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Prevention of DNA damage in renal transplantation by losartan and enalapril: the role of renin-angiotensin system polymorphisms

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Abstract

Background

In this study the effect of losartan and enalapril on the reduction of DNA damage was evaluated in regard to renin-angiotensin system (RAS) polymorphisms.

Methods

After determination of genotypes of RAS polymorphism by PCR, 64 renal transplant recipients were randomly allocated to one of four groups: the first and second groups were treated with E (E+: 10 mg/day) and L (L+: 50 mg/day) alone, respectively. The third group received E+L (E+L+: 10 + 50 mg/day), and the forth group received no medication (E−L−). The subjects were followed for 8 weeks. After a 2-week washout period, the E group changed to L and vice versa as a cross-over design. They were followed for another 8 weeks. Before and after treatment, we checked 8-OHdG and malondialdehyde (MDA) as biomarkers of DNA damage and lipid peroxidation, respectively.

Results

8-OHdG levels were significantly decreased after treatment in the E+L+ and L+ groups (P < 0.001, P = 0.001, respectively). Only the TT genotype of AGT had the most antioxidative role regarding the treatment (P = 0.01). We found a remarkable correlation between MDA and DNA damage levels before and after intervention (r = 0.48, P < 0.001; r = 0.35, P = 0.006).

Conclusion

The protective effects of L+ and E+L+ on DNA breaks are surprising regarding the RAS polymorphisms.

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References

  1. Schriner SE, Ogburn CE, Smith AC, Newcomb TG, Ladiges WC, Dolle ME, et al. Levels of dna damage are unaltered in mice overexpressing human catalase in nuclei. Free Radic Bio Med. 2000;29:664–73.

    Article  CAS  Google Scholar 

  2. Grune T, Davies KJ. Breakdown of oxidized proteins as a part of secondary antioxidant defenses in mammalian cells. Biofactors. 1997;6:165–72.

    Article  CAS  PubMed  Google Scholar 

  3. Halliwell B. Why and how should we measure oxidative DNA damage in nutritional studies? How far have we come? Am J Clin Nutr. 2000;72:1082–7.

    Article  CAS  PubMed  Google Scholar 

  4. de Groot H. Reactive oxygen species in tissue injury. Hepatogastroenterology. 1994;41:328–32.

    PubMed  Google Scholar 

  5. Basaga HS. Biochemical aspects of free radicals. Biochem Cell Biol. 1990;68:989–98.

    Article  CAS  PubMed  Google Scholar 

  6. Floyd RA. Role of oxygen free radicals in carcinogenesis and brain ischemia. FASEB J. 1990;4:2587–97.

    Article  CAS  PubMed  Google Scholar 

  7. Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN. Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci USA. 1990;87:4533–7.

    Article  CAS  PubMed  Google Scholar 

  8. Mei S, Yao Q, Wu C, Xu G. Determination of urinary 8-hydroxy-2′-deoxyguanosine by two approaches-capillary electrophoresis GC/MS: an assay for in vivo oxidative DNA damage in cancer patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;827:83–7.

    Article  CAS  PubMed  Google Scholar 

  9. Kuchino Y, Mori F, Kasai H, Inoue H, Iwai S, Miura K, et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature. 1987;327:77–9.

    Article  CAS  PubMed  Google Scholar 

  10. Shi M, Takeshita H, Komatsu M, Xu B, Aoyama K, Takeuchi T. Generation of 8-hydroxydeoxyguanosine from DNA using rat liver homogenates. Cancer Sci. 2005;96:13–8.

    Article  CAS  PubMed  Google Scholar 

  11. Arnett SD, Osbourn DM, Moore KD, Vandaveer SS, Lunte CE. Determination of 8-oxoguanine and 8-hydroxy-2′-deoxyguanosine in the rat cerebral cortex using microdialysis sampling and capillary electrophoresis with electrochemical detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;827:16–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Miwa M, Matsumaru H, Akimoto Y, Naito S, Ochi H. Quantitative determination of urinary 8-hydroxy-2′-deoxyguanosine level in healthy Japanese volunteers. Biofactors. 2004;22:249–53.

    Article  CAS  PubMed  Google Scholar 

  13. Shigenaga MK, Ames BN. Assays for 8-hydroxy-2′-deoxyguanosine: a biomarker of in vivo oxidative DNA damage. Free Radic Biol Med. 1991;10:211–6.

    Article  CAS  PubMed  Google Scholar 

  14. Loft S, Vistisen K, Ewertz M, Tjonneland A, Overvad K, Poulsen HE. Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: influence of smoking, gender and body mass index. Carcinogenesis. 1992;13:2241–7.

    Article  CAS  PubMed  Google Scholar 

  15. Bogdanov MB, Beal MF, McCabe DR, Griffin RM, Matson WR. A carbon column-based liquid chromatography electrochemical approach to routine 8-hydroxy-2′-deoxyguanosine measurements in urine and other biologic matrices: a one-year evaluation of methods. Free Radic Biol Med. 1999;27:647–66.

    Article  CAS  PubMed  Google Scholar 

  16. Vural A, Yilmaz MI, Caglar K, Aydin A, Sonmez A, Eyileten T, et al. Assessment of oxidative stress in the early posttransplant period: comparison of cyclosporine A and tacrolimus-based regimens. Am J Nephrol. 2005;25:250–5.

    Article  CAS  PubMed  Google Scholar 

  17. Krivosikova Z, Dusinska M, Spustova V, Sebekova K, Blazicek P, Heidland A, et al. DNA damage of lymphocytes in experimental chronic renal failure: beneficial effects of losartan. Kidney Int Suppl. 2001;78:212–5.

    Article  Google Scholar 

  18. Mailloux LU, Napolitano B, Bellucci AG, Vernace M, Wilkes BM, Mossey RT. Renal vascular disease causing end-stage renal disease, incidence, clinical correlated, and outcomes: a 20-year clinical experience. Am J Kidney Dis. 1994;24:622–9.

    Article  CAS  PubMed  Google Scholar 

  19. Akcay A, Ozdemir FN, Atac FB, Sezer S, Verdi H, Arat Z, et al. Angiotensin-converting enzyme genotype is a predictive factor in the peak panel-reactive antibody response. Transplant Proc. 2004;36:35–7.

    Article  CAS  PubMed  Google Scholar 

  20. Yavuz D, Koc M, Toprak A, Akpinar I, Velioglu A, Deyneli O, et al. Effects of ACE inhibition and AT1-receptor antagonism on endothelial function and insulin sensitivity in essential hypertensive patients. J Renin Angiotensin Aldosterone Syst. 2003;4:197–203.

    Article  CAS  PubMed  Google Scholar 

  21. Pechter U, Aunapuu M, Riispere Z, Vihalemm T, Kullissaar T, Zilmer K, et al. Oxidative stress status in kidney tissue after losartan and atenolol treatment in experimental renal failure. Nephron Exp Nephrol. 2004;97:33–7.

    Article  CAS  Google Scholar 

  22. Bayorh MA, Ganafa AA, Eatman D, Walton M, Feuerstein GZ. Simvastatin and losartan enhance nitric oxide and reduce oxidative stress in salt-induced hypertension. Am J Hypertens. 2005;18:1496–502.

    Article  CAS  PubMed  Google Scholar 

  23. Khaper N, Singal PK. Modulation of oxidative stress by a selective inhibition of angiotensin II type1 receptors in MI rats. J Am Coll Cardiol. 2001;37:1461–6.

    Article  CAS  PubMed  Google Scholar 

  24. Agarwal R. Proinflammatory effects of oxidative stress in chronic kidney disease: role of additional angiotensin II blockade. Am J Physiol Renal Physiol. 2003;284:863–9.

    Article  CAS  Google Scholar 

  25. Bartosz M, Kedziora J, Bartosz G. Antioxidant and prooxidant properties of captopril and enalapril. Free Radic Bio Med. 1997;23:729–35.

    Article  CAS  Google Scholar 

  26. Schupp N, Schinzel R, Heidland A, Stopper H. Genotoxicity of advanced glycation end products: involvement of oxidative stress and of angiotensin II type 1 receptors. Ann N Y Acad Sci. 2005;1043:685–95.

    Article  CAS  PubMed  Google Scholar 

  27. Hilgers KF, Mann JF. ACE inhibitors versus AT(1) receptor antagonists in patients with chronic renal disease. J Am Soc Nephrol. 2002;13:1100–8.

    PubMed  CAS  Google Scholar 

  28. Frishberg Y, Becker-Cohen R, Halle D, Feigin E, Eisenstein B, Halevy R. Genetic polymorphisms of the renin-angiotensin system and the outcome of focal segmental glomerulosclerosis in children. Kidney Int. 1998;54:1843–9.

    Article  CAS  PubMed  Google Scholar 

  29. Ohno T, Kawazu S, Tomono S. Association analyses of the polymorphisms of angiotensin-converting enzyme and angiotensinogen genes with diabetic nephropathy in Japanese non-insulin-dependent diabetics. Metabolism. 1996;45:218–22.

    Article  CAS  PubMed  Google Scholar 

  30. Toyokuni S, Tanaka T, Hattori Y, Nishiyama Y, Yoshida A, Uchida K, et al. Quantitative immunohistochemical determination of 8-hydroxy-2′-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model. Lab Invest. 1997;76:365–74.

    PubMed  CAS  Google Scholar 

  31. Yagi K. Lipid peroxides in hepatic, gastrointestinal, and pancreatic diseases. Adv Exp Med Biol. 1994;366:165–9.

    Article  CAS  PubMed  Google Scholar 

  32. Vaziri ND, Oveisi F, Ding Y. Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int. 1998;53:1748–54.

    Article  CAS  PubMed  Google Scholar 

  33. Collins AR, Dusinska M, Gedik CM, Stetina R. Oxidative damage to DNA: do we have a reliable biomarker? Environ Health Perspect. 1996;104:465–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Verbeelen DL, De Craemer D, Peeters P, Vanden Houte K, Van den Branden C. Enalapril increases antioxidant enzyme activity in renal cortical tissue of five-sixths-nephrectomized rats. Nephron. 1998;80:214–9.

    Article  CAS  PubMed  Google Scholar 

  35. Demple B. Genetic responses against nitric oxide toxicity. Braz J Med Biol Res. 1999;32:1417–27.

    Article  CAS  PubMed  Google Scholar 

  36. Vamvakas S, Bahner U, Becker P, Steinle A, Gotz R, Heidland A. Impairment of DNA repair in the course of long-term hemodialysis and under cyclosporine immunosuppression after renal transplantation. Transplant Proc. 1996;28:3468–73.

    PubMed  CAS  Google Scholar 

  37. Halliwell B. Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Problems, resolutions and preliminary results from nutritional supplementation studies. Free Radic Res. 1998;29:469–86.

    Article  CAS  PubMed  Google Scholar 

  38. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2’-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res. 1997;387:147–63.

    Article  CAS  PubMed  Google Scholar 

  39. Rehman A, Bourne LC, Halliwell B, Rice-Evans CA. Tomato consumption modulates oxidative DNA damage in humans. Biochem Biophys Res commun. 1999;262:828–31.

    Article  CAS  PubMed  Google Scholar 

  40. England T, Beatty E, Rehman A, Nourooz-Zadeh J, Pereira P, O’Reilly J, et al. The steady-state levels of oxidative DNA damage and of lipid peroxidation (F2-isoprostanes) are not correlated in healthy human subjects. Free Radic Res. 2000;32:355–62.

    Article  CAS  PubMed  Google Scholar 

  41. van Zeeland AA, de Groot AJ, Hall J, Donato F. 8-Hydroxydeoxyguanosine in DNA from leukocytes of healthy adults: relationship with cigarette smoking, environmental tobacco smoke, alcohol and coffee consumption. Mutat Res. 1999;439:249–57.

    Article  PubMed  Google Scholar 

  42. Bianchini F, Elmstahl S, Martinez-Garcia C, van Kappel AL, Douki T, Cadet J, et al. Oxidative DNA damage in human lymphocytes: correlations with plasma levels of alpha-tocopherol and carotenoids. Carcinogenesis. 2000;21:321–4.

    Article  CAS  PubMed  Google Scholar 

  43. Frimat L, Philippe C, Maghakian MN, Jonveaux P, Hurault de Ligny B, et al. Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS-a study of 274 Men. J Am Soc Nephrol. 2000;11:2062–7.

    PubMed  CAS  Google Scholar 

  44. Slowinski T, Diehr P, Kleemann P, Fritsche L, Renders L, Budde K, et al. No association between renin-angiotensin system gene polymorphisms and early and long-term allograft dysfunction in kidney transplant recipients. Nephrol Dial Transplant. 2004;19:2846–51.

    Article  CAS  PubMed  Google Scholar 

  45. Nicod J, Richard A, Frey FJ, Ferrari P. Recipient RAS gene variants and renal allograft function. Transplantation. 2002;73:960–5.

    Article  CAS  PubMed  Google Scholar 

  46. Boratynska M, Boratynski J, Klinger M, Szyber P, Pawlowski S, Pupka A, et al. Lipid peroxidation and cytokines in chronic allograft failure: influence of nonimmunological risk factors. Transplant Proc. 2000;32:1384–6.

    Article  CAS  PubMed  Google Scholar 

  47. Perez Fernandez R, Martin Mateo MC, De Vega L, Bustamante Bustamante J, Herrero M, Bustamante Munguira E. Antioxidant enzyme determination and a study of lipid peroxidation in renal transplantation. Ren Fail. 2002;24:353–9.

    Article  CAS  PubMed  Google Scholar 

  48. Scribner AW, Loscalzo J, Napoli C. The effect of angiotensin-converting enzyme inhibition on endothelial function and oxidant stress. Eur J Pharmacol 2003;482:95–9.

    Article  CAS  PubMed  Google Scholar 

  49. Strawn WB, Chappell MC, Dean RH, Kivlighn S, Ferrario CM. Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia. Circulation. 2000;101:1586–93.

    Article  CAS  PubMed  Google Scholar 

  50. Kramer C, Sunkomat J, Witte J, Luchtefeld M, Walden M, Schmidt B, et al. Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. Circ Res. 2002;90:770–6.

    Article  PubMed  Google Scholar 

  51. Da Ros R, Assaloni R, Ceriello A. Molecular targets of diabetic vascular complications and potential new drugs. Curr Drug Targets. 2005;6:503–9.

    Article  CAS  PubMed  Google Scholar 

  52. Abdi R, Tran TB, Zee R, Brenner BM, Milford EL. Angiotensin gene polymorphism as a determinant of posttransplantation renal dysfunction and hypertension. Transplantation. 2001;72:726–9.

    Article  CAS  PubMed  Google Scholar 

  53. Martinez-Alfaro M, Palma-Tirado L, Sandoval-Zapata F, Carabez-Trejo A. Correlation between formamidopyrimidine DNA glycosylase (Fpg)-sensitive sites determined by a comet assay, increased MDA, and decreased glutathione during long exposure to thinner inhalation. Toxicol Lett 2005 (Epub ahead of print).

  54. Kocyigit A, Kelaes H, Selek S, Guzel S, Celik H, Erel O. Increased DNA damage and oxidative stress in patients with cutaneous leishmaniasis. Mutat Res. 2005;585:71–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work is one part of a project that supported by a grant from the Drug-Applied Research Center (DARC) and the Vice-Chancellor for Research of Tabriz Medical University. We express appreciation to the all patients. The participation of the staff of Sheikh ol Raeis specialist and sub-specialist clinic is gratefully acknowledged.

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Authors and Affiliations

  1. Drug Applied Research Center (DARC), Biotechnology Research Center, Tabriz Medical University, P.O.Box: 51665-134, Tabriz, Iran

    Amir Ghorbanihaghjo, Pegah Veisi, Hassan Argani, Mohammad Aghaeishahsavari, Masood Noroozianavval, Nadereh Rashtchizadeh, Mehran Mesgari, Javid Safa & Hosain Babaei

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  1. Amir Ghorbanihaghjo
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  2. Pegah Veisi
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  3. Hassan Argani
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Correspondence to Amir Ghorbanihaghjo.

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Ghorbanihaghjo, A., Veisi, P., Argani, H. et al. Prevention of DNA damage in renal transplantation by losartan and enalapril: the role of renin-angiotensin system polymorphisms. Clin Exp Nephrol 12, 65–73 (2008). https://doi.org/10.1007/s10157-007-0001-x

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