Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-κB inflammatory cascade

  • Sara A. Wahdan
  • Samar S. Azab
  • Doaa A. Elsherbiny
  • Ebtehal El-DemerdashEmail author
Original Article


This study investigates the molecular mechanisms of the nephroprotective effect of piceatannol (PIC) against cisplatin-induced nephrotoxicity in rats. PIC (10 mg/kg i.p.) was given for 7 days, starting 2 days before cisplatin single injection (7 mg/kg i.p.). Serum creatinine, blood urea nitrogen (BUN), kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin were used as nephrotoxicity markers. Oxidative stress, inflammatory, and apoptotic markers were determined. In addition, the role of PIC in Nrf2 activation and its subsequent induction of antioxidant enzymes, as well as its potential cross talk with nuclear factor kappa-B, were addressed. PIC reversed cisplatin-induced elevation of nephrotoxicity markers and restored the normal kidney ultrastructure. PIC attenuated cisplatin-induced reduction in Nrf2 expression and the relative mRNA level of antioxidant enzymes: hemeoxygenase-1, cysteine ligase catalytic, and modifier subunits, as well as superoxide dismutase and glutathione-S-transferase activities. Cisplatin pro-inflammatory response was reduced by PIC treatment as evidenced by the suppression of nuclear factor kappa-B activation and the subsequent decreased tissue levels of interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and inducible nitric oxide synthase. PIC suppressed cisplatin-induced apoptosis by decreasing p53 and cytochrome C expression and caspase-3 activity. Therefore, PIC may protect against cisplatin-induced nephrotoxicity by modulating Nrf2/HO-1 signaling and hindering the inflammatory and apoptotic pathways.


Cisplatin Nephrotoxicity Inflammation Oxidative stress Piceatannol 



Glutamate cysteine ligase catalytic subunit


Glutamate cysteine ligase modifier subunit


Glutathione S transferase




Kidney injury molecule 1


Neutrophil gelatinase associated lipocalin


Nuclear factor E2-related factor 2


Nuclear factor kappa-B


Organic cation transporter 2



The authors would like to thank Dr. Ahmed Esmat, Associate Professor of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, for his cooperation in the Western blotting analysis.

Author contribution

SAW executed the experimental model and most of the experimental methods, analyzed the data, and wrote the first draft of the manuscript. SSA and DAE executed part of the experiments, analyzed the data, and wrote the final draft the manuscript draft. EE-D put the rational of the study, designed the experimental model, analyzed the data, and wrote the final draft of the manuscript.

Compliance with ethical standards

The study was approved by the ethical committee of Faculty of Pharmacy, Ain Shams University (Cairo, Egypt) (REC-ASU PhD No. 5).

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

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Supplementary Figure 6 (PNG 189 kb)


  1. Arany I, Safirstein RL (2003) Cisplatin nephrotoxicity. Semin Nephrol 23:460–464.
  2. Ashikawa K, Majumdar S, Banerjee S, Bharti AC, Shishodia S, Aggarwal BB (2002) Piceatannol inhibits TNF-induced NF- κB activation and NF- κB-mediated gene expression through suppression of I κB α kinase and p65 phosphorylation. J Immunol 169:6490–6497. CrossRefGoogle Scholar
  3. Banchroft JD, Stevens A, Turner DRY (1996) Theory and practice of histological techniques, fourth edn. Churchil Livingstone, New York, p 766Google Scholar
  4. Bellezza I, Mierla AL, Minelli A (2010) Nrf2 and NF-κB and their concerted modulation in cancer pathogenesis and progression. Cancers 2:483–497. CrossRefGoogle Scholar
  5. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888Google Scholar
  6. Bozzola JJ, Russell LD (1991) Electron microscopy principles and techniques for biologists. Jones and Bartlett, BostonGoogle Scholar
  7. Buchwalow IB, Böcker W (2010) Immunohistochemistry: basics and methods, 1st edn. Springer Science & Business Media.
  8. Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, Pavenstadt H, Lanvers-Kaminsky C, Zehnhoff-Dinnesen A, Schinkel AH et al (2010) Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol 176:1169–1180. CrossRefGoogle Scholar
  9. Cummings BS, Schnellmann RG (2002) Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways. J Pharmacol Exp Ther 302:8–17.
  10. Dias SJ, Li K, Rimando AM, Dhar S, Mizuno CS, Penman AD, Levenson AS (2013) Trimethoxy-resveratrol and picetannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts. Prostate 73:1135–1146. CrossRefGoogle Scholar
  11. Dugbartey GJ, Bouma HR, Lobb I, Sener A (2016) Hydrogen sulfide: a novel nephroprotectant against cisplatin-induced renal toxicity. Nitric Oxide 16:15–20. CrossRefGoogle Scholar
  12. Erickson AM, Nevarea ZJ, Gipp J, Mulcahy RT (2002) Identification of a variant antioxidant response element in the promoter of the human glutamate-cysteine ligase modifier subunit gene. J Biol Chem 277:30730–30737.
  13. Farrand L, Byun S, Kim JY, Im-Aram A, Lee J, Lim S, Lee KW, Suh JY, Lee HJ, Tsang BK (2013) Piceatannol enhances cisplatin sensitivity in ovarian cancer via modulation of p53, X-linked inhibitor of apoptosis protein (XIAP), and mitochondrial fission. J Biol Chem 288:23740–23750.
  14. Flohe L, Otting F. 1984. Superoxide dismutase assays. Methods Enzymol 1984; 105:93–104Google Scholar
  15. Franklin CC, Backos DS, Mohar I, White CC, Forman HJ, Kavanagh TJ (2009) Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol Asp Med 30:86–98. CrossRefGoogle Scholar
  16. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem:249–7130-9Google Scholar
  17. Hanigan MH, Devarajan P (2003) Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 1:47–61Google Scholar
  18. Hayes JD, Dinkova-Kostova AT (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39:199–218. CrossRefGoogle Scholar
  19. Higgins LG, Kelleher MO, Eggleston IM, Itoh K, Yamamoto M, Hayes JD (2009) Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox- cycling agents. TAAP 237:267–280. Google Scholar
  20. Huang Q, Dunn RT, Jayadev S, DiSorbo O, Pack FD, Farr SB, Stoll RE, Blanchard KT (2001) Assessment of cisplatin induced nephrotoxocity by microarray technology. Toxicol Sci 63:196–207. CrossRefGoogle Scholar
  21. Jeong SO, Son Y, Lee JH, Cheong YK, Park SH, Chung HT, Pae HO (2015) Resveratrol analog piceatannol restores the palmitic acid-induced impairment of insulin signaling and production of endothelial nitric oxide via activation of anti-inflammatory and antioxidative heme oxygenase-1 in human endothelial cells. Mol Med Rep 12:937–944. CrossRefGoogle Scholar
  22. Jiang M, Wei Q, Wang J, Du Q, Yu J, Zhang L, Dong Z (2006) Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis. Oncogene 25:4056–4066. CrossRefGoogle Scholar
  23. Jin CY, Moon DO, Lee KJ, Kim MO, Lee JD, Choi YH (2006) Piceatannol attenuates lipopolysaccharide-induced NF-kappaB activation and NF-kappaB-related proinflammatory mediators in BV2 microglia. Pharmacol Res 54:461–467. CrossRefGoogle Scholar
  24. Kilic U, Kilic E, Tuzcu Z, Tuzcu M, Ozercan IH, Yilmaz O (2013) Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Met 10:1–8. CrossRefGoogle Scholar
  25. Kukreja A, Wadhwa N, Tiwari A (2014) Therapeutic role of resveratrol andpiceatannol in disease prevention. J Blood Disord Transfus 5:1–6. CrossRefGoogle Scholar
  26. Lee HH, Sin-Aye Park SA, Almazari I, Kim EH, Na HK, Surh YJ (2010) Piceatannol induces heme oxygenase-1 expression in human mammary epithelial cells through activation of ARE-driven Nrf2 signaling. Arch Biochem Biophys 501:142–150. CrossRefGoogle Scholar
  27. Levonen AL, Inkala M, Heikura T, Jauhiainen S, Jyrkkänen HK, Kansanen E (2007) Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arterioscler Thromb Vasc Biol 27:741–747. CrossRefGoogle Scholar
  28. Liu GH, Qu J, Shen X (2008) NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochem Biophys Acta 1783:713–727. CrossRefGoogle Scholar
  29. Maghsoudi O, Mirjalili SH, Dolatabadi M, Joshaghani MF, Zarea M, Yahaghi E, Mokarizadeh A (2015) Investigations of renal function using the level of neutrophil gelatinase-associated lipocalin associated with single-dose of cisplatin during chemotherapy. Diagn Pathol 14:1–7Google Scholar
  30. Máthé C, Szénási G, Sebestény A, Blázovics A, Szentmihályi K, Hamar P, Albert M (2014) Protective effect of CV247 against cisplatin nephrotoxicity in rats. Hum Exp Toxicol 33:789–799. CrossRefGoogle Scholar
  31. Menze ET, Esmat A, Tadros MG, Abdel-Naim AB, Khalifa AE (2015) Genistein improves 3-NPA-induced memory impairment in ovariectomized rats: impact of its antioxidant, anti-inflammatory and acetylcholinesterase modulatory properties. PLoS One 10:e0117223CrossRefGoogle Scholar
  32. Miller RP, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of cisplatin nephrotoxicity. Toxins (Basel) 2:2490–2518. CrossRefGoogle Scholar
  33. Oh GS, Kim HJ, Shen A, Lee SB, Khadka D, Pandit A, So HS (2014) Cisplatin-induced kidney dysfunction and perspectives on improving treatment strategies. Elect Blood Press 12:55–65. CrossRefGoogle Scholar
  34. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefGoogle Scholar
  35. Ozkok A, Edelstein CL (2014) Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res Int 2014:1:1–1:117.
  36. Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007. CrossRefGoogle Scholar
  37. Pedraza-Chaverri J, Murali NS, Croatt AJ, Alam J, Grande JP, Nath KA (2006) Proteinuria as a determinant of renal expression of heme oxygenase-1: studies in models of glomerular and tubular proteinuria in the rat. Am J Physiol Renal Physiol. 290:196–204. CrossRefGoogle Scholar
  38. Piotrowska H, Kucinska M, Murias M (2012) Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat Res 750:60–82. CrossRefGoogle Scholar
  39. Roupe KA, Yáñez LA, Teng XW, Davies NM (2006) Pharmacokinetics of selected stilbenes: rhapontigenin, piceatannol and pinosylvin in rats. J Pharmacy Pharmacol 58:1443–1450Google Scholar
  40. Sahin K, Orhan C, Tuzcu M, Muqbil I, Sahin N, Gencoglu H, Guler O, Padhye SB, Sarkar FH, Mohammad RM (2014) Comparative in vivo evaluations of curcumin and its analog difluorinated curcumin against cisplatin-induced nephrotoxicity. Biol Trace Elem Res 157:156–163. CrossRefGoogle Scholar
  41. Sahu BD, Kumar JM, Sistla R (2015) Baicalein, a bioflavonoid, prevents cisplatin-induced acute kidney injury by up-regulating antioxidant defenses and down-regulating the MAPKs and NF-κB pathways. PLoS One 10:1–19. Google Scholar
  42. Saleh S, El-Demerdash E (2005) Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity: role of nitric oxide. Basic Clin Pharmacol Toxicol 97:91–97CrossRefGoogle Scholar
  43. Satoh, T., Okamoto, S.I., Cui, J., Watanabe, Y., Furuta, K., Suzuki, M, Tohyama K, . Lipton S. 2006. Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers. Proc Natl Acad Sci 103:768–773. doi: CrossRefGoogle Scholar
  44. Schaaf GJ, Maas RF, de Groene EM, Fink-Gremmels J (2002) Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells. Free Rad Res 36:835–843. CrossRefGoogle Scholar
  45. Seyed MA, Jantan I, Bukhari SN, Vijayaraghavan K (2016) A comprehensive review on the chemotherapeutic potential of piceatannol for cancer treatment, with mechanistic insight. J Agric Food Chem 64:725–737. CrossRefGoogle Scholar
  46. Shiraishi F, Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, Agarwal A (2000) Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Am J Physiol Renal Physiol. 278:726–736CrossRefGoogle Scholar
  47. Son PS, Park SA, Na HK, Jue DM, Kim S, Surh YJ (2010) Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-kB activation and cyclooxygenase-2 expression in human breast epithelial cells: cysteine 179 of IKKb as a potential target. Carcinogenesis 31:1442–1449. CrossRefGoogle Scholar
  48. Song H, Jung JI, Cho HJ, Her S, Kwon SH, Yu R, Kang YH, Lee KW, Park JH (2015) Inhibition of tumor progression by oral piceatannol in mouse 4T1 mammary cancer is associated with decreased angiogenesis and macrophage infiltration. J Nutr Biochem 26:1368–1378. CrossRefGoogle Scholar
  49. Surh YJ, Na HK (2008) NF-kappaB and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with anti-inflammatory and antioxidant phytochemicals. Genes Nutr 2:313–317. CrossRefGoogle Scholar
  50. Szekeres T, Saiko P, Fritzer-Szekeres M, Djavan B, Jäger W (2011) Chemopreventive effects of resveratrol and resveratrol derivatives. Ann N Y Acad Sci 1215:89–95. CrossRefGoogle Scholar
  51. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S (2006) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116:984–995. CrossRefGoogle Scholar
  52. Tyagi S, Chirag JP, Raghvendra (2012) Biological and clinical spectrum of piceatannol -a hydroxylated analogue of resveratrol: a phytochemical review. J Biomed Pharm Res 1:1–5Google Scholar
  53. Wahdan SA, Azab SS, Elsherbiny DA, El-Demerdash E (2017) Piceatannol ameliorates cisplatin-induced histological and biochemical alterations in rats kidney. IJPPS 9:305–311Google Scholar
  54. Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans 43:621–626. CrossRefGoogle Scholar
  55. Wei Q, Dong G, Franklin J, Dong Z (2007a) The pathological role of Bax in cisplatin nephrotoxicity. Kidney Int 72:53–62. CrossRefGoogle Scholar
  56. Wei Q, Dong G, Yang T, Megyesi J, Price PM, Dong Z (2007b) Activation an involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol 293:1282–1129. CrossRefGoogle Scholar
  57. Yang H, Magilnick N, Lee C, Kalmaz D, Ou X, Chan JY, Lu SC (2005) Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-κB and AP-1. Mol Cell Biol 25(14):5933–5946. CrossRefGoogle Scholar
  58. Youn J, Lee JS, Na HK, Kundu JK, Surh YJ (2009) Resveratrol and piceatannol inhibit iNOS expression and NF-κ B activation in dextran sulfate sodium-induced mouse colitis. Nut Cancer 61:847–854. CrossRefGoogle Scholar
  59. Zhang B, Ramesh G, Norbury C, Reeves WB (2007) Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-α produced by renal parenchymal cells. Kidney Int 72:37–44. CrossRefGoogle Scholar
  60. Zhang PL, Rothblum LI, Han WK, Blasick TM, Potdar S, Bonventre JV (2008) Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury. Kidney Int 73:608–614CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmacology & Toxicology Department, Faculty of PharmacyAin Shams UniversityCairoEgypt

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