubMed  CAS  Google Scholar 

  121. Okuda M, Masaki K, Fukatsu S, Hashimoto Y, and Inui K. Role of apoptosis in cisplatin-induced toxicity in the renal epithelial cell line LLC-PK1. Implication of the functions of apical membranes. Biochem Pharmacol 59: 195-201, 2000.

    PubMed  CAS  Google Scholar 

  122. Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M, Fukuda K, Kanai H, Kishihara K, Hirakata H, and Iida M. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 63: 72-82, 2003.

    PubMed  CAS  Google Scholar 

  123. Park MS, De Leon M, and Devarajan P. Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol 13: 858-865, 2002.

    PubMed  CAS  Google Scholar 

  124. Takeda M, Kobayashi M, Shirato I, Osaki T, and Endou H. Cisplatin-induced apoptosis of immortalized mouse proximal tubule cells is mediated by interleukin-1 beta converting enzyme (ICE) family of proteases but inhibited by overexpression of Bcl-2. Arch Toxicol 71: 612-621, 1997.

    PubMed  CAS  Google Scholar 

  125. Weidemann A, Bernhardt WM, Klanke B, Daniel C, Buchholz B, Campean V, Amann K, Warnecke C, Wiesener MS, Eckardt KU, and Willam C. HIF activation protects from acute kidney injury. J Am Soc Nephrol 19: 486-494, 2008.

    PubMed  CAS  Google Scholar 

  126. Yokozawa T, Nakagawa T, Lee KI, Cho EJ, Terasawa K, and Takeuchi S. Effects of green tea tannin on cisplatin-induced nephropathy in LLC-PK1 cells and rats. J Pharm Pharmacol 51: 1325-1331, 1999.

    PubMed  CAS  Google Scholar 

  127. Bragado P, Armesilla A, Silva A, and Porras A. Apoptosis by cisplatin requires p53 mediated p38alpha MAPK activation through ROS generation. Apoptosis 12: 1733-1742, 2007.

    PubMed  CAS  Google Scholar 

  128. Hannemann J and Baumann K. Inhibition of lactate-dehydrogenase by cisplatin and other platinum-compounds: enzyme leak-age of LDH is not a suitable method to measure platinum-compound-induced kidney cell damage in vitro. Res Commun Chem Pathol Pharmacol 60: 371-379, 1988.

    PubMed  CAS  Google Scholar 

  129. Martinez-Salgado C, Lopez-Hernandez FJ, and Lopez-Novoa JM. Glomerular nephrotoxicity of aminoglycosides. Toxicol Appl Pharmacol 223: 86-98, 2007.

    PubMed  CAS  Google Scholar 

  130. Montie T and Patamasucon P. Aminoglycosides: the complex problem of antibiotic mechanisms and clinical applications. Eur JClin Microbiol Infect Dis 14: 85-87, 1995.

    CAS  Google Scholar 

  131. Rivas-Cabanero L, Rodriguez-Lopez AM, Martinez-Salgado C, Saura M, Lamas S, and Lopez-Novoa JM. Gentamicin treatment increases mesangial cell nitric oxide production. Exp Nephrol 5: 23-30, 1997.

    PubMed  CAS  Google Scholar 

  132. Martinez-Salgado C, Rodriguez-Barbero A, Tavares P, Eleno N, and Lopez-Novoa JM. Role of calcium in gentamicin-induced mesangial cell activation. Cell Physiol Biochem 10: 65-72, 2000.

    PubMed  CAS  Google Scholar 

  133. Klotman PE and Yarger WE. Reduction of renal blood flow and proximal bicarbonate reabsorption in rats by gentamicin. Kidney Int 24: 638-643, 1983.

    PubMed  CAS  Google Scholar 

  134. Schor N, Ichikawa I, Rennke HG, Troy JL, and Brenner BM. Pathophysiology of altered glomerular function in aminoglycoside-treated rats. Kidney Int 19: 288-296, 1981.

    PubMed  CAS  Google Scholar 

  135. Morales AI, Rodriguez-Barbero A, Vicente-Sanchez C, Mayoral P, Lopez-Novoa JM, and Perez-Barriocanal F. Resveratrol inhibits gentamicin-induced mesangial cell contraction. Life Sci 78: 2373-2377, 2006.

    PubMed  CAS  Google Scholar 

  136. Kiyomiya K, Matsushita N, Matsuo S, and Kurebe M. Differential toxic effects of gentamicin on cultured renal epithelial cells (LLC-PK1) on application to the brush border membrane or the basolateral membrane. J Vet Med Sci 62: 971-975, 2000.

    PubMed  CAS  Google Scholar 

  137. Nagai J. [Molecular mechanisms underlying renal accumulation of aminoglycoside antibiotics and mechanism-based approach for developing nonnephrotoxic aminoglycoside therapy]. Yakugaku Zasshi 126: 327-335, 2006.

    PubMed  CAS  Google Scholar 

  138. Sandoval RM, Dunn KW, and Molitoris BA. Gentamicin traffics rapidly and directly to the Golgi complex in LLC-PK(1) cells. Am J Physiol Renal Physiol 279: F884-890, 2000.

    PubMed  CAS  Google Scholar 

  139. Sandoval RM and Molitoris BA. Gentamicin traffics retrograde through the secretory pathway and is released in the cytosol via the endoplasmic reticulum. Am J Physiol Renal Physiol 286: F617-624, 2004.

    PubMed  CAS  Google Scholar 

  140. Takamoto K, Kawada M, Ikeda D, and Yoshida M. Apolipoprotein E3 (apoE3) safeguards pig proximal tubular LLC-PK1 cells against reduction in SGLT1 activity induced by gentamicin C. Biochim Biophys Acta 1722: 247-253, 2005.

    PubMed  CAS  Google Scholar 

  141. Inui K, Saito H, Iwata T, and Hori R. Aminoglycoside-induced alterations in apical membranes of kidney epithelial cell line (LLC-PK1). Am J Physiol 254: C251-257, 1988.

    PubMed  CAS  Google Scholar 

  142. Hori R, Yamamoto K, Saito H, Kohno M, and Inui K. Effect of aminoglycoside antibiotics on cellular functions of kidney epithelial cell line (LLC-PK1): a model system for aminoglycoside nephrotoxicity. J Pharmacol Exp Ther 230: 724-728, 1984.

    PubMed  CAS  Google Scholar 

  143. Choi KH, Kim TI, Chong DL, Lee HY, and Han DS. Gentamicin induced apoptosis of renal tubular epithelial (LLC-PK1) cells. Korean J Intern Med 15: 218-223, 2000.

    PubMed  CAS  Google Scholar 

  144. El Mouedden M, Laurent G, Mingeot-Leclercq MP, and Tulkens PM. Gentamicin-induced apoptosis in renal cell lines and embry-onic rat fibroblasts. Toxicol Sci 56: 229-239, 2000.

    PubMed  CAS  Google Scholar 

  145. Robertson EE and Rankin GO. Human renal organic anion transporters: characteristics and contributions to drug and drug metabolite excretion. Pharmacol Ther 109: 399-412, 2006.

    PubMed  CAS  Google Scholar 

  146. Takeda M, Tojo A, Sekine T, Hosoyamada M, Kanai Y, and Endou H. Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity. Kidney Int 56: 2128-2136, 1999.

    PubMed  CAS  Google Scholar 

  147. Jung KY, Takeda M, Shimoda M, Narikawa S, Tojo A, Kim DK, Chairoungdua A, Choi BK, Kusuhara H, Sugiyama Y, Sekine T, and Endou H. Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparison with rOAT1. Life Sci 70: 1861-1874, 2002.

    PubMed  CAS  Google Scholar 

  148. Ueo H, Motohashi H, Katsura T, and Inui K. Human organic anion transporter hOAT3 is a potent transporter of cephalosporinantibiotics, in comparison with hOAT1. Biochem Pharmacol 70: 1104-1113, 2005.

    PubMed  CAS  Google Scholar 

  149. Hori R, Okamura M, Takayama A, Hirozane K, and Takano M. Transport of organic anion in the OK kidney epithelial cell line. Am J Physiol 264: F975-980, 1993.

    PubMed  CAS  Google Scholar 

  150. Nagai J, Takano M, Hirozane K, Yasuhara M, and Inui K. Specificity of p-aminohippurate transport system in the OK kidney epithelial cell line. J Pharmacol Exp Ther 274: 1161-1166, 1995.

    PubMed  CAS  Google Scholar 

  151. Kiyomiya K, Matsushita N, Matsuo S, and Kurebe M. Roles of oxygen radical production and lipid peroxidation in the cytotoxicityof cephaloridine on cultured renal epithelial cells (LLC-PK1). J Vet Med Sci 62: 977-981, 2000.

    PubMed  CAS  Google Scholar 

  152. Kiyomiya K, Matsushita N, Matsuo S, and Kurebe M. Cephaloridine-induced inhibition of cytochrome c oxidase activity in the mitochondria of cultured renal epithelial cells (LLC-PK(1)) as a possible mechanism of its nephrotoxicity. Toxicol Appl Pharmacol 167: 151-156, 2000.

    PubMed  CAS  Google Scholar 

  153. Steinmassl D, Pfaller W, Gstraunthaler G, and Hoffmann W. LLC-PK1 epithelia as a model for in vitro assessment of proximal tubularnephrotoxicity. In vitro Cell Dev Biol Anim 31: 94-106, 1995.

    PubMed  CAS  Google Scholar 

  154. Goldman RD and Koren G. Amphotericin B nephrotoxicity in children. J Pediatr Hematol Oncol 26: 421-426, 2004.

    PubMed  Google Scholar 

  155. Warnock DW. Amphotericin B: an introduction. J Antimicrob Chemother 28 Suppl B: 27-38, 1991.

    Google Scholar 

  156. Zager RA. Polyene antibiotics: relative degrees of in vitro cytotoxicity and potential effects on tubule phospholipid and ceramide content. Am J Kidney Dis 36: 238-249, 2000.

    PubMed  CAS  Google Scholar 

  157. Hsu S and Burnette RR. Characterization of the effects of amphotericin B on ion channels in MDCK cells using the patch-clamp technique. Biochim Biophys Acta 1329: 26-38, 1997.

    PubMed  CAS  Google Scholar 

  158. Sabra R and Branch RA. Effect of amphotericin B on intracellular calcium levels in cultured glomerular mesangial cells. Eur J Pharmacol 226: 79-85, 1992.

    PubMed  CAS  Google Scholar 

  159. Varlam DE, Siddiq MM, Parton LA, and Russmann H. Apoptosis contributes to amphotericin B-induced nephrotoxicity. Antimicrob Agents Chemother 45: 679-685, 2001.

    PubMed  CAS  Google Scholar 

  160. Wasan KM, Rosenblum MG, Cheung L, and Lopez-Berestein G. Influence of lipoproteins on renal cytotoxicity and antifungal activity of amphotericin B. Antimicrob Agents Chemother 38: 223-227, 1994.

    PubMed  CAS  Google Scholar 

  161. Wasan KM and Lopez-Berestein G. Modification of amphotericin B’s therapeutic index by increasing its association with serum high-density lipoproteins. Ann N Y Acad Sci 730: 93-106, 1994.

    PubMed  CAS  Google Scholar 

  162. Bartlett K, Yau E, Hartsel SC, Hamer A, Tsai G, Bizzotto D, and Wasan KM. Effect of heat-treated amphotericin B on renal and fungal cytotoxicity. Antimicrob Agents Chemother 48: 333-336, 2004.

    PubMed  CAS  Google Scholar 

  163. Leon C, Taylor R, Bartlett KH, and Wasan KM. Effect of heat-treatment and the role of phospholipases on Fungizone-induced cytotoxicity within human kidney proximal tubular (HK-2) cells and Aspergillus fumigatus. Int J Pharm 298: 211-218, 2005.

    PubMed  CAS  Google Scholar 

  164. Jarup L. Cadmium overload and toxicity. Nephrol Dial Transplant 17 Suppl 2: 35-39, 2002.

    PubMed  CAS  Google Scholar 

  165. Kimura O, Endo T, and Sakata M. Comparison of cadmium uptakes from apical and basolateral membranes of LLC-PK1 cells. Toxicol Appl Pharmacol 137: 301-306, 1996.

    PubMed  CAS  Google Scholar 

  166. Endo T, Kimura O, and Sakata M. Cadmium uptake from apical membrane of LLC-PK1 cells via inorganic anion exchanger. Pharmacol Toxicol 82: 230-235, 1998.

    PubMed  CAS  Google Scholar 

  167. Endo T, Kimura O, and Sakata M. Further analysis of cadmium uptake from apical membrane of LLC-PK1 cells via inorganic anion exchanger. Pharmacol Toxicol 84: 187-192, 1999.

    PubMed  CAS  Google Scholar 

  168. Prozialeck WC and Niewenhuis RJ. Cadmium (Cd2+) disrupts Ca(2+)-dependent cell-cell junctions and alters the pattern of Ecadherin immunofluorescence in LLC-PK1 cells. Biochem Biophys Res Commun 181: 1118-1124, 1991.

    PubMed  CAS  Google Scholar 

  169. Zimmerhackl LB, Momm F, Wiegele G, and Brandis M. Cadmium is more toxic to LLC-PK1 cells than to MDCK cells acting on the cadherin-catenin complex. Am J Physiol 275: F143-153, 1998.

    PubMed  CAS  Google Scholar 

  170. Klaassen CD, Liu J, and Choudhuri S. Metallothionein: an intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 39: 267-294, 1999.

    PubMed  CAS  Google Scholar 

  171. Klassen RB, Crenshaw K, Kozyraki R, Verroust PJ, Tio L, Atrian S, Allen PL, and Hammond TG. Megalin mediates renal uptake of heavy metal metallothionein complexes. Am J Physiol Renal Physiol 287: F393-403, 2004.

    PubMed  CAS  Google Scholar 

  172. Wolff NA, Abouhamed M, Verroust PJ, and Thevenod F. Megalin-dependent internalization of cadmium-metallothionein and cytotoxicity in cultured renal proximal tubule cells. J Pharmacol Exp Ther 318: 782-791, 2006.

    PubMed  CAS  Google Scholar 

  173. Ishido M, Tohyama C, and Suzuki T. Cadmium-bound metallothionein induces apoptosis in rat kidneys, but not in cultured kidney LLC-PK1 cells. Life Sci 64: 797-804, 1999.

    PubMed  CAS  Google Scholar 

  174. Zhai XY, Nielsen R, Birn H, Drumm K, Mildenberger S, Freudinger R, Moestrup SK, Verroust PJ, Christensen EI, and Gekle M. Cubilin-and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int 58: 1523-1533, 2000.

    PubMed  CAS  Google Scholar 

  175. Nielsen R, Birn H, Moestrup SK, Nielsen M, Verroust P, and Christensen EI. Characterization of a kidney proximal tubule cell line, LLC-PK1, expressing endocytotic active megalin. J Am Soc Nephrol 9: 1767-1776, 1998.

    PubMed  CAS  Google Scholar 

  176. Thevenod F. Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93: p87-93, 2003.

    PubMed  CAS  Google Scholar 

  177. Abouhamed M, Wolff NA, Lee WK, Smith CP, and Thevenod F. Knockdown of endosomal/lysosomal divalent metal transporter 1 by RNA interference prevents cadmium-metallothionein-1 cytotoxicity in renal proximal tubule cells. Am J Physiol Renal Physiol 293: F705-712, 2007.

    PubMed  CAS  Google Scholar 

  178. Liu Y, Zhang SP, and Cai YQ. Cytoprotective effects of selenium on cadmium-induced LLC-PK1 cells apoptosis by activating JNK pathway. Toxicol In vitro 21: 677-684, 2007.

    PubMed  CAS  Google Scholar 

  179. Yokouchi M, Hiramatsu N, Hayakawa K, Okamura M, Du S, Kasai A, Takano Y, Shitamura A, Shimada T, Yao J, and Kitamura M. Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem 283: 4252-4260, 2008.

    PubMed  CAS  Google Scholar 

  180. Ding W and Templeton DM. Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium. Toxicol Appl Pharmacol 162: 93-99, 2000.

    PubMed  CAS  Google Scholar 

  181. Templeton DM, Wang Z, and Miralem T. Cadmium and calcium-dependent c-fos expression in mesangial cells. Toxicol Lett 95: 1-8, 1998.

    PubMed  CAS  Google Scholar 

  182. Alvarez-Barrientos A, O’Connor JE, Nieto Castillo R, Moreno Moreno AB, and Prieto P. Use of flow cytometry and confocal microscopy techniques to investigate early CdCl(2)-induced nephrotoxicity in vitro. Toxicol In vitro 15: 407-412, 2001.

    PubMed  CAS  Google Scholar 

  183. Bonham RT, Fine MR, Pollock FM, and Shelden EA. Hsp27, Hsp70, and metallothionein in MDCK and LLC-PK1 renal epithelial cells: effects of prolonged exposure to cadmium. Toxicol Appl Pharmacol 191: 63-73, 2003.

    PubMed  CAS  Google Scholar 

  184. Urani C, Melchioretto P, Canevali C, and Crosta GF. Cytotoxicity and induction of protective mechanisms in HepG2 cells exposed to cadmium. Toxicol In vitro 19: 887-892, 2005.

    PubMed  CAS  Google Scholar 

  185. Endo T, Kimura O, and Sakata M. Effects of P-glycoprotein inhibitors on cadmium accumulation in cultured renal epithelial cells, LLC-PK1, and OK. Toxicol Appl Pharmacol 185: 166-171, 2002.

    PubMed  CAS  Google Scholar 

  186. Kimura O, Endo T, Hotta Y, and Sakata M. Effects of P-glycoprotein inhibitors on transepithelial transport of cadmium in cultured renal epithelial cells, LLC-PK1 and LLC-GA5-COL 150. Toxicology 208: 123-132, 2005.

    PubMed  CAS  Google Scholar 

  187. Nicholson JK, Kendall MD, and Osborn D. Cadmium and mercury nephrotoxicity. Nature 304: 633-635, 1983.

    PubMed  CAS  Google Scholar 

  188. Zalups RK. Molecular interactions with mercury in the kidney. Pharmacol Rev 52: 113-143, 2000.

    PubMed  CAS  Google Scholar 

  189. Bohets HH, Van Thielen MN, Van der Biest I, Van Landeghem GF, D’Haese PC, Nouwen EJ, De Broe ME, and Dierickx PJ. Cytotoxicity of mercury compounds in LLC-PK1, MDCK and human proximal tubular cells. Kidney Int 47: 395-403, 1995.

    PubMed  CAS  Google Scholar 

  190. Aleo MD, Taub ML, and Kostyniak PJ. Primary cultures of rabbit renal proximal tubule cells. III. Comparative cytotoxicity of inorganic and organic mercury. Toxicol Appl Pharmacol 112: 310-317, 1992.

    PubMed  CAS  Google Scholar 

  191. Matsuoka M, Wispriyono B, Iryo Y, and Igisu H. Mercury chloride activates c-Jun N-terminal kinase and induces c-jun expression in LLC-PK1 cells. Toxicol Sci 53: 361-368, 2000.

    PubMed  CAS  Google Scholar 

  192. Duncan-Achanzar KB, Jones JT, Burke MF, Carter DE, and Laird HEn. Inorganic mercury chloride-induced apoptosis in the cultured porcine renal cell line LLC-PK1. J Pharmacol Exp Ther 277: 1726-1732, 1996.

    PubMed  CAS  Google Scholar 

  193. Sutton DJ and Tchounwou PB. Mercury induces the externalization of phosphatidyl-serine in human renal proximal tubule (HK-2) cells. Int J Environ Res Public Health 4: 138-144, 2007.

    PubMed  CAS  Google Scholar 

  194. Dieguez-Acuna FJ, Polk WW, Ellis ME, Simmonds PL, Kushleika JV, and Woods JS. Nuclear factor kappaB activity determines the sensitivity of kidney epithelial cells to apoptosis: implications for mercury-induced renal failure. Toxicol Sci 82: 114-123, 2004.

    PubMed  CAS  Google Scholar 

  195. Woods JS, Dieguez-Acuna FJ, Ellis ME, Kushleika J, and Simmonds PL. Attenuation of nuclear factor kappa B (NF-kappaB) pro-motes apoptosis of kidney epithelial cells: a potential mechanism of mercury-induced nephrotoxicity. Environ Health Perspect 110 Suppl 5: 819-822, 2002.

    PubMed  CAS  Google Scholar 

  196. Zalups RK, Aslamkhan AG, and Ahmad S. Human organic anion transporter 1 mediates cellular uptake of cysteine-S conjugates of inorganic mercury. Kidney Int 66: 251-261, 2004.

    PubMed  CAS  Google Scholar 

  197. O’Brien E and Dietrich DR. Ochratoxin A: the continuing enigma. Crit Rev Toxicol 35: 33-60, 2005.

    PubMed  Google Scholar 

  198. Groves CE, Nowak G, and Morales M. Ochratoxin A secretion in primary cultures of rabbit renal proximal tubule cells. J Am Soc Nephrol 10: 13-20, 1999.

    PubMed  CAS  Google Scholar 

  199. Babu E, Takeda M, Narikawa S, Kobayashi Y, Enomoto A, Tojo A, Cha SH, Sekine T, Sakthisekaran D, and Endou H. Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim Biophys Acta 1590: 64-75, 2002.

    PubMed  CAS  Google Scholar 

  200. Jung KY, Takeda M, Kim DK, Tojo A, Narikawa S, Yoo BS, Hosoyamada M, Cha SH, Sekine T, and Endou H. Characterization of ochratoxin A transport by human organic anion transporters. Life Sci 69: 2123-2135, 2001.

    PubMed  CAS  Google Scholar 

  201. Dai J, Park G, Perry JL, Il’ichev YV, Bow DA, Pritchard JB, Faucet V, Pfohl-Leszkowicz A, Manderville RA, and Simon JD. Molecular aspects of the transport and toxicity of ochratoxin a. Acc Chem Res 37: 874-881, 2004.

    PubMed  CAS  Google Scholar 

  202. Gekle M, Gassner B, Freudinger R, Mildenberger S, Silbernagl S, Pfaller W, and Schramek H. Characterization of an ochratoxin-A-dedifferentiated and cloned renal epithelial cell line. Toxicol Appl Pharmacol 152: 282-291, 1998.

    PubMed  CAS  Google Scholar 

  203. Gekle M, Schwerdt G, Freudinger R, Mildenberger S, Wilflingseder D, Pollack V, Dander M, and Schramek H. Ochratoxin A induces JNK activation and apoptosis in MDCK-C7 cells at nanomolar concentrations. J Pharmacol Exp Ther 293: 837-844, 2000.

    PubMed  CAS  Google Scholar 

  204. Jonasch E and Haluska FG. Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities. Oncologist 6: 34-55, 2001.

    PubMed  CAS  Google Scholar 

  205. Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahlke F, Beckmann K, Polman C, McFarland H, and for the European and North American Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committees and Independent Advisory Boards. Interferon beta-1b in secondary progressive MS: A combined analysis of the two trials. Neurology 63: 1779-1787, 2004.

    Google Scholar 

  206. Wadler S and Schwartz EL. New Advances in Interferon Therapy of Cancer. Oncologist 2: 254-267, 1997.

    PubMed  CAS  Google Scholar 

  207. Belardelli F and Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity. Trends Immunol 23: 201-208, 2002.

    PubMed  CAS  Google Scholar 

  208. Samuel CE. Antiviral Actions of Interferons. Clin Microbiol Rev 14: 778-809, 2001.

    PubMed  CAS  Google Scholar 

  209. Izzedine H, Launay-Vacher V, and Deray G. Antiviral drug-induced nephrotoxicity. American Journal of Kidney Diseases 45: 804-817, 2005.

    PubMed  CAS  Google Scholar 

  210. Kurschel E, Metz-Kurschel U, Niederle N, and Aulbert E. Investigations on the subclinical and clinical nephrotoxicity of interferon alpha-2B in patients with myeloproliferative syndromes. Ren Fail 13: 87-93, 1991.

    PubMed  CAS  Google Scholar 

  211. Al Harbi A, Al Ghamdi S, Subaity Y, and Khalil A. Interferon-induced renal failure in nephrotic syndrome. Nephrol Dial Transplant 13: 1316-1318, 1998.

    PubMed  CAS  Google Scholar 

  212. Averbuch S, Austin H, Sherwin S, Antonovych T, Bunn P, and Longo D. Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte a interferon therapy for mycosis fungoides. N Engl J Med 310: 32-35, 1984.

    PubMed  CAS  Google Scholar 

  213. Fahal IH, Murry N, Chu P, and Bell GM. Acute renal failure during interferon treatment. Brit medical J 306: 973., 1993.

    CAS  Google Scholar 

  214. Parker M, Atkins M, Ucci A, and Levey A. Rapidly progressive glomerulonephritis after immunotherapy for cancer. J Am Soc Nephrol 5: 1740-1744, 1995.

    PubMed  CAS  Google Scholar 

  215. Rostaing L, Modesto A, Baron E, Cisterne J, Chabannier M, and Durand D. Acute renal failure in kidney transplant patients treated with interferon alpha 2b for chronic hepatitis C. Nephron 74: 512-516, 1996.

    PubMed  CAS  Google Scholar 

  216. Lechner J, Malloth N, Seppi T, Beer B, Jennings P, and Pfaller W. IFN-{alpha} induces barrier destabilization and apoptosis in renal proximal tubular epithelium. Am J Physiol Cell Physiol 294: C153-C160 [Epub 2007, Nov 2021], 2008.

    PubMed  CAS  Google Scholar 

  217. Chawla-Sarkar M, Lindner D, Liu Y, Williams B, Sen G, Silverman R, and Borden E. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 8: 237-249, 2003.

    PubMed  CAS  Google Scholar 

  218. Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S, and Borden EC. Identification of X-linked Inhibitor of Apop-tosis-associated Factor-1 as an Interferon-stimulated Gene That Augments TRAIL Apo2L-induced Apoptosis. J Biol Chem 277: 28504-28511, 2002.

    PubMed  CAS  Google Scholar 

  219. Lechner J, Krall M, Netzer A, Radmayr C, Ryan M, and Pfaller W. Effects of interferon alpha-2b on barrier function and junctional complexes of renal proximal tubular LLC-PK1 cells. Kidney Int 55: 2178-2191, 1999.

    PubMed  CAS  Google Scholar 

  220. Lechner J and Pfaller W. Interferon alpha2b increases paracellular permeability of renal proximal tubular LLC-PK1 cells via a mitogen activated protein kinase signaling pathway. Ren Fail 23: 573-588, 2001.

    PubMed  CAS  Google Scholar 

  221. Seger R and Krebs EG. The MAPK signaling cascade. FASEB J 9: 726-735, 1995.

    PubMed  CAS  Google Scholar 

  222. Singh AB and Harris RC. Epidermal Growth Factor Receptor Activation Differentially Regulates Claudin Expression and Enhances Transepithelial Resistance in Madin-Darby Canine Kidney Cells. J Biol Chem 279: 3543-3552, 2004.

    PubMed  CAS  Google Scholar 

  223. Saladik DT, Soler AP, Lewis SA, and Mullin JM. Cell Division Does Not Increase Transepithelial Permeability of LLC-PK1 Cell Sheets. Experimental Cell Research 220: 446-455, 1995.

    PubMed  CAS  Google Scholar 

  224. Nigam SK and Lieberthal W. Acute renal failure. III. The role of growth factors in the process of renal regeneration and repair. Am J Physiol Renal Physiol 279: F3-11, 2000.

    PubMed  CAS  Google Scholar 

  225. Schena FP. Role of growth factors in acute renal failure. Kidney Int Suppl 66: S11-15., 1998.

    PubMed  CAS  Google Scholar 

  226. Wang Z, Chen J-K, Wang S-w, Moeckel G, and Harris RC. Importance of Functional EGF Receptors in Recovery from Acute Nephrotoxic Injury. J Am Soc Nephrol 14: 3147-3154, 2003.

    PubMed  CAS  Google Scholar 

  227. Hammerman M. Growth factors and apoptosis in acute renal injury. Curr Opin Nephrol Hypertens 7: 419-424, 1998.

    PubMed  CAS  Google Scholar 

  228. Zhuang S, Dang Y, and Schnellmann RG. Requirement of the epidermal growth factor receptor in renal epithelial cell proliferation and migration. Am J Physiol Renal Physiol 287: F365-372, 2004.

    PubMed  CAS  Google Scholar 

  229. Lechner J, Malloth NA, Jennings P, Hekl D, Pfaller W, and Seppi T. Opposing roles of EGF in IFN-{alpha}-induced epithelial barrier destabilization and tissue repair. Am J Physiol Cell Physiol 293: C1843-1850 [Epub 2007, Oct 1843], 2007.

    PubMed  CAS  Google Scholar 

  230. Rother RP, Bell L, Hillmen P, and Gladwin MT. The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin: A Novel Mechanism of Human Disease. JAMA 293: 1653-1662, 2005.

    PubMed  CAS  Google Scholar 

  231. Sever MS, Vanholder R, and Lameire N. Management of Crush-Related Injuries after Disasters. N Engl J Med 354: 1052-1063, 2006.

    PubMed  CAS  Google Scholar 

  232. Moore KP, Holt SG, Patel RP, Svistunenko DA, Zackert W, Goodier D, Reeder BJ, Clozel M, Anand R, Cooper CE, Morrow JD, Wilson MT, Darley-Usmar V, and Roberts II LJ. A Causative Role for Redox Cycling of Myoglobin and Its Inhibition by Alkalinization in the Pathogenesis and Treatment of Rhabdomyolysis-induced Renal Failure. J Biol Chem 273: 31731-31737, 1998.

    PubMed  CAS  Google Scholar 

  233. Rosenberger C, Goldfarb M, Shina A, Bachmann S, Frei U, Eckardt K-U, Schrader T, Rosen S, and Heyman SN. Evidence for Sustained Renal Hypoxia and Transient Hypoxia Adaptation in Experimental Rhabdomyolysis-Induced Acute Kidney Injury. Nephrol Dial Transplant doi: 10.1093/ndt/gfm808, 2007.

    Google Scholar 

  234. Paller MS. Hemoglobin-and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity. Am J Physiol Renal Physiol 255: F539-544, 1988.

    CAS  Google Scholar 

  235. Shah SV and Walker PD. Evidence suggesting a role for hydroxyl radical in glycerol-induced acute renal failure. Am J Physiol Renal Physiol 255: F438-443, 1988.

    CAS  Google Scholar 

  236. Andreoli S and McAteer J. Reactive oxygen molecule-mediated injury in endothelial and renal tubular epithelial cells in vitro. Kidney Int 38: 785-794, 1990.

    PubMed  CAS  Google Scholar 

  237. Tracz MJ, Alam J, and Nath KA. Physiology and Pathophysiology of Heme: Implications for Kidney Disease. J Am Soc Nephrol 18: 414-420, 2007.

    PubMed  CAS  Google Scholar 

  238. Iwata M and Zager R. Myoglobin inhibits proliferation of cultured human proximal tubular (HK-2) cells. Kidney Int 50: 796-804, 1996.

    PubMed  CAS  Google Scholar 

  239. Zager R and Burkhart K. Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack. Kidney Int 53: 1661-1672, 1998.

    PubMed  CAS  Google Scholar 

  240. Nath K, Grande J, Croatt A, Likely S, Hebbel R, and Enright H. Intracellular targets in heme protein-induced renal injury. Kidney Int 53: 100-111, 1998.

    PubMed  CAS  Google Scholar 

  241. Gonzalez-Michaca L, Farrugia G, Croatt AJ, Alam J, and Nath KA. Heme: a determinant of life and death in renal tubular epithelial cells. Am J Physiol Renal Physiol 286: F370-377, 2004.

    PubMed  CAS  Google Scholar 

  242. Somers M, Piqueras AI, Strange K, Zeidel ML, Pfaller W, Gawryl M, and Harris HW. Interactions of ultrapure bovine hemoglobin with renal epithelial cells in vivo and in vitro. Am J Physiol Renal Physiol 273: F38-52, 1997.

    CAS  Google Scholar 

  243. Hahn H, Huck CW, Rainer M, Najam-ul-Haq M, Bakry R, Abberger T, Jennings P, Pfaller W, and Bonn GK. Analysis of glutathione in supernatants and lysates of a human proximal tubular cell line from perfusion culture upon intoxication with cadmium chloride by HPLC and LC-ESI-MS. Anal Bioanal Chem 388: 1763-1769, 2007.

    PubMed  CAS  Google Scholar 

  244. Minuth WW, Dermietzel R, Kloth S, and Hennerkes B. A new method culturing renal cells under permanent superfusion and producing a luminal-basal medium gradient. Kidney Int 41: 215-219, 1992.

    PubMed  CAS  Google Scholar 

  245. Gstraunthaler G, Steinmassl D, and Pfaller W. Renal cell cultures: a tool for studying tubular function and nephrotoxicity. Toxicol Lett 53: 1-7, 1990.

    PubMed  CAS  Google Scholar 

  246. Gstraunthaler G and Handler JS. Isolation, growth, and characterization of a gluconeogenic strain of renal cells. Am J Physiol 252: C232-238, 1987.

    PubMed  CAS  Google Scholar 

  247. Gstraunthaler G. Standardisation in Cell and Tissue Culture -The Need for Specific GLP Guidelines in the Cell Culture Laboratory (Good Cell Culture Practice -GCCP). ALTEX 23 Suppl: 274-277, 2006.

    PubMed  Google Scholar 

  248. Balls M, Coecke S, Bowe G, Davis J, Gstraunthaler G, Hartung T, Hay R, Merten OW, Price A, Schechtman LM, Stacey G, and Stokes W. The Importance of Good Cell Culture Practice (GCCP). ALTEX 23 Suppl: 270-273, 2006.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Medical Physics, Division of Physiology, Innsbruck Medical University, Fritz-Pregl Strasse 3, Innsbruck, A-6020, Austria

    Paul Jennings, Judith Lechner & Walter Pfaller

  2. St. Joseph-Krankenhaus Berlin, Bäumerplan 24, D-12101, Berlin, Germany

    Christian KoppelstÄtter

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  1. Paul Jennings
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  2. Christian KoppelstÄtter
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  3. Judith Lechner
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  4. Walter Pfaller
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Editors and Affiliations

  1. Laboratory of Pathophysiology Universiteitsplein 1, University of Antwerp, Wilrijk, B-2610, Belgium

    Marc E. De Broe

  2. Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR, 97201, USA

    George A. Porter

  3. Legacy Good Samaritan Hospital, 1015 NW 22nd Avenue, W004, Portland, OR, 97201, USA

    William M. Bennett

  4. Groupe Hôspitalier Pitié Salpétrière Service De Néphrologie 83, Boulevard de l′Hôpital, Paris, F-75013, France

    Gilbert Deray

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Jennings, P., KoppelstÄtter, C., Lechner, J., Pfaller, W. (2008). Renal cell culture models: Contribution to the understanding of nephrotoxic mechanisms . In: De Broe, M.E., Porter, G.A., Bennett, W.M., Deray, G. (eds) Clinical Nephrotoxins. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-84843-3_10

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