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Clinical and Experimental Nephrology

, Volume 19, Issue 4, pp 591–597 | Cite as

Amelioration of cisplatin-induced nephrotoxicity in rats by triterpenoid saponin of Terminalia arjuna

  • Iman O. SherifEmail author
Original Article

Abstract

Background

Cisplatin is a potent anti-tumor compound. Nephrotoxicity-inducing oxidative stress is a common side effect. This study was conducted to find out whether, the triterpenoid saponin of Terminalia arjuna (TA), Arjunolic acid which is a natural antioxidant, could prevent cisplatin-induced renal toxicity and if so, explore its possible renoprotective mechanism.

Methods

Thirty male Sprague–Dawley rats were divided into three groups: Control group: rats received saline injection, cisplatin group: rats injected intraperitoneally with 7 mg/kg cisplatin and Arjunolic acid group: rats received 20 mg/kg Arjunolic acid daily for 10 days with cisplatin injection on day 5. Serum creatinine and blood urea nitrogen (BUN) were determined and kidney sections were obtained for histopathology. Oxidative stress was evaluated in kidney homogenates by measuring malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) levels. Renal gene expressions of transforming growth factor-beta (TGF-β), nuclear factor-kappa B (NF-κB), kidney injury molecule-1 (Kim-1) and B cell lymphoma-2 (Bcl-2) were estimated.

Results

Cisplatin-treated rats showed a significant reduction in renal GSH and a significant elevation of serum creatinine, BUN, MDA and NO renal levels when compared with control. Moreover, upregulation of TGF-β, NF-κB and Kim-1 along with downregulation of Bcl-2 renal expressions were also observed in cisplatin-treated rats in comparison to control. All these markers were significantly reversed by TA triterpenoid saponin administration.

Conclusion

Arjunolic acid ameliorated the nephrotoxic biochemical changes induced by cisplatin supporting its renoprotective effects which may be mediated by attenuation of oxidative stress markers, downregulation of renal expressions of fibrotic (TGF-β), inflammatory (NF-κB) and kidney injury (Kim-1) markers along with upregulation of renal antiapoptotic marker (Bcl-2) gene expressions.

Keywords

Cisplatin Nephrotoxicity Arjunolic acid TGF-beta NF-κB Kim-1 

Notes

Acknowledgments

The author acknowledges Dr. Azza Abdel-Aziz, Associate Professor of Pathology, Faculty of Medicine, Mansoura University, for histopathological examination of the kidney. This research received no specific Grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The author declares no conflict of interest.

References

  1. 1.
    Schrier RW. Cancer therapy and renal injury. J Clin Invest. 2002;110(6):743–5.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007;334(2):115–24.CrossRefPubMedGoogle Scholar
  3. 3.
    Launay-Vacher V, Rey J-B, Isnard-Bagnis C, Deray G, Daouphars M. Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol. 2008;61(6):903–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Miyawaki Y, Ueki M, Ueno M, Asaga T, Tokuda M, Shirakami G. d-Allose ameliorates cisplatin-induced nephrotoxicity in mice. Tohoku J Exp Med. 2012;228(3):215–21.Google Scholar
  5. 5.
    Mukhopadhyay P, Horváth B, Zsengellér Z, Zielonka J, Tanchian G, Holovac E, Kechrid M, Patel V, Stillman IE, Parikh SM. Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic Biol Med. 2012;52(2):497–506.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Mukhopadhyay P, Horváth B, Kechrid M, Tanchian G, Rajesh M, Naura AS, Boulares AH, Pacher P. Poly (ADP-ribose) polymerase-1 is a key mediator of cisplatin-induced kidney inflammation and injury. Free Radic Biol Med. 2011;51(9):1774–88.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Ahmad MS, Ahmad S, Gautam B, Arshad M, Afzal M. Terminalia arjuna, a herbal remedy against environmental carcinogenicity: an in vitro and in vivo study. Egypt J Med Hum Genet. 2014;15(1):61–7.CrossRefGoogle Scholar
  8. 8.
    Ghosh J, Sil PC. Arjunolic acid: a new multifunctional therapeutic promise of alternative medicine. Biochimie. 2013;95(6):1098–109.CrossRefPubMedGoogle Scholar
  9. 9.
    Manna P, Sinha M, Sil PC. Aqueous extract of Terminalia arjuna prevents carbon tetrachloride induced hepatic and renal disorders. BMC Complement Altern Med. 2006;6(1):33.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Sinha M, Manna P, Sil PC. Aqueous extract of the bark of Terminalia arjuna plays a protective role against sodium-fluoride-induced hepatic and renal oxidative stress. J Nat Med. 2007;61(3):251–60.CrossRefGoogle Scholar
  11. 11.
    Ulu R, Dogukan A, Tuzcu M, Gencoglu H, Ulas M, İlhan N, Muqbil I, Mohammad RM, Kucuk O, Sahin K. Regulation of renal organic anion and cation transporters by thymoquinone in cisplatin induced kidney injury. Food Chem Toxicol. 2012;50(5):1675–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Sinha M, Manna P, Sil PC. Arjunolic acid attenuates arsenic-induced nephrotoxicity. Pathophysiology. 2008;15(3):147–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Song J, Liu D, Feng L, Zhang Z, Jia X, Xiao W. Protective effect of standardized extract of Ginkgo biloba against cisplatin-induced nephrotoxicity. Evid Based Complement Altern Med. 2013;2013:1–11.Google Scholar
  14. 14.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Ali B, Al-Moundhri M, Eldin MT, Nemmar A, Al-Siyabi S, Annamalai K. Amelioration of cisplatin-induced nephrotoxicity in rats by tetramethylpyrazine, a major constituent of the Chinese herb Ligusticum wallichi. Exp Biol Med. 2008;233(7):891–6.CrossRefGoogle Scholar
  16. 16.
    Rashed LA, Hashem RM, Soliman HM. Oxytocin inhibits NADPH oxidase and P38 MAPK in cisplatin-induced nephrotoxicity. Biomed Pharmacother. 2011;65(7):474–80.CrossRefPubMedGoogle Scholar
  17. 17.
    Talebi A, Nasri H, Khazaei M, Baradaran-Mahdavi M-M, Jafapisheh A, Olia B, Pirhaji O, Hashemi-Nia SJ, Eshraghi F, Pezeshki Z. A combination of Vitamin C and Losartan for cisplatin-induced Nephrotoxicity in Rats. Iran J Kidney Dis. 2012;6(5):361–5.Google Scholar
  18. 18.
    Özen S, Akyol Ö, Iraz M, Söğüt S, Özuğurlu F, Özyurt H, Odacı E, Yıldırım Z. Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin-induced nephrotoxicity in rats. J Appl Toxicol. 2004;24(1):27–35.CrossRefPubMedGoogle Scholar
  19. 19.
    Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol. 2009;61(3):223–42.CrossRefPubMedGoogle Scholar
  20. 20.
    Chirino YI, Trujillo J, Sánchez-González DJ, Martínez-Martínez CM, Cruz C, Bobadilla NA, Pedraza-Chaverri J. Selective iNOS inhibition reduces renal damage induced by cisplatin. Toxicol Lett. 2008;176(1):48–57.CrossRefPubMedGoogle Scholar
  21. 21.
    El-Sayed E-SM, Abd-Ellah MF, Attia SM. Protective effect of captopril against cisplatin-induced nephrotoxicity in rats. Pak J Pharm Sci. 2008;21(3):255–61.Google Scholar
  22. 22.
    Yildirim Z, Sogut S, Odaci E, Iraz M, Ozyurt H, Kotuk M, Akyol O. Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats. Pharmacol Res. 2003;47(2):149–56.CrossRefPubMedGoogle Scholar
  23. 23.
    Mansour MA, Mostafa AM, Nagi MN, Khattab MM, Al-Shabanah OA. Protective effect of aminoguanidine against nephrotoxicity induced by cisplatin in normal rats. Comp Biochem Physiol C Toxicol Pharmacol. 2002;132(2):123–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Atasayar S, Gürer-Orhan H, Orhan H, Gürel B, Girgin G, Özgüneş H. Preventive effect of aminoguanidine compared to vitamin E and C on cisplatin-induced nephrotoxicity in rats. Exp Toxicol Pathol. 2009;61(1):23–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Palipoch S, Punsawad C. Biochemical and histological study of rat liver and kidney injury induced by cisplatin. J Toxicolog Pathol. 2013;26(3):293.CrossRefGoogle Scholar
  26. 26.
    Ghosh J, Das J, Manna P, Sil PC. Acetaminophen induced renal injury via oxidative stress and TNF-α production: therapeutic potential of Arjunolic acid. Toxicology. 2010;268(1):8–18.CrossRefPubMedGoogle Scholar
  27. 27.
    El-Naga RN. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: impact on NOX-1, inflammation and apoptosis. Toxicol Appl Pharmacol. 2014;274(1):87–95.CrossRefPubMedGoogle Scholar
  28. 28.
    Chaney SG, Campbell SL, Temple B, Bassett E, Wu Y, Faldu M. Protein interactions with platinum—DNA adducts: from structure to function. J Inorg Biochem. 2004;98(10):1551–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Pal S, Pal PB, Das J, Sil PC. Involvement of both intrinsic and extrinsic pathways in hepatoprotection of Arjunolic acid against cadmium induced acute damage. Toxicology. 2011;283(2):129–39.CrossRefPubMedGoogle Scholar
  30. 30.
    Manna P, Sil PC. Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology. Free Radic Res. 2012;46(7):815–30.CrossRefPubMedGoogle Scholar
  31. 31.
    Manna P, Sil PC. Impaired redox signaling and mitochondrial uncoupling contributes vascular inflammation and cardiac dysfunction in type 1 diabetes: protective role of Arjunolic acid. Biochimie. 2012;94(3):786–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Luo J, Tsuji T, Yasuda H, Sun Y, Fujigaki Y, Hishida A. The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats. Nephrol Dial Transplant. 2008;23(7):2198–205.CrossRefPubMedGoogle Scholar
  33. 33.
    Liu W, Zhang X, Liu P, Shen X, Lan T, Li W, Jiang Q, Xie X, Huang H. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol. 2010;638(1–3):150–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Ilbey YO, Ozbek E, Cekmen M, Simsek A, Otunctemur A, Somay A. Protective effect of curcumin in cisplatin-induced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum Reprod. 2009;24(7):1717–25.CrossRefPubMedGoogle Scholar
  35. 35.
    Moraes PA, Yonamine CY, Pinto DC Jr, Esteves JV, Machado UF, Mori RC. Insulin acutely triggers transcription of Slc2a4 gene: participation of the AT-rich. E-box and NFKB-binding sites. Life Sci. 2014;114(1):36–44.CrossRefPubMedGoogle Scholar
  36. 36.
    Ross JW, Ashworth MD, Mathew D, Reagan P, Ritchey JW, Hayashi K, Spencer TE, Lucy M, Geisert RD. Activation of the transcription factor, nuclear factor kappa-B, during the estrous cycle and early pregnancy in the pig. Reprod Biol Endocrinol. 2010;8:39.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Pérez-Rojas JM, Cruz C, García-López P, Sánchez-González DJ, Martínez-Martínez CM, Ceballos G, Espinosa M, Melendez-Zajgla J, Pedraza-Chaverri J. Renoprotection by α-mangostin is related to the attenuation in renal oxidative/nitrosative stress induced by cisplatin nephrotoxicity. Free Radic Res. 2009;43(11):1122–32.CrossRefPubMedGoogle Scholar
  38. 38.
    Wolf G. Renal injury due to renin–angiotensin–aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int. 2006;70(11):1914–9.PubMedGoogle Scholar
  39. 39.
    Kusumoto M, Kamobayashi H, Sato D, Komori M, Yoshimura M, Hamada A, Kohda Y, Tomita K, Saito H. Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats. Clin Exp Nephrol. 2011;15(6):820–30.CrossRefPubMedGoogle Scholar
  40. 40.
    Al-Kharusi N, Babiker H, Al-Salam S, Waly M, Nemmar A, Al-Lawati I, Yasin J, Beegam S, Ali B. Ellagic acid protects against cisplatin-induced nephrotoxicity in rats: a dose-dependent study. Eur Rev Med Pharmacol Sci. 2013;17(3):299–310.PubMedGoogle Scholar
  41. 41.
    Zhou Y, Vaidya VS, Brown RP, Zhang J, Rosenzweig BA, Thompson KL, Miller TJ, Bonventre JV, Goering PL. Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol Sci. 2008;101(1):159–70.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Prozialeck WC, Edwards JR, Lamar PC, Liu J, Vaidya VS, Bonventre JV. Expression of kidney injury molecule-1 (Kim-1) in relation to necrosis and apoptosis during the early stages of Cd-induced proximal tubule injury. Toxicol Appl Pharmacol. 2009;238:306–14.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    van Timmeren MM, Van Den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA. Tubular kidney injury molecule-1 (Kim-1) in human renal disease. J Pathol. 2007;212:209–17.CrossRefPubMedGoogle Scholar
  44. 44.
    Qi S, Wu D. Bone marrow-derived mesenchymal stem cells protect against cisplatin-induced acute kidney injury in rats by inhibiting cell apoptosis. Int J Mol Med. 2013;32(6):1262–72.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Ognjanović BI, Djordjević NZ, Matić MM, Obradović JM, Mladenović JM, Štajn AS, Saičić ZS. Lipid peroxidative damage on cisplatin exposure and alterations in antioxidant defense system in rat kidneys: a possible protective effect of selenium. Int J Mol Sci. 2012;13(2):1790–803.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Tanabe K, Tamura Y, Lanaspa MA, Miyazaki M, Suzuki N, Sato W, Maeshima Y, Schreiner GF, Villarreal FJ, Johnson RJ, Nakagawa T. Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy. Am J Physiol Renal Physiol. 2012;303:F1264–74.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2014

Authors and Affiliations

  1. 1.Biochemistry Department, Faculty of Pharmacy, Emergency HospitalMansoura UniversityMansouraEgypt

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