Skip to main content
SpringerLink
Log in

Ellagic acid prevents kidney injury and oxidative damage via regulation of Nrf-2/NF-κB signaling in carbon tetrachloride induced rats

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Phytochemicals, bioactive food compounds, found in plants have been described as protective agents against renal injury. This work was planned to evaluate the effects of EA on anti-oxidative and anti-inflammation pathways in kidney damage induced with carbon tetrachloride. In this study, experimental animals (n = 36, 8 weeks old rats) were divided into 4 groups as follows: 1) Control group 2) EA group (10 mg/kg body weight) 3) CCl4 group (1.5 ml/kg, body weight) 4) EA + CCl4 group. The potentially protective effect of EA on kidney damage exposed by CCl4 in rats were evaluated. EA administration protects CCl4 induced kidney damage against oxidative stress through its antioxidant protection. Treatment of EA significantly reduced lipid peroxidation and improved glutathione and catalase enzyme activity. Recently studies showed that EA activated caspase-3 and nuclear transcription factor erythroid 2 related factor driven antioxidant signal pathway and protected the kidney against damage induced by oxidative stress. Furthermore, EA also markedly decreased the level of cyclooxygenase-2, the vascular endothelial growth factor and tumor necrosis factor-alpha and suppressed the protein synthesis of nuclear factor-kappa-B. This study reveals that EA has kidney protective effect against CCl4 induced oxidative damage and inflammation.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

EA:

Ellagic acid

MDA:

Malondialdehyde

CCl4 :

Carbon tetrachloride

NF-κB:

Nuclear factor kappa B

PAGE:

Polyacrylamide gel electrophoresis

PMSF:

Phenylmethylsulfonyl fluoride

ROS:

Reactive oxygen species

TCA:

Trichloroacetic acid

EDTA:

Ethylenediaminetetraacetic acid

FUDAM:

Firat University Experimental Animals Research Institute

Ip:

Intraperitoneal

TNF-α:

Tumor necrosis factor-α

COX-2:

Cyclooxygenase-2

SDS:

Sodium dodecyl sulphate

ARE:

Antioxidant response element

GSH:

Glutathione

TBA:

Thiobarbutric acid

DMSO:

Dimethyl sulfoxide

Nrf-2:

Nuclear factor erythroid-related factor-2

VEGF:

Vascular endothelial growth factor family

HO-1:

Hem oxygenase-1

GST:

Glutathione S-transferase

GPx:

Glutathione peroxidase

OS:

Oxidative stress

DSS:

Dextran sulfate sodium

GST:

Glutathione S-transferase

SOD:

Superoxide dismutase

NAR:

Naringin

TMZ:

Trimetazidine

References

  1. Webb CF, Ratliff ML, Powell R, Wirsig-Wiechmann CR, Lakiza O, Obara T (2015) A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures. Biochem Biophys Res Commun 463:1334–1340

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Akilesh S (2014) Normal kidney function and structure. In: Akilesh S (ed) Pathobiology of Human Disease. Elsevier, London, pp 2716–2733

    Google Scholar 

  3. Chávez-Morales RM, Jaramillo-Juárez F, Rodríguez-Vázquez ML, Martínez-Saldaña MC, Posadas del Río FA, Garfias-López JA (2017) The Ginkgo biloba extract (GbE) protects the kidney from damage produced by a single and low dose of carbon tetrachloride in adult male rats. ExpToxicol Pathol 69:430–434

    Google Scholar 

  4. Ma JQ, Ding J, Xiao ZH, Liu CM (2014) Ursolic acid ameliorates carbon tetrachloride-induced oxidative DNA damage and inflammation in mouse kidney by inhibiting the STAT3 and NF-κB activities. Int Immunopharmacol 21:389–395

    CAS  PubMed  Google Scholar 

  5. Mbarki S, Alimi H, Bouzenna H, Elfeki A, Hfaiedh N (2017) Phytochemical study and protective effect of Trigonella foenum graecum (Fenugreek seeds) against carbon tetrachloride-induced toxicity in liver and kidney of male rat. Biomed Pharmacother 88:19–26

    CAS  PubMed  Google Scholar 

  6. Young Kang K, Kim JN, Chang IY, Park SH, Yoon SP (2011) Calretinin immunoreactivity in normal and carbon tetrachloride-induced nephrotoxic rats. Acta Histochem 113:712–716

    Google Scholar 

  7. Aslan A, Can MI (2014) Milk thistle impedes the development of carbontetrachloride-induced liver damage in rats through suppression of bcl-2 and regulating caspase pathway. Life Sci 117(1):13–18

    CAS  PubMed  Google Scholar 

  8. Kaur S, Sharma D, Singh AP, Kaur S (2019) Amelioration of hepatic function, oxidative stress, and histopathologic damages by Cassia fistula L. fraction in thioacetamide-induced liver toxicity. Environ Sci Pollut Res 26:29930–29945

    CAS  Google Scholar 

  9. Pavlova EL, Simeonova LS, Gegova GA (2018) Combined efficacy of oseltamivir, isoprinosine and ellagic acid in influenza A(H3N2)-infected mice. Biomed Pharmacother 98:29–35

    CAS  PubMed  Google Scholar 

  10. Firdaus F, Zafeer MF, Anis E, Ahmed M, Afza M (2018) Ellagic acid attenuates arsenic induced neuro-inflammation and mitochondrial dysfunction associated apoptosis. Toxicol Rep 5:411–417

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Dávalos JZ, Lima C, Santos L, Romero VL, Liebman JF (2019) Thermochemical and structural studies of gallic and ellagic acids. J Chem Thermodynamics 129:108–113

    Google Scholar 

  12. Szmagara A, Krzyszczak A, Sadok I, Karczmarz K, Staniszewska MM, Stefaniak EA (2019) Determination of ellagic acid in rose matrix by spectrofluorimetry. J Food Composit Anal 78:91–100

    CAS  Google Scholar 

  13. Aslan A, Gok O, Beyaz S, Arslan E, Erman O, Ağca CA (2020) The preventive effect of ellagic acid on brain damage in rats via regulating of Nrf-2, NF-κB and apoptotic pathway. J Food Biochem 44:1–9

    Google Scholar 

  14. Bharathi E, Jagadeesan G (2014) Antioxidant potential of hesperidin and ellagic acid on renal toxicity induced by mercuric chloride in rats. Biomed Prevent Nutr 4:131–136

    Google Scholar 

  15. Ahad A, Ganai AA, Mujeeb M, Siddiqui WA (2014) Ellagic acid, an NF-κB inhibitor, ameliorates renal function in experimental diabetic nephropathy. Chem-Biol Interact 219:64–75

    CAS  PubMed  Google Scholar 

  16. Nejad KH, Gharib-Naseri MK, Sarkaki A, Dianat M, Badavi M, Farbood Y (2015) Effects of ellagic acid pretreatment on renal functions disturbances induced by global cerebral ischemic-reperfusion in rat. Iran J Basic Med Sci 20:75–82

    Google Scholar 

  17. Ayhanci A, Cengiz M, Kutlu HM, Vejselova D (2016) Protective effects of ellagic acid in D-galactosamine-induced kidney damage in rats. Cytotechnology 68:1763–1770

    CAS  PubMed  Google Scholar 

  18. Basaranlar G, Derin N, Manas CK, Tanriover G, Aslan M (2019) The effects of sulfite on cPLA2, caspase-3, oxidative stress and locomotor activity in rats. Food Chem Toxicol 123:453–458

    CAS  PubMed  Google Scholar 

  19. Abdel-Gaber SA, Geddawy A, Moussa RA (2019) The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway. Pharmacol Rep. https://doi.org/10.1016/j.pharep.2019.06.006

    Article  PubMed  Google Scholar 

  20. Cheng H, Lu C, Tang R, Pan Y, Bao S, Qiu Y, Xie M (2017) Ellagic acid inhibits the proliferation of human pancreatic carcinoma PANC-1 cells in vitro and in vivo. Oncotarget 8(7):12301–12310

    PubMed  PubMed Central  Google Scholar 

  21. Yazır Y, Gonca S, Filiz S, Dalçık H (2004) An important protein family for endothelial cells; vascular endothelial growth factor (vegf) members of the family, structure and synthesis. C Ü Tıp Fakültesi Dergisi 26(4):181–184

    Google Scholar 

  22. Nirwana I, Rachmadi P, Rianti D (2017) Potential of pomegranate fruit extract (Punica granatum Linn.) to increase vascular endothelial growth factor and platelet-derived growth factor expressions on the post-tooth extraction wound of Cavia cobaya. Veterinary World 10(8):999–1003

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Aslan A, Gok O, Erman O, Kuloglu T (2018) Ellagic acid impedes carbontetrachloride-induced liver damage in rats through suppression of NF-κB, Bcl-2 and regulating Nrf-2 and caspase pathway. Biomed Pharmacother 105:662–669

    CAS  PubMed  Google Scholar 

  24. Grossi MR, Berni A, Pepe G, Filippi S, Meschini R, Papeschi C et al (2014) Evaluation of the effects of ellagic acid on 7,12-dimethylbenz(α)anthracene (DMBA) induced micronuclei in mammalian cells in vitro and in vivo. Toxicol Lett 224:240–245

    CAS  PubMed  Google Scholar 

  25. Kaya I (2012) Effect of ellagic acid on plasma paraoxonase, sialic acid and oxidative stress parameters in chronic fluorosis mice. Phd Thesis, Kafkas University Institute of Health Sciences Institute Kars

  26. Gu L, Deng WS, Liu Y, Jiang CH, Sun LC, Sun XF et al (2014) Ellagic acid protects lipopolysaccharide/D-galactosamine-induced acute hepatic injury in mice. Int Immunopharmacol 22:341–345

    CAS  PubMed  Google Scholar 

  27. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    CAS  PubMed  Google Scholar 

  28. Gumus B (2012) Investigation of the changes in brain and kidney tissues of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in postmortem period. Medical Specialty Thesis,Gaziosmanpaşa University Faculty of Medicine Department of Forensic Medicine Tokat

  29. Aslan A, Boydak D, Can MI, Kuloglu T (2015) Nigella sativa improves the carbon tetrachloride-induced lung damage in rats through repression of erk/akt pathway. Bangladesh J Pharmacol 10:654–659

    Google Scholar 

  30. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    CAS  PubMed  Google Scholar 

  31. Gungormez Y (2019) Examination of antıoxidant system mechanisms and enzyme levels (CAT, GSH, MDA) of muay thai sports. Master Thesis, Agrı İbrahim Cecen University Institute of Social Sciences Agrı

  32. Yiğit M (2015) Effects of astaxanthin on antioxidant parameters (GSH, GSH-Px, MDA), Ca2+ signaling and apoptosis levels in ARPE-19 cells on cigarette smoke-related hydrokuinon induced oxidative stress model. Medical thesis, Süleyman Demirel University Health Sciences Institute Isparta

  33. Aslan A, Beyaz S, Gok O, Erman O (2020) The effect of ellagic acid on caspase-3/bcl-2/Nrf-2/NF-κB/TNF-α /COX-2 gene expression product apoptosis pathway: a new approach for muscle damage therapy. Mol Biol Rep 47:2573–2582

    CAS  PubMed  Google Scholar 

  34. Aslan A (2015) The effects of different essential fruit juice and their combination on Saccharomyces cerevisiae cell growth. Prog Nutr 17(1):36–40

    CAS  Google Scholar 

  35. Elgawish RAR, Rahman HGA, Abdelrazek HMA (2015) Green tea extract attenuates CCl4-induced hepatic injury in malehamsters via inhibition of lipid peroxidation and p53-mediatedapoptosis. Toxicol Rep 2:1149–1156

    PubMed  PubMed Central  Google Scholar 

  36. El-haskoury R, Al-Waili N, Kamoun Z, Mohamed Makni M, Al-Waili H, Lyoussia B (2018) Antioxidant activity and protective effect of carob honey in CCl4-induced kidney and liver injury. Arch Med Res 49:306–313

    CAS  PubMed  Google Scholar 

  37. Tekeli IO, Atessahin A, Sakin F, Aslan A, Ceribasi S, Yipel M (2019) Protective efects of conventional and colon targeted lycopene and linalool on ulcerative colitis induced by acetic acid in rats. Inflammopharmacology 27(2):313–322

    CAS  Google Scholar 

  38. Tomsa AM, Alexa AL, Junie ML, Rachisan AL, Ciumarnean L (2019) Oxidative stress as a potential target in acute kidney injury. PeerJ 7:e8046

    PubMed  PubMed Central  Google Scholar 

  39. Devaraj E, Roy A, Royapuram Veeraragavan G, Magesh A, Varikalam Sleeba A, Arivarasu L et al (2020) β-Sitosterol attenuates carbon tetrachloride–induced oxidative stress and chronic liver injury in rats. Naunyn Schmiedebergs Arch Pharmacol 393:1067–1075

    CAS  PubMed  Google Scholar 

  40. Alayunt ÖN, Aksoy L, Karafakıoğlu YS, Sevimli S (2019) Assessment of anti-inflammatory and antioxidant properties of safranal on CCl4-induced oxidative stress and inflammation in rats. An Acad Bras Cienc 91(2):e20181235

    PubMed  Google Scholar 

  41. Zhou B, Li Q, Wang J, Chen P, Jiang S (2019) Ellagic acid attenuates streptozocin induced diabetic nephropathy via the regulation of oxidative stress and inflammatory signaling. Food Chem Toxicol 123:16–27

    CAS  PubMed  Google Scholar 

  42. Busto R, Serna J, Cachero AP, Portillo RQ, Seisdedos DG, Duque AC et al (2018) Ellagic acid protects from myelin-associated sphingolipid loss in experimental autoimmune encephalomyelitis. BBA - Mol Cell Biol Lipids 1863:958–967

    CAS  Google Scholar 

  43. Ding X, Jian T, Wu Y, Zuo Y, Li J, Lv H et al (2019) Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose-treated HepG2 cells via miR-223/keap1-Nrf-2 pathway. Biomedicine Pharmacother 110:85–94

    CAS  Google Scholar 

  44. Makni M, Chtourou Y, Garoui EM, Boudawara T, Fetoui H (2012) Carbon tetrachloride-induced nephrotoxicity and DNA damage in rats: protective role of vanillin. Hum Exp Toxicol 31:844–852

    CAS  PubMed  Google Scholar 

  45. Mates JM, Perez-Gomez C, Nunez de Castro I (1999) Antioxidant enzymes and human diseases. Clinic Biochem 32:595–603

    CAS  Google Scholar 

  46. Padma VV, Selvi PK, Sravani S (2014) Protective effect of ellagic acid against TCDD-induced renal oxidative stress: Modulation of CYP1A1 activity and antioxidant defense mechanisms. Mol Biol Rep 41:4223–4232

    Google Scholar 

  47. Akkoyun HT, Karadeniz A (2015) Investigation of the protective effect of ellagic acid for preventing kidney injury in rats exposed to nicotine during the fetal period. Biotech Histochem 91(2):108–115

    PubMed  Google Scholar 

  48. Maher J, Yamamoto M (2010) The rise of antioxidant signaling–the evolution and hormetic actions of Nrf-2. Toxicol Appl Pharmacol 244(1):4–15

    CAS  PubMed  Google Scholar 

  49. Gao P, Li L, Ji L, Wei Y, Li H, Shang G et al (1839) (2014) Nrf-2 ameliorates diabetic nephropathy progression by transcriptional repression of TGFβ1 through interactions with c-Jun and SP1. Biochim Biophys Acta (BBA)-Gene Regul Mech 11:1110–1120

    Google Scholar 

  50. Cui G, ChuiWahLuk S, Lietal SRA (2015) Cytoprotection of baicalein against oxidative stress-induced cardiomyocytes injury through the Nrf-2/Keap1 pathway. J Cardiovasc Pharmacol 65(1):39–46

    CAS  PubMed  Google Scholar 

  51. Elgawish RA, Abdelrazek HMA, Ismail SAA, Loutfy NM (2019) Soliman MTA Hepato protective activity of Uncaria tomentosa extract against sub-chronic exposure to fipronil in male rats. Environ Sci Pollut Res 26:199–207

    CAS  Google Scholar 

  52. Polce SA, Burke C, França L, Kramer B, Paes AMDA, Carrillo-Sepulveda M (2018) Ellagic acid alleviates hepatic oxidative stress and insulin resistance in diabetic female rats. Nutrients 10(5):2–15

    Google Scholar 

  53. Bashir N, Manoharan V, Miltonprabu S (2016) Grape seed proanthocyanidins protects against cadmium induced oxidative pancreatitis in rats by attenuating oxidative stress, inflammation and apoptosis via Nrf-2/HO-1 signaling. J Nutr Biochem 32:128–141

    CAS  PubMed  Google Scholar 

  54. Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A, Badavi M (2019) Protective effects of naringin and trimetazidine on remote effect of acute renal injury on oxidative stress and myocardial injury through Nrf-2 regulation. Pharmacol Rep 71(6):1059–1066

    PubMed  Google Scholar 

  55. Srigopalram S, Ilavenil S, Jayraaj IA (2012) Apoptosis associated inhibition of DEN-induced hepatocellular carcinogenesis by ellagic acid in experimental rats. Biomed Prevent Nutr 2:1–8

    Google Scholar 

  56. Guada M, Ganugula R, Vadhanam M, Kumar MNVR (2017) Urolithin a mitigates cisplatin-induced nephrotoxicity by inhibiting renal inflammation and apoptosis in an experimental rat models. J Pharmacol Exp Ther 363:58–65

    CAS  PubMed  Google Scholar 

  57. Asci H, Ozmen O, Ellidag HY, Aydin B, Bas E, Yilmaz N (2017) The impact of gallic acid on the methotrexate-induced kidney damage in rats. J Food Drug Anal 25:890–897

    CAS  PubMed  Google Scholar 

  58. Aslan A, Hussein YT, Gok O, Beyaz S, Erman O, Baspinar S (2020) Ellagic acid ameliorates lung damage in rats via modulating antioxidant activities, inhibitory effects on inflammatory mediators and apoptosis-inducing activities. Environ Sci Pollut Res 27:7526–7537

    CAS  Google Scholar 

  59. Harikrishnan H, Jantan I, Haque MA, Kumolosasi E (2018) Antiinflammatory effects of Phyllanthus amarus Schum. & Thonn. through inhibition of NF-κB, MAPK, and PI3K-Akt signaling pathways in LPS-induced human macrophages. BMC Complement Altern Med 18(224):1–13

    Google Scholar 

  60. Rosillo MA, Hidalgo MS, CárdenoA SMA, Fidalgo SS, Villegas I, Lastra CA (2012) Dietary supplementation of an ellagic acid-enriched pomegranate extract attenuates chronic colonic inflammation in rats. Pharmacol Res 66:235–242

    CAS  PubMed  Google Scholar 

  61. Marin M, Giner RM, Ríos JL, Recio MC (2013) Intestinal antiinflammatory activity of ellagic acid in the acute and chronic dextrane sulfate sodium models of mice colitis. J Ethnopharmacol 150:925–934

    CAS  PubMed  Google Scholar 

  62. Gokdeniz D (2016) Expression of VEGF-A, FGF-2, VEGFR-2, VD105 (endoglin) in endometrioma cyst tissue and eutopic endometrium tissue in patient with endometrioma, determine serum and peritoneal fluid levels of VEGF-A, iron and ferritin. Medical specialty thesis, Dokuz Eylul University Institute of Health Sciences Izmir

  63. Youssef S, Salah M (2019) Differential expression of CD3, TNF-α, and VEGF induced by olanzapine on the spleen of adult male albino rats and the possible protective role of vitamin C. Biomedicines 7(2):39

    CAS  PubMed Central  Google Scholar 

  64. Aslan A, Can MI, Kuloglu T, Baspinar S (2016) Milk thistle may induce apoptosis in development of carbontetrachloride-induced liver DNA damage in rats. Prog Nutr 18:146–151

    Google Scholar 

  65. Aslan A, Boydak D, Can MI, Kuloglu T, Baspinar S (2016) Black cumin may be a potential drug for development of carbon-tetrachloride-induced lung damage in rats. Prog Nutr 18:56–62

    Google Scholar 

Download references

Funding

The article supported by Firat University Scientific Research Projects Unit (FUBAP) with FF.16.42 project number. In addition, some of the results of this article were presented at the 20th International Biotechnology Congress with International Participation, 10–12 October 2019, Baskent University–Ankara.

Author information

Authors and Affiliations

  1. Faculty of Science, Department of Biology-Molecular Biology and Genetics Program, Firat University, Elazig, Turkey

    Abdullah Aslan

  2. Faculty of Science, Department of Biology, Firat University, Elazig, Turkey

    Ozlem Gok, Seda Beyaz & Orhan Erman

  3. Faculty of Science, Department of Molecular Biology and Genetics, Bingol University, Bingol, Turkey

    Can Ali Ağca

  4. Veterinary Faculty, Department of Veterinary Parasitology, Mustafa Kemal University, Hatay, Turkey

    Aykut Zerek

Authors
  1. Abdullah Aslan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ozlem Gok
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seda Beyaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Can Ali Ağca
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Orhan Erman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aykut Zerek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdullah Aslan.

Ethics declarations

Conflict of interest

There are no conflicts of interests among the authors.

Ethical approval

All applicable international, national and institutional guidelines for the care and use of experimental animals were followed. The animal section of this study was performed by the approval of the Animal Experiments Ethics Committee of Firat University with the approval number of 14.03.2018 and decision number 61.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aslan, A., Gok, O., Beyaz, S. et al. Ellagic acid prevents kidney injury and oxidative damage via regulation of Nrf-2/NF-κB signaling in carbon tetrachloride induced rats. Mol Biol Rep 47, 7959–7970 (2020). https://doi.org/10.1007/s11033-020-05873-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05873-x

Keywords

Search

Navigation