Cell Biochemistry and Biophysics

, Volume 77, Issue 4, pp 367–377 | Cite as

Grape Seed Procyanidins Attenuates Cisplatin-induced Human Embryonic Renal Cell Cytotoxicity by Modulating Heme Oxygenase-1 in Vitro

  • Hedan Han
  • Hai Wang
  • Yuemei Du
  • Liping GaoEmail author
Original Paper


Cisplatin is a widely used anti-cancer drug. However, cisplatin is limited in clinical treatment because of its severe nephrotoxicity. This study reported whether O-GSP can antagonize the cisplatin-induced cytotoxicity in HEK293 cells through inducing HO-1 protein expression. We previously demonstrated O-GSP can increase the survival rate of HEK293 and have protective effect on HEK293 cells. Herein, We found that O-GSP can antagonize cisplatin nephrotoxicity through regulating the expression of HO-1. O-GSP promotes the translocation of Nrf2 in the nucleus, and activates the ERKN JNK pathway and p38 MAPK pathway. Interestingly, p38 MAPK plays a major role in HO-1 expression induced by O-GSP. And O-GSP can modulate the decrease of Nrf2 and HO-1 expression induced by cisplatin, and improve the cisplatin-induced activity and apoptosis rate of cells by stimulating the expression of HO-1. However, the protective effects of O-GSP are inhibited by ZnPP IX. Collectively, the results indicated that O-GSP induced the expression of HO-1 through p38MAPK and Nrf2 pathway in HEK293 cells.


Oligomeric grape seed procyanidins Cisplatin HO-1 Nrf2 Nephrotoxicity 



This work project is founded by grants from Scientific Research Project of Beijing Union University: Opening Project of Key Laboratory (NO.LDSP201801).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Houde, V., Grenier, D., & Chandad, F. (2006). Protective effects of grape seed proanthocyanidins against oxidative stress induced by lipopolysaccharides of periodontopathogens. Journal of Periodontol, 77(8), 1371–1379. Scholar
  2. 2.
    Bao, L., Cai, X., & Zhang, Z., et al. (2014). Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase–silent mating type information regulation 2 homologue 1–PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine. British Journal of Nutrition, 113(1), 1–10. Scholar
  3. 3.
    Dan L., Jianjun D., Snehal J., et al. (2018). Monomeric catechin and dimeric procyanidin B2 against human norovirus surrogates and their physicochemical interactions. Food Microbiology, S0740002018300637. Scholar
  4. 4.
    Talalay, P., Dinkova-Kostova, A. T., & Holtzclaw, W. D. (2003). Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis.J. Advances in Enzyme Regul, 43, 121–134. Scholar
  5. 5.
    Rubiolo, J. A., Mithieux, G., & Vega, F. V. (2008). Resveratrol protects primary rat hepatocytes against oxidative stress damage: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. European Journal of Pharmacolgy, 591(1/2/3), 66–72. Scholar
  6. 6.
    Ryters, W., Xis, C., & Hartefieidc, L. (2002). Mitogen activeted protein kinase(mapk) pathway regulates heme oxygenase-1 gene expression by hypoxia in vascular cells. Antioxidants & Redox Signaling, 4(4), 587–592. Scholar
  7. 7.
    Paine, A., Eiz-Vesper, B., & Blasczyk, R., et al. (2010). Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochemical Pharmacology, 80(12), 1895–1903. Scholar
  8. 8.
    Park, S. Y., Park, D. J., & Kim, Y. H., et al. (2011). Upregulation of heme oxygenase-1 via PI3K/Akt and Nrf-2 signaling pathways mediates the anti-inflammatory activity of Schisandrin in Porphyromonas gingivas LPS-stimulated macrophages. Immunology Letters, 139(1-2), 93–101. Scholar
  9. 9.
    Tiwari, M., Gupta, A., & Sharma, A., et al. (2018). Role of mitogen activated protein kinase and maturation promoting factor during the achievement of meiotic Competency in mammalian oocytes. Journal of Cellular Biochemistry, 119(1), 123–129.CrossRefGoogle Scholar
  10. 10.
    Yaffe, M. B., & Fink, M. P. (2000). Cellular signaling in critical care–putting the pieces together. Critical Care Medicine, 28(4 Suppl), 1–2. Scholar
  11. 11.
    Fiorani, M. I., Guidarelli, A., & Blasa, M., et al. (2010). Mitochondria accumulate large amounts of quercetin: prevention of mitochondrial damage and release upon oxidation of the extramitochondrial fraction of the flavonoid. The Journal of Nutritional Biochemistry, 21(5), 397–404. Scholar
  12. 12.
    Saad, A. A., Youssef, I. M., & El-Shennawy, K. L. (2009). Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: the protective effect of grape seed proan -thocyanidin extract. Food and Chemical Toxicology, 47, 1499–1506. Scholar
  13. 13.
    Karasawa, T., & Steyger, P. S. (2015). An integrated view of cisplatin-induced nephrotoxicity and ototoxicity. Toxicology Letters, 237(3), 219–227. Scholar
  14. 14.
    Chirino, I. Y., & Pedraza-Chaverri., J. (2008). Role of oxidative and nitrosative stress in cisplatin -induced nephrotoxicity. Experimental and Toxicologic Pathology, 9(30), 1–20. Scholar
  15. 15.
    Lian, Y., Gao, L., & Guo, Y., et al. (2016). Protective effect of grape seed oligomeric proanthocyanidins extract against cisplatin-induced nephrotoxicity in HEK293 cell and effect on anticancer activity of cisplatin in human lung cancer cells. Food Science, 37(07), 182–186. Scholar
  16. 16.
    Guo, Z., Gao, L., & Li, Z. (2014). Protective effect of grape seed proanthocyanidin extract against cisplatin-induced apoptosis in human embryonic kidney cells. Food Science, 35(01), 234–238. Scholar
  17. 17.
    Guo, Z., Gao, L., & Li, Z. (2013). Protective effect of grape seed proanthocyanidin extract against cisplatin-induced nephrotoxicity in mice. Food Science, 34(21), 325 Scholar
  18. 18.
    Choi, B. M., Kim, Y. M., & Jeong, Y. R., et al. (2004). Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells. Biochemical and Biophysical Research Communications, 321(1), 132–137.CrossRefGoogle Scholar
  19. 19.
    Kietzmann, T., Samoylenko, A., & Immenschuh, S. (2003). Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. The Journal of Biological Chemistry, 278(20), 17927–17936.CrossRefGoogle Scholar
  20. 20.
    Li, C., Hossieny, P., & Wu, B. J., et al. (2007). Pharmacologic induction of heme oxygenase-1. Antioxidants & Redox Signaling, 9, 2227–2239. Scholar
  21. 21.
    Motterlini, R., & Foresti, R. (2014). Heme oxygenase-1 as a target for drug discovery. Antioxidants & Redox Signaling, 20(11), 1810–1826. Scholar
  22. 22.
    Moon, M. K., Choi, B. M., & Oh, G. S., et al. (2003). Catalposide protects Neuro 2A cells from hydrogen peroxide-induced cytotoxicity via the expression of heme oxygenase-1. Toxicology Letters, 145, 46–54. Scholar
  23. 23.
    Chen, C. Y., Jang, J. H., & Li, M. H., et al. (2005). Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor2 in PC12 cells. Biochemical and Biophysical Research Communications, 331, 993–1000. Scholar
  24. 24.
    Scapagnini, G., Foresti, R., & Calabrese, V., et al. (2002). Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers. Molecular Pharmacology, 61, 554–561. Scholar
  25. 25.
    Hu, Q., Zhang, D. D., & Wang, L., et al. (2012). Eriodictyol-7-O-glucoside, a novel Nrf2 activator, confers protection against cisplatin-induced toxicity. Food and Chemical Toxicology, 50(6), 1927–1932. Scholar
  26. 26.
    Sahin, K., Tuzcu, M., & Sahin, N., et al. (2010). Nrf2/HO-1 signaling pathway may be the prime target for chemoprevention of cisplatin-induced nephrotoxicity by lycopene. Food and Chemical Toxicology, 48(10), 2670–2674. Scholar
  27. 27.
    Sahin, K., Tuzcu, M., & Gencoglu, H., et al. (2010). Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sciences, 87(7-8), 240–245. Scholar
  28. 28.
    Choi, B. M., Kim, S. M., & Park, T. K., et al. (2007). Piperine protects cisplatin-induced apoptosis via hemeoxygenase-1 induction in auditory cells. The Journal of Nutritional Biochemistry, 18(9), 615–622. Scholar
  29. 29.
    Tayem, Y., Green, C. J., & Motterlini, R., et al. (2014). Isothiocyanate-cysteine conjugates protect renal tissue against cisplatin-induced apoptosis via induction of heme oxygenase-1. Pharmacological Research, 81, 1–9. Scholar
  30. 30.
    Katoh, Y., & Itoh, K. (2001). Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transription.Genes to Cells, 6, 857–868. Scholar
  31. 31.
    Ohta, T., & lijima, K. (2008). Loss of keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Research, 68, 1303–1309. Scholar
  32. 32.
    Miao, L., Shu-Hua, Y., & Jian-Xin, H., et al. (2016). The protective effect of grape-seed proantho- cyanidin extract on oxidative damage induced by zearalenone in kunming mice liver. International Journal of Molecular Sciences, 17(6), 808 Scholar
  33. 33.
    Biying L., Haili Z., Xiao T., et al. (2017). GSPE reduces lead-induced oxidative stress by activating the Nrf2 pathway and suppressing miR153 and GSK-3β in rat kidneyJ. Oncotarget, 8(26).
  34. 34.
    Anil, K. J. (2004). Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radical Biology and Medicine, 36(10), 1199–1207. Scholar
  35. 35.
    Yu, R., Chen, C., & Mo, Y. Y., et al. (2000). Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. Journal of Biological Chemistry, 275(51), 39907–39913. Scholar
  36. 36.
    Kietzmann, T., Samoylenko, A., & Immenschuh, S. (2003). Heme oxygenase-1 gene activation by the NAD(P)H oxidase inhibitor4-(2-amino-ethyl) benzenesulfonyl fluoride via a protein kinase B, p38-dependent signaling pathway in monocytes. Journal of Biological Chemistry, 280, 21820–21829. Scholar
  37. 37.
    Elbirt, K. K., Whitmarsh, A. J., & Davis, R. J., et al. (1998). Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases. Journal of Biological Chemistry, 273, 8922–8931. Scholar
  38. 38.
    Xu, C., Yuan, X., & Pan, Z., et al. (2006). Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Molecular Cancer Therapeutics, 5(8), 1918–1926. Scholar
  39. 39.
    Balogun, E., Hoque, M., & Gong, P., et al. (2003). Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochemical Journal, 371(3), 887–895. Scholar
  40. 40.
    Juan, S. H., Cheng, T. H., & Lin, H. C., et al. (2005). Mechanism of concentration-dependent induction of heme oxygenase-1 by resveratrol in human aortic smooth muscle cells. Biochemical Pharmacology, 69(1), 41–48. Scholar
  41. 41.
    Maines, M. D. (1997). The heme oxygenase system: a regulator of second messenger gases. Annual Review of Pharmacology and Toxicology, 37, 517–554. Scholar
  42. 42.
    Choi, B. M., Pae, H. O., & Kim, Y. M., et al. (2003). Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1. Hepatology, 37(4), 810–823. Scholar
  43. 43.
    Nath, K. A. (2006). Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney International, 70(3), 432–443. Scholar
  44. 44.
    Ferris, C. D., Jaffrey, S. R., & Sawa, A., et al. (1999). Heme oxygenase-1 prevents cell death by regulating cellular iron.Nature Cell Biology, 1(3), 152–157. Scholar
  45. 45.
    Petrache, I. L., Otterbein, E., & Alam, J., et al. (2000). Heme oxygenase-1 inhibits TNF-α-induced apoptosis in cultured fibroblasts. American Journal of Physiology. Lung Cellular and Molecular Physiology, 278(2), L312–L319. Scholar
  46. 46.
    Motterlini, R., Foresti, R., & Bassi, R., et al. (2000). Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radical Biology and Medicine, 28(8), 1303–1312. Scholar
  47. 47.
    Brouard, S., Otterbein, L. E., & Anrather, J., et al. (2000). Carbon monoxide generated by suppresses endothelial cell apoptosis. Journal of Experimental Medicine, 192(7), 1015–1026. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hedan Han
    • 1
    • 2
  • Hai Wang
    • 1
    • 2
  • Yuemei Du
    • 1
    • 2
  • Liping Gao
    • 1
    • 2
    Email author
  1. 1.College of Biochemical EngineeringBeijing Union UniversityBeijingChina
  2. 2.Beijing Municipal Key Laboratory of Biologically Active Substances and Functional FoodBeijingChina

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