Cellular mechanisms of nephrotoxicity

  • Istvan Arany
  • Gur P. Kaushal
  • Didier Portilla
  • Judit Megyesi
  • Peter M. Price
  • Robert L. Safirstein

The changes in renal epithelial morphology that accompany acute kidney injury are often subtle. At least four cellular fates can be identified in acute kidney injury: cells may be necrotic; cells may become apoptotic; they may replicate and divide; or they may appear indifferent to the stress (Figure 1). Frank necrosis, as is often seen experimentally, is not prominent in the vast majority of human cases. Necrosis is usually patchy, involving small clusters of cells, sometimes resulting in small areas of denuded basement membrane. Less obvious injury is more often noted, including loss of brush borders, flattening of the epithelium, intratubular cast formation, and dilatation of the lumen. While proximal tubules show many of theses changes, injury to the distal nephron can also be demonstrated when human biopsy material is closely examined. The distal nephron is also the site of obstruction by desquamated cells and cellular debris.

Necrosis is a catastrophic breakdown of regulated cellular homeostasis and is accompanied by massive tissue damage leading to rapid collapse of internal homeostasis of the cell [1]. It is characterized by cell swelling with early loss of plasma-membrane integrity, major alterations of the organelles, and swelling of the nucleus with flocculation of the chromatin. Affected cells rupture and the cellular components spill into the surrounding tissue space evoking an inflammatory response. Apoptosis is also a feature of nephrotoxic injury and a distinction can be made between necrosis and apoptosis based on morphological criteria (Table 1).


Acute Kidney Injury Proximal Tubule Cell Distal Nephron Renal Tubular Epithelial Cell Thick Ascend Limb 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nolan C, Anderson R. Hospital-acquired acute renal failure. J Am Soc Nephrol 1998; 9: 710-718.PubMedGoogle Scholar
  2. 2.
    Kerr J, Wyllie A, Currie A. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257.PubMedGoogle Scholar
  3. 3.
    Wyllie A. Apoptosis (The 1992 Frank Rose Memorial Lecture). Br J Cancer 2001; 67: 205-208.Google Scholar
  4. 4.
    Morris R, Hargreaves A, Duvall E, Wyllie AH. Hormone-induced cell death: surface changes in thymocytes undergoing apoptosis. Am J Pathol 1984; 115: 426-436.PubMedGoogle Scholar
  5. 5.
    Lieberthal W, Menza S, Levine J. Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Physiol 1998; 274: F315-F327.PubMedGoogle Scholar
  6. 6.
    Lieberthal W, Triaca V, Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol 1996; 270: F700-F708.PubMedGoogle Scholar
  7. 7.
    Ueda N, Walker P, Hsu S, Shah SV. Activation of a 15-kDa endonuclease in hypoxia/reoxygenation injury without morphologic features of apoptosis. Proc Natl Acad Sci USA 1995; 92: 7202-7206.PubMedGoogle Scholar
  8. 8.
    Iwata M, Myerson D, Torok-Storb B, Zager RA. An evaluation of renal tubular DNA laddering in response to oxygen deprivation and oxidant injury. J Am Soc Nephrol 1994; 5: 1307-1313.PubMedGoogle Scholar
  9. 9.
    LeHir M, Dubach U. Distribution of two enzymes of b-oxidation of fatty acids along the rat nephron; in Anonymous Biochemistry of kidney functions. Elsevier Biochemical Press, Amsterdam 1982, 82-94.Google Scholar
  10. 10.
    LeHir M, Dubach U. Peroxisomal and mitochondrial b-oxidation in the rat kidney. Distribution of fatty acyl coenzyme A oxidase and 3-hydroxyacyl-coenzyme A dehydrogenase activities along the nephron. J Histochem Cytochem 1982; 30: 441-444.Google Scholar
  11. 11.
    Bell D, Bars R, Elcombe C. Differential tissue-specific expression and induction of cytochrome P450IVA1 and acyl-CoA oxidase. Eur J Biochem 1992; 206: 979-986.PubMedGoogle Scholar
  12. 12.
    Portilla D, Dai G, Peters JM, Gonzalez FJ, Crew MD, Proia AD. Etomoxir-induced PPARa-modulated enzymes protects during acute renal failure. Am J Physiol 2000; 278: F667-F675.Google Scholar
  13. 13.
    Portilla D, Dai G, McClure T, Bates L, Kurten R, Megyesi J, Price P, Li S. Alterations of PPARa and its Coactivator PGC-1 in Cisplatininduced acute renal failure. Kidney Int 2002; 62: 1208-1218.PubMedGoogle Scholar
  14. 14.
    Li S, Wu P, Proia A, Megyesi J, Li S, Harris RH, Portilla D. PPARalpha ligands protect during cisplatin-induced ARF by preventing inhibition of renal FAO and PDC activity, Am J Physiol Renal Physiol. 2004 Mar;286(3):F572-80. Epub 2003 Nov 11.PubMedGoogle Scholar
  15. 15.
    Li S., Bhatt R., Megyesi J., Gokden N., Shah S.V., Portilla D.. PPARalpha ligand ameliorates acute renal failure by reducing cisplatininduced increased expression of Renal Endonuclease G. Am J Physiol Renal Physiol, 2004; 286:F572-F580.PubMedGoogle Scholar
  16. 16.
    Li S, Gokden N, Okusa M, Bhatt R, Portilla D Anti-inflammatory effect of fibrate protects from cisplatin induced ARF. Am J of Physiol Renal Physiol, 2005; 289:F469-F480.Google Scholar
  17. 17.
    Nagothu KK, Bhatt R, Kaushal GP, Portilla D Fibrate prevents cisplatin-induced proximal tubule cell death Kid International 2005; 68: 2680-2693.Google Scholar
  18. 18.
    Portilla D, Li S, Nagothu KK, Megyesi J, Kaissling B, Schackenberg L, Safirstein RL, Beger RD Metabolomic study of cisplatin-induced nephrotoxicity Kid International,2006; 69, 2194-2204.Google Scholar
  19. 19.
    Negishi K., Noiri E., Sugaya T, Li S, Megyesi J., Nagothu KK, Portilla D. Role of L-FABP in cisplatin induced acute renal failure. Kidney Int 2007; Aug: 72(3):348-358.PubMedGoogle Scholar
  20. 20.
    Portilla D, Schnackenberg L, Beger R. Metabolomics as an extension of proteomic analysis: Study of acute kidney injury Seminars in Nephrology, Nov 2007; 27 (6): 609-620.Google Scholar
  21. 21.
    Santos NA, Catao CS, Martins NM, Curti C, Bianchi ML, Santos AC Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria Arch Toxicol 2007 Jul; 81 (7):495-504.PubMedGoogle Scholar
  22. 22.
    Vega R, Huss J, Kelly D. the coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor a in transcriptional of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000; 20: 1868-1876.PubMedGoogle Scholar
  23. 23.
    Lemasters JJ, Nieminen AL, Qian T, Trost LC, Herman B. The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem 1997; 174: 159-165.PubMedGoogle Scholar
  24. 24.
    Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Ann Rev Physiol 1998; 60: 619-642.Google Scholar
  25. 25.
    Scarpulla R. Nuclear control of respiratory chain expression in mammalian cells. J Bioenerg Biomembr 1997;29:109-119.PubMedGoogle Scholar
  26. 26.
    Virbasius J, Scarpulla R. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: A potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci 1994;91:1309-1313.PubMedGoogle Scholar
  27. 27.
    Di Mari J, Davis R, Safirstein R. MAPK activation determines renal epithelial cell survival during oxidative injury. Am J Physiol 1999; 277:F195-F203.PubMedGoogle Scholar
  28. 28.
    Walker P, Shah S Hydrogen Peroxide cytotoxicity on LLC-PK1 cells: a role for iron. Kidney Int 1991;40:891-898.PubMedGoogle Scholar
  29. 29.
    Kruidering M, Van de Water b, de Heer E, Mulder GJ, Nagelkerke JF. Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: Mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J Pharmacol Exp 1997;280:638-649.Google Scholar
  30. 30.
    Gunter T, Pfeiffer D. Mechanisms by which mitochondria transport calcium. Am J. Physiol 1990; 258:C755-C786 (Abstract).PubMedGoogle Scholar
  31. 31.
    Lemasters JJ, Nieminen AL, Qian T, Trost LC, Herman B. The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem 1997; 174:159-165.PubMedGoogle Scholar
  32. 32.
    Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. An Rev Physiol 1998; 60: 619-642.Google Scholar
  33. 33.
    Saikumar P, Dong Z, Weinberg JM, Venkatachalam MA. Mechanisms of cell death in hypoxia/reoxygenation injury. Oncogene 1998; 17: 3341-3349.PubMedGoogle Scholar
  34. 34.
    Varnes ME, Chiu SM, Xue LY, Oleinick NL. Photodynamic therapy-induced apoptosis in lymphoma cells: translocation of cyto- chrome c causes inhibition of respiration as well as caspase activation. Biochem Biophys Res Commun 1999; 255: 673-679.PubMedGoogle Scholar
  35. 35.
    Nowak G. Protein kinase C-a and ERK ½ mediate mitochondrial dysfunction, decreases in Active Na+ transport, and cisplatin- induced apoptosis in renal cells. J Biol Chem 2002;277:43377-43388.PubMedGoogle Scholar
  36. 36.
    Dzeja PP, Homuhamedov EL, Ozcan C, Pucar D, Jahangir A, Terzic A. Mitochondria: gateway for cytoprotection. Circ Res 2001;89:744- 746.PubMedGoogle Scholar
  37. 37.
    Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J. Human ICE/CED-3 protease nomenclature. Cell 1996; 87: 171.PubMedGoogle Scholar
  38. 38.
    Thornberry N, Lazebnik Y. Caspases: enemies within. Science 1998; 281: 1312-1316.PubMedGoogle Scholar
  39. 39.
    Fraser A, Evan G. A license to kill. Cell 1996; 85: 781-786.PubMedGoogle Scholar
  40. 40.
    Earnshaw W, Martins L, Kaufmann S. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999; 68: 383-424.PubMedGoogle Scholar
  41. 41.
    Cryns V, Yuan J. Proteases to die for. Genes Dev 1998; 12: 1551-1570.PubMedGoogle Scholar
  42. 42.
    Vaux D. Caspases and apoptosis-biology and terminology. Cell Death Differ 1999; 6: 493-494.PubMedGoogle Scholar
  43. 43.
    Nicholson D. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 1999; 6: 1028-1042.PubMedGoogle Scholar
  44. 44.
    Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1b-converting enzyme. Cell 1993; 75: 641-652.PubMedGoogle Scholar
  45. 45.
    Wolf B, Green D. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 1999; 274: 20049-20052.PubMedGoogle Scholar
  46. 46.
    Ahmad M, Srinivasula SM, Hegde R, Mukattash R, Fernandes-Alnemri T, Alnemri ES. Identification and characterization of murine caspase 14, a new member of the caspase family. Cancer Res 1998; 58: 5201-5205.PubMedGoogle Scholar
  47. 47.
    Salvesen G, Dixit V. Caspases: intracellular signaling by proteolysis. Cell 1997; 91: 443-446.PubMedGoogle Scholar
  48. 48.
    Cohen G. Caspases: the executioners of apoptosis. Biochem J 1997; 326: 1-16.PubMedGoogle Scholar
  49. 49.
    Nicholson D, Thornberry N. Caspases: killer proteases. Trends Biochem Sci 1997; 257: 299-306.Google Scholar
  50. 50.
    Nagata S. Apoptosis by death factor. Cell 1997; 88: 355-365.PubMedGoogle Scholar
  51. 51.
    Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of Mach, a novel MORT1/FADD-interacting protease, in Fas/APO-1 and TNF receptor-induced cell death. Cell 1996; 85: 803-815.PubMedGoogle Scholar
  52. 52.
    Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME. Cytotoxicity-dependent APO-1 (Fas/CD95) associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 1995; 14: 5579-5588.PubMedGoogle Scholar
  53. 53.
    Takahashi A, Hirata H, Yonehara S, Imai Y, Lee KK, Moyer RW, Turner PC, Mesner PW, Okazaki T, Sawai H, Kishi S, Yamamoto K, Okuma M, Sasada M. Affinity labeling displays the stepwise activation of ICE-related proteases by Fas, staurosporine, and CrmAsensitive caspase-8. Oncogene 1997; 14: 2741-2752.PubMedGoogle Scholar
  54. 54.
    Tewari M, Dixit V. Fas and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem 1995; 270: 3255-3260.PubMedGoogle Scholar
  55. 55.
    Miura M, Friedlander R, Yuan J: Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Proc Natl Acad Sci USA 1995; 92: 8318-8322.PubMedGoogle Scholar
  56. 56.
    Newton K, Strasser A. The Bcl-2 family and cell death regulation. Curr Opin Genet Dev 1998; 8: 68-75.PubMedGoogle Scholar
  57. 57.
    Green D, Reed J. Mitochondria and apoptosis. Science 1998; 281: 1309-1312.PubMedGoogle Scholar
  58. 58.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and dATP-dependent formation of apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479-489.PubMedGoogle Scholar
  59. 59.
    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90: 405-413.PubMedGoogle Scholar
  60. 60.
    Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB. Bcl-xl regulate the membrane potential and volume homeostasis of mitochondria. Cell 1997; 91: 627-637.PubMedGoogle Scholar
  61. 61.
    Zamzami N, Marchetti P, Castedo M, Hirsch T, Susin SA, Masse B, Kroemer G. Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett 1996; 384: 53-57.PubMedGoogle Scholar
  62. 62.
    Kaushal G, Singh A, Shah S. Identification of caspase (ICE-like proteases) gene family in rat kidney and altered expression in ischemia/reperfusion injury. Am J Physiol 1998; 274: F587-F595.PubMedGoogle Scholar
  63. 63.
    Kaushal G, Singh A, Shah S. Caspases in kidney: cloning, expression and alteration in ischemia/reperfusion injury. J Am Soc Nephrol 1998; 9: 579A.Google Scholar
  64. 64.
    Kaushal G, Ueda N, Shah S. Role of caspases (ICE/CED 3 proteases) in DNA damage and cell death in hypoxic injury. Kidney Int 1997;52:438-445.PubMedGoogle Scholar
  65. 65.
    Feldenberg LR, Thevananther S, del Rio M, de Leon M, Devarajan P. Partial ATP depletion induces Eas-and caspase-medicated apoptosis in MDCK cells. Am J Physiol 1999; 276:F837-F9846.PubMedGoogle Scholar
  66. 66.
    Edelstein C, Shi Y, Schrier R. Role of caspases in hypoxia-induced necrosis of rat renal proximal tubules. J Am Soc Nephrol 1999; 10: 1940-1949.PubMedGoogle Scholar
  67. 67.
    Saikumar P, Dong Z, Patel Y, Hall K, Hopfer U, Weinberg JM, Venkatachalam MA. Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury. Oncogene 1998; 17: 3401-3415.PubMedGoogle Scholar
  68. 68.
    Kaushal GP, Kaushal V, Hong X, Shah SV. Role of caspases and their regulation by Akt/protein kinase B phosphorylation pathway in cisplatin-induced injury to renal tubular epithelial cells. Kidney Int 2001; 60: 1726-1736.PubMedGoogle Scholar
  69. 69.
    Takeda M, Kobayashi M, Shirato I, Osaki T, Endou H. Cisplatin-induced apoptosis of immortalized mouse proximal tubule cells is mediated by interleukin-1b converting enzyme (ICE) family of proteases but inhibited by overexpression of Bcl-2. Arch Toxicol 1997; 71: 612-621.PubMedGoogle Scholar
  70. 70.
    Daemen MA, van ‘t Veer C, Denecker G, Heemskerk VH, Wolfs TG, Clauss M, Vandenabeele P, Buurman WA. Inhibition of apoptosis induced by ischemia/reperfusion prevents inflammation. J Clin Invest 1999; 104: 541-549.Google Scholar
  71. 71.
    Zhang X, Zheng X, Sun H, Feng B, Chen G, Vladau C, Li M, Chen D, Suzuki M, Min L, Liu W, Garcia B, Zhong R, Min WP. Prevention of renal ischemic injury by silencing the expression of renal caspase 3 and caspase 8. Transplantation. 2006;82(12):1728-1732.PubMedGoogle Scholar
  72. 72.
    Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 2001; 107: 1145-1152.PubMedGoogle Scholar
  73. 73.
    Shi Y, Melnikov VY, Schrier RW, Edelstein CL. Down-regulation of the calpain inhibitor protein, calpastatin, by caspases during renal ischemia. Am J Physiol 2000; 279: F509-F517.Google Scholar
  74. 74.
    Cummings BS, Schnellmann RG. Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways. J Pharmacol Exp Ther 2002; 302: 8-17PubMedGoogle Scholar
  75. 75.
    Jiang M, Yi X, Hsu S, Wang CY, Dong Z. Role of p53 in cisplatin-induced tubular cell apoptosis: dependence on p53 transcriptional activity. Am J Physiol Renal Physiol 2004; 287: F1140-F1147.PubMedGoogle Scholar
  76. 76.
    Seth R, Yang C, Kaushal V, Shah SV, Kaushal GP. p53-dependent caspase-2 activation in mitochondrial release of apoptosis-inducing factor and its role in renal tubular epithelial cell injury. J Biol Chem 2005; 280: 31230-31239.PubMedGoogle Scholar
  77. 77.
    Megyesi J, Udvarhelyi N, Safirstein RL, Price PM. The p53-independent activation of transcription of p21 WAF1/CIP1/SDI1 after acute renal failure. Am J Physiol 1996; 271: F1211-F1216.PubMedGoogle Scholar
  78. 78.
    Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M et al. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 2003; 63: 72-82.PubMedGoogle Scholar
  79. 79.
    Sheikh-Hamad D, Cacini W, Buckley AR, Isaac J, Truong LD, Tsao CC et al. Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch Toxicol 2004; 78: 147-155.PubMedGoogle Scholar
  80. 80.
    Faubel S, Ljubanovic D, Reznikov L, Somerset H, Dinarello CA, Edelstein CL. Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis. Kidney Int 2004; 66: 2202-2213.PubMedGoogle Scholar
  81. 81.
    Yang C, Kaushal V, Haun RS, Seth R, Shah SV, Kaushal GP. Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity. Cell Death and Dfferentiation, 2008; 15: 530-544.Google Scholar
  82. 82.
    Wei Q, Dong G, Yang T, Megyesi J, Price PM, Dong Z. Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2007;293(4):F1282-91.PubMedGoogle Scholar
  83. 83.
    Bossy-Wetzel E, Newmeyer D, Green D. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1997; 17: 37-49.Google Scholar
  84. 84.
    Qian T, Nieminen AL, Herman B, Lemasters JJ. Mitochondrial permeability transition in pH-dependent reperfusion injury to rat hepatocytes. Am J Physiol 1997; 273: C1783-C1792.PubMedGoogle Scholar
  85. 85.
    Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, Kroemer G. Mitochondrial control of nuclear apoptosis. J Exp Med 1996; 183: 1533-1544.PubMedGoogle Scholar
  86. 86.
    Xiang J, Chao D, Korsmeyer S. BAX-induced cell death may not require interleukin 1 b-converting enzyme-like proteases. Proc Natl Acad Sci USA 1996; 93:14559-14563.PubMedGoogle Scholar
  87. 87.
    Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, Daugas E, Geuskens M, Kroemer G. Bcl-2 inhibits the mtiochondrial release of an apoptogenic protease. J Exp Med 1996; 184:1331-1341.PubMedGoogle Scholar
  88. 88.
    Schendel SL, Xie Z, Montal MO, Matsuyama S, Montal M, Reed JC. Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci USA 1997;94:5113-5118.PubMedGoogle Scholar
  89. 89.
    Oltvai Z, Korsmeyer S. Checkpoints of dueling dimers foil death wishes. Cell 1994; 79:189-192.PubMedGoogle Scholar
  90. 90.
    Han J, Sabbatini P, Perez D, Rao L, Modha D, White E. The E1B 19K protein blocks apoptosis by interacting with and inhibiting the p53-inducible and death-promoting Bax protein. Genes Dev 1996;10:461-477.PubMedGoogle Scholar
  91. 91.
    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. Regulation of cell death protease casepase-9 by phosphorylation. Science 1998;282:1318-1321.PubMedGoogle Scholar
  92. 92.
    di Mari JF, Davis R, Safirstein RL. MAPK activation determines renal epithelial cell survival during oxidative injury. American Journal of Physiology Renal Physiology 277: F195-203, 1999.Google Scholar
  93. 93.
    Park KM, Kramers C, Vayssier-Taussat M, Chen A, Bonventre JV. Prevention of Kidney Ischemia/Reperfusion-induced Functional Injury, MAPK and MAPK Kinase Activation, and Inflammation by Remote Transient Ureteral Obstruction. J Biol Chem, 2002;277: 2040-2049.PubMedGoogle Scholar
  94. 94.
    Blagosklonny MV. A node between proliferation, apoptosis, and growth arrest. Bioessays, 1999;21: 704-709.PubMedGoogle Scholar
  95. 95.
    Roovers K, Assoian RK. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays 2000;22: 818-826.PubMedGoogle Scholar
  96. 96.
    Arany I, Megyesi JK, Kaneto H, Tanaka S, Safirstein RL. Activation of ERK or inhibition of JNK ameliorates H2O2 cytotoxicity in mouse renal proximal tubule cells. Kidney Int, 2004;65: 1231-1239.PubMedGoogle Scholar
  97. 97.
    Arany I, Megyesi JK, Kaneto H et al. Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. Am J Physiol Renal Physiol 2004; 287: F543-F549.PubMedGoogle Scholar
  98. 98.
    Wang Z, Chen JK, Wang SW, Moeckel G, Harris RC. Importance of functional EGF receptors in recovery from acute nephrotoxic injury. J Am Soc Nephrol, 2003;14: 3147-3154.PubMedGoogle Scholar
  99. 99.
    Harris RC. Potential physiologic roles for epidermal growth factor in the kidney. Am J Kidney Dis, 1991; 17: 627-630.PubMedGoogle Scholar
  100. 100.
    English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S, Cobb MH. New insights into the control of MAP kinase pathways. Exp Cell Res,1999;253: 255-270.PubMedGoogle Scholar
  101. 101.
    Bonfini L, Migliaccio E, Pelicci G, Lanfrancone L, Pelicci PG. Not all Shc’s roads lead to Ras. Trends Biochem Sci 1996;21: 257-261.PubMedGoogle Scholar
  102. 102.
    Schlessinger J. How receptor tyrosine kinases activate Ras. Trends Biochem Sci 1993;18: 273-275.PubMedGoogle Scholar
  103. 103.
    Rao GN. Hydrogen peroxide induces complex formation of SHC-Grb2-SOS with receptor tyrosine kinase and activates Ras and extracellular signal-regulated protein kinases group of mitogen-activated protein kinases. Oncogene, 1996; 13: 713-719.PubMedGoogle Scholar
  104. 104.
    Safirstein R, Price PM, Saggi SJ, Harris RC. Changes in gene expression after temporary renal ischemia. Kidney Int 1990;37: 1515-1521.PubMedGoogle Scholar
  105. 105.
    Pellegrini M, Pacini S, Baldari CT. p66SHC: the apoptotic side of Shc proteins. Apoptosis,2005;10: 13-18.PubMedGoogle Scholar
  106. 106.
    Purdom S, Chen QM. p66(Shc): at the crossroad of oxidative stress and the genetics of aging. Trends Mol Med,2003;9: 206-210.PubMedGoogle Scholar
  107. 107.
    Arany I, Faisal A, Nagamine Y, Safirstein RL. P66SHC inhibits the pro-survival EGFR/ERK signaling during severe oxidative stress in mouse renal proximal tubule cells. J Biol Chem 2008.Google Scholar
  108. 108.
    Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. American Journal of Physiology; Cell Physiology, 1998; 275: C1640-1652.Google Scholar
  109. 109.
    Stephanou A. Role of STAT-1 and STAT-3 in ischaemia/reperfusion injury. J Cell Mol Med, 2004; 8: 519-525.PubMedGoogle Scholar
  110. 110.
    Vinkemeier U. Getting the message across, STAT! Design principles of a molecular signaling circuit. J Cell Biol, 2004;167: 197- 201.PubMedGoogle Scholar
  111. 111.
    Kritikou EA, Sharkey A, Abell K, Came PJ, Anderson E, Clarkson RWE, Watson CJ. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development, 2003;130: 3459-3468.PubMedGoogle Scholar
  112. 112.
    Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res, 2003, 63: 3923-3930.PubMedGoogle Scholar
  113. 113.
    Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, Platt A, Gilmer TM, Fu X-Y, Chin YE. Identification of Both Positive and Negative Domains within the Epidermal Growth Factor Receptor COOH-terminal Region for Signal Transducer and Activator of Transcription (STAT ) Activation. J Biol Chem, 2003; 277: 30716-30723.Google Scholar
  114. 114.
    Zhang T, Ma J, Cao X. Grb2 regulates Stat3 activation negatively in epidermal growth factor signaling. Biochem J, 2003;376: 457- 464.PubMedGoogle Scholar
  115. 115.
    Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol, 2001; 2: 599-609, 2001.PubMedGoogle Scholar
  116. 116.
    Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem,1999;68: 821-861.PubMedGoogle Scholar
  117. 117.
    Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science,1999;286: 1358-1362.PubMedGoogle Scholar
  118. 118.
    Du K, and Montminy M. CREB Is a Regulatory Target for the Protein Kinase Akt/PKB. J Biol Chem,1998;273: 32377-32379.PubMedGoogle Scholar
  119. 119.
    Walton MR, and Dragunow I. Is CREB a key to neuronal survival? Trends Neurosc,2000; 23: 48-53.Google Scholar
  120. 120.
    Yamada M, Tanabe K, Wada K, Shimoke K, Ishikawa Y, Ikeuchi T, Koizumi S, Hatanaka H. Differences in survival-promoting effects and intracellular signaling properties of BDNF and IGF-1 in cultured cerebral cortical neurons. Journal of Neurochemistry,2001; 78: 940-951.PubMedGoogle Scholar
  121. 121.
    Crossthwaite AJ, Hasan S, Williams RJ. Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase.J Neurochem,2002; 80: 24-35.PubMedGoogle Scholar
  122. 122.
    Ichiki T, Tokunou T, Fukuyama K, Iino N, Masuda S, Takeshita A. Cyclic AMP Response Element-Binding Protein Mediates Reactive Oxygen Species-Induced c-fos Expression. Hypertension,2003; 42: 177-183.PubMedGoogle Scholar
  123. 123.
    Iwata E, Asanuma M, Nishibayashi S, Kondo Y, Ogawa N. Different effects of oxidative stress on activation of transcription factors in primary cultured rat neuronal and glial cells. Brain Res Mol Brain Res,1997; 50: 213-220.PubMedGoogle Scholar
  124. 124.
    Pugazhenthi S, Nesterova A, Jambal P, Audesirk G, Kern M, Cabell L, Eves E, Rosner MR, Boxer LM, Reusch JE. Oxidative stressmediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem,2003;84: 982-996.PubMedGoogle Scholar
  125. 125.
    Xing J, Ginty DD, Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science,1996; 273: 959-963.PubMedGoogle Scholar
  126. 126.
    Arany I, Megyesi JK, Reusch JE, Safirstein RL. CREB mediates ERK-induced survival of mouse renal tubular cells after oxidant stress. Kidney Int,2005;68: 1573-1582.PubMedGoogle Scholar
  127. 127.
    Megyesi J, Udvarhelyi N, Safirstein RL, Price PM. 1996. p53-Independent activation of transcription of p21WAF1/CIP1/SDI1 after acute renal failure. Am. J. Physiol. 271: F1211-F1216.PubMedGoogle Scholar
  128. 128.
    Megyesi J, Safirstein RL, Price PM. Induction of p21 WAFI/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J Clin Invest 1998;101:777-782.PubMedGoogle Scholar
  129. 129.
    Megyesi J, Andrade L, Vieira J, Safirstein RL, Price PM. Positive effect of the induction of p21 WAF1/CIP1 on the course of ischemic acute renal failure. Kidney Int 2001;60:2164-2172.PubMedGoogle Scholar
  130. 130.
    Price PM, Safirstein RL, Megyesi J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am. J. Physiol. Renal Physiol, 2004; 286: F378-F384.PubMedGoogle Scholar
  131. 131.
    Yu F, Megyesi J, Safirstein RL, Price PM. Identification of the functional domain of p21WAF1/Cip1 that protects from cisplatin cytotoxicity Am. J. Physiol. Renal Physiol. 2005; 289: F514-F520.PubMedGoogle Scholar
  132. 132.
    Price PM, Yu F, Kaldis P, Aleem E, Nowak G, Safirstein RL, Megyesi J. Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin dependentkinase 2. J. Am. Soc. Nephrol. 2006;17: 2434-2442.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Istvan Arany
    • 1
  • Gur P. Kaushal
    • 1
  • Didier Portilla
    • 1
  • Judit Megyesi
    • 1
  • Peter M. Price
    • 1
  • Robert L. Safirstein
    • 1
  1. 1.Central Arkansas Veterans Health Care SystemLittle RockUSA

Personalised recommendations