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Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon

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Abstract

Ischemia followed by reperfusion has a number of clinically significant consequences. A number of pathophysiological processes appear to be involved in ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK) are integral components of the parallel MAP kinase cascades activated in response to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory cytokines. Many studies suggest that members of the MAP kinase family in particular Jun N-terminal kinase (JNK) are activated in kidney following ischemia/reperfusion of this tissue. The present study underlines the therapeutic potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage during renal ischemia/reperfusion injury. Our previous results showed that 90 min of ischemia followed by reperfusion caused very severe injury and that the untreated animals had 100% mortality after the 3rd day whereas there was improved renal function and 100% survival of animals in the three drug combination treatment group. The present study, mainly on tissue sections, further supports the protection provided by the triple drug therapy. A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three classes of MAPK and ameliorates AP-1 whereas individual or a combination of any two drugs is not as effective.

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References

  1. Dobashi K, Singh I, Orak JK, Singh AK: Combination therapy of Nacetylcysteine, sodium nitroprusside, and phosphormidon attenuates ischemia/reperfusion injury in rat kidney (communicated)

  2. Najarian JS, Gillinghan KK, Sutherland DE, Reinsm-oen NL, Payne WD, Matas AJ: The impact of the quality of initial graft function on cadaver kidney transplants. Transplantation 57: 812, 1994

    Google Scholar 

  3. Troppmann C, Gillingham KJ, Benedett E et al.: Delayed graft function, acute rejection and outcome after cadaver renal transplantation. Transplantation 59: 962, 1995

    Google Scholar 

  4. Ozo AO, Wolfe RA, Held PJ, Port FK, Schmader RL: Delayed graft function and implications for renal allograft survival. Transplantation 63: 968, 1997

    Google Scholar 

  5. Borghi-Scoazoam G, Soazoa J, Durrand F et al.: Apoptosis after ischemia/reperfusion in human liver allografts. Liver Transplant Surg 3: 406, 1997

    Google Scholar 

  6. John F, Mari DI, Davison R, Safirestein RL: MAPK activation determines renal epithelial cell survival during oxidative injury. Am J Physiol 277: K195-F203, 1999

    Google Scholar 

  7. Kyriakis JM, Avruch J: Sounding the alarm: Protein kinase cascades activated by stress and inflammation. J Biol Chem 271: 24313-24316, 1996

    Google Scholar 

  8. Kyriakis JM, Avruch J: Protein kinase cascades activated by stress and inflammatory cytokines. Bio Essays 18: 567-577, 1996

    Google Scholar 

  9. Saklatvla J, Davis W, Guesdon F: Interleukin (IL-1) and tumor necrosis factor (TNF) signal transduction. Philos Trans R Soc Lond B Biol Sci 851: 151-157, 1996

    Google Scholar 

  10. Woodgett JR, Avruch J, Dyriabis JM: Regulation of nuclear transcription factors by stress signals. Clin Exp Pharmacol Physiol 22: 281-283, 1995

    Google Scholar 

  11. Mizukami Y, Yoshiokia K, Morimoto S, Yoshida K: Novels mechanism of JNK 1 activation. Nuclear translocation and activation of JNK 1 during ischemia and reperfusion. J Biol Chem 272: 16657-16662, 1997

    Google Scholar 

  12. Barone FC, Ferestein GZ, White RF, Irving LA, Parsons AA, Hardingham SJ, Roberts J, Hunter AJ, Arder GL, Kumar S, Lec JC, Smith BR: Selective inhibition of P38 mitogen activated kinase reduces brain injury and neurological deficits in rat focal stroke models 191(suppl):(abstr), S613, 1999

    Google Scholar 

  13. Boulton T, Nye SH, Robbins DJ et al.: ERK, a family of protein-serine/ threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65: 663-675, 1991

    Google Scholar 

  14. Chen YR, Wang W, Kong AN, Tan TH: Molecular mechanisms of C-Jun N-terminal kinase mediated apoptosis induced by anti carcinogenic isotheriocyamates. J Biol Chem 273: 1768-1775, 1998

    Google Scholar 

  15. Maroney AC, Glicksman MA, Basma AN, Walton KM, Knight E, Murphy CA, Bartlett BA, Finn JP, Angeles T, Malsuda Y, Neff NT, Dionne CA: Motor neuron apoptosis is blocked by CEP-1347 (KT7515) a morel inhibitor of the JNK signaling pathway. J Neurosci 18: 104-111, 1998

    Google Scholar 

  16. Xia Z, Dickens M, Ramingeard J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK P38 MAP kinases on apoptosis. Science 270: 1326-1331, 1995

    Google Scholar 

  17. Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G: Suppression of c-Myc-induced apoptosis by Ras signaling through PI (3) K and PkB. Nature 385: 544-548, 1997

    Google Scholar 

  18. Simi A, Ingelman-Sundberg M, Tindber N: Neuroprotective agent chlomethiazole attenuates C-fos, C-Jun, and AP-1 activation through inhibition of p38 MAP kinase. J Cereb Blood Flow Metab 20: 1677-1988, 2000

    Google Scholar 

  19. Pombo CM, Bomentre JU, Avruch J, Woodgett JR, Kyriabis JM, Force T: The stress activated protein kinases are major C-Jun amino terminal kinases activated by ischemia and reperfusion. J Biol Chem 269: 26546-26551, 1999

    Google Scholar 

  20. Dimare J, dMeggesi J, Udvarhelyi N, Price P, Davins R, Safirstein R: N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol 272: F292-F298, 1997

    Google Scholar 

  21. Sabai M, Tsukada T, Harris RC: Oxidant stress activates AP-1 and heparin binding epidermal growth factor like growth factor transcription in renal epithelial cells. Exp Nephrol 9: 28-39, 2001

    Google Scholar 

  22. Morooka H, Boncentre JV, Pombo CM, Kyriakis JM, Force T: Ischemia and reperfusion enhance ATF2 and C-Jun binding to CAMP response elements and to an AP-1 binding side from the C-Jun promotes. J Biol Chem 270: 30084-30092, 1995

    Google Scholar 

  23. Kapinya K, Penzel R, Sommer C, Kiessling M: Temporary changes of the AP-1 transcription factor binding activity in the gerbil hoppocampus after transient global ischemia, and ischemic tolerance induction. Brain Res 872 252-293, 2000

    Google Scholar 

  24. Kavin M: The regulation of AP-1 activity by mitogen activated protein kinases. J Biol Chem 270: 6483, 1995

    Google Scholar 

  25. Karin MA, Zandi C: Ap-1 function and regulation. Curr Opin Cell Biol 9: 240, 1997

    Google Scholar 

  26. Singh I, Pahan K, Khan M, Singh AK: Cytokine-mediated induction of ceramide production is redox sensitive: Implications to proinflammatory diseases. J Biol Chem 273: 20354-20362, 1998

    Google Scholar 

  27. Singh AK, Dobashi K, Orak JK, Singh I: N-acetyl cysteine attenuates ischemia/reperfusion injury: Evidence of diminished oxidative stress with improved antioxidant enzyme defense systems. In: E. Manuchair (ed). 2nd International Conference on Antioxidants. Prominent Press, 2000

  28. Koeppel TA, Thies JC, Lehamann T, Gebhard MM, Herfarth C, Otto G, Post S: Improvement of hepatic microhemodynamics by N-acetylcysteine after warm ischemia. Eur Surg Res 28: 270-277, 1996

    Google Scholar 

  29. Noiri E, Peresieni T, Miller F, Goligorsky MS: In vivo targeting of inducible No synthase with oligodeoxynucleotides protects rat kidney against warm ischemia. J Clin Invest 97: 2377-2383, 1996

    Google Scholar 

  30. Lopez-Neblina F, Toledo-Pereyra LH, Mirmiran, Paez-Rollys AJ: Time dependence of Na Nitroprusside administration in the prevention of neurtrophil infiltration in the rat ischemic kidney. Transplantation 61: 179-183, 1996

    Google Scholar 

  31. Bird EJ, Webb ML, Wasserman AJ, Liu EC, Giancarli MR, Durham SK: Comparison of a novel ETA receptor antagonist and phosphoramidon in renal ischemia. Pharmacol 50: 9-23, 1955

    Google Scholar 

  32. Vermulapalli S, Chiu PJS, Chintala M, Bernardino V: Attenuation of ischemic acute renal failure by phosphoramidon in rats. Pharmacol 47: 188-193, 1993

    Google Scholar 

  33. Pahan K, Sheikh FG, Namboodiri AM, Singh I: N-acetyl cysteine inhibits induction of NO production by endotoxin or cytokine stimulated rat peritoneal macrophages, C6 glial cells and astrocytes. Free Rad Biol Med 24: 39-48, 1998

    Google Scholar 

  34. Molders P, Cotgreare IA: Oxygen radicals in the biologic systems. In: L. Packer (ed). Methods of Enzymology. Academic Press, New York, 1994, pp 482-492

    Google Scholar 

  35. Gamelin LM, Zager RA: Evidence against oxidant injury as a critical mediator of post ischemic acute renal failure. Am J Physiol 255: r450-r460, 1998

    Google Scholar 

  36. Paller MS, Ferris JR: Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 74: 1156-1164, 1984

    Google Scholar 

  37. Zager RA, Fuerstenberg SM, Baehr PH, Myeri D, Torok-Storb B: An evaluation of antioxidant enzyme recovery from post ischemic acute renal failure. J Am Nephrol 4: 1588-1597, 1994

    Google Scholar 

  38. Thielemann LW, Rosenblut EW: Sulfur-containing amino acids that increase renal glutathiol protect the kidney against papillary neurons induced by bromothylamine. Cell Biochem Funct 8: 19-24, 1990

    Google Scholar 

  39. Stefan B, Schanabel R, Wever H, Preffer F, Wilsoer R, Breitenbuck PV, Nizze H, Schareck W, Hopt VT: The nitric oxide donor sodium nitroprusside is protective in ischemia/reperfusion injury of the pancreas. Transplantation 66: 944-949, 1998

    Google Scholar 

  40. Yin T, Sandhu G, Curt DW, Burrier A, Webb PL, Rigel DF, Hai T, Wevelam J: Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem 272: 19943-19950, 1997

    Google Scholar 

  41. Xia Z, Dickens M, Raingerard J, Davis R, Greenberg ME: Opposing Effects of ERK and JNK-P38 MAP kinases on apoptosis. Science 270: 1326-1331, 1995

    Google Scholar 

  42. Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LJ, Kyriabis JM, Haimoritz-Freidman A, Fuks Z, Kolesnick RN: Requirement for ceramide-initiated SAPK/JNK signaling in stress-induced apoptosis. Nature 380: 75-79, 1996

    Google Scholar 

  43. Kumar S, Jiang MS, Adams JL, Lee JC: Pyridimylimdazole compound SB 203580 inhibits the activity but not the activation of P38 mitogenactivated protein kinase. Biochem Biophys Res Commun 263: 825-831, 1999

    Google Scholar 

  44. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNutty D, Blumenthal MJ, Heys JR, Landvalter SW: A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739-746, 1994

    Google Scholar 

  45. Carpenter G, Cohen S: Epidermal growth factor. Annu Rev Biochem 48: 193, 1979

    Google Scholar 

  46. Yang D, Kuan A, Whitmarsh J, Rincon M, Zheng TS, Davis RJ, Pacik P, Flarell RA: Absence of excitotoxicity induced apoptosis in the hippocampus of mice lacking the JNK 3 gene. Nature 389: 865-870, 1997

    Google Scholar 

  47. Harris RC: Epidermal growth factor and transforming growth factor alpha. In: S. Goldfarb, F. Zlyadch (eds). New Insights into the Cellular and Molecular Action of Hormones and Autocoids in the Kidney. Churchill Livingston, New York, 1991, pp 365-389

    Google Scholar 

  48. Gardner AM, Johnson GL: Fibroblast growth factor-α suppression of tumor necrosis factor-α-mediated apoptosis requires RAS and the activation of mitogen-activated protein kinase. J Biol Chem 271: 14560-14566, 1996

    Google Scholar 

  49. Karin M: The regulation of AP-1 activity by mitogen activated protein kinases. J Biol Chem 270: 16483-16486, 1995

    Google Scholar 

  50. Polte T, Oberle S, Schroder H: Nitric oxide protects endothelial cells from tumor necrosis factor-alpha-mediated-cytotoxicity: Possible involvement of cyclic GMP. FEBS Lett 409: 46, 1997

    Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, 29425, USA

    A. Mehta, C.P.S. Sekhon, S. Giri & J.K. Orak

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Mehta, A., Sekhon, C., Giri, S. et al. Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon. Mol Cell Biochem 240, 19–29 (2002). https://doi.org/10.1023/A:1020675721351

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