Skip to main content
SpringerLink
Log in

The renoprotective effects of gallic acid on cisplatin-induced nephrotoxicity through anti-apoptosis, anti-inflammatory effects, and downregulation of lncRNA TUG1

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Cisplatin, an antineoplastic drug used in cancer therapy, -induced nephrotoxicity mediated by the production of reactive oxygen species (ROS). Gallic acid (GA) is identified as an antioxidant substance with free radical scavenging properties. This research was designed to examine the ameliorative impact of GA caused by cisplatin-induced nephrotoxicity through apoptosis and long non-coding RNA (lncRNA) Taurine-upregulated gene 1 (TUG1) expression. Thirty-two male Sprague Dawley rats (200 − 220 g) were randomly allocated to four groups: (1) control group; (2) rats treated with cisplatin (7.5 mg/kg, i.p.) on the fourth day; and the two other groups include rats pretreated with GA (20 and 40 mg/kg by gavage) for s7 days and cisplatin (7.5 mg/kg, i.p.) at the fourth day. The rats were anesthetized and sacrificed for collecting samples, 72 h after cisplatin administration. The blood samples were used to investigate biochemical factors and kidney tissue was evaluated for measuring oxidative stress and inflammatory factors and the gene expression of molecular parameters. The results indicated that GA administration increased the B-cell lymphoma-2 (Bcl-2) mRNA and lncRNA TUG1 expression, and reduced Bcl-2-associated x protein (Bax), and caspase-3 expression. Likewise, the TAC level increased, and kidney MDA content decreased by administration of GA. GA also decreased the inflammatory factor levels, including IL-1β and TNF-α. Moreover, GA led to the improvement of kidney dysfunction as evidenced by reducing plasma BUN (blood urea nitrogen) and Cr (creatinine). Taken together, GA could protect the kidney against cisplatin-induced nephrotoxicity through antioxidant, anti-inflammatory, and anti-apoptosis properties and reduction of lncRNA TUG1 expression.

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
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All data analyzed during this study are included in this article as single values within the graphs.

Abbreviations

ROS:

Reactive oxygen species

GA:

Gallic acid

LncRNA:

Long non-coding RNA

TUG1:

Taurine-upregulated gene 1

Bcl-2:

B-cell lymphoma-2

Bax:

Bcl-2 associated x protein

IL-1β:

Interleukin-1β

TNF-α:

Tumor necrosis factor-α

NF-κB:

Nuclear factor-kappa

BUN:

Blood urea nitrogen

Cr:

Creatinine

AKI:

Acute kidney injury

CKD:

Chronic kidney diseases

PBS:

Phosphate-buffered saline

TAC:

Total antioxidant capacity

MDA:

Malondialdehyde

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

H&E:

Hematoxylin and eosin

I/R:

Ischemia-reperfusion

GPX :

Glutathione peroxidase

CAT:

Catalase

SOD:

Superoxide dismutase

GSH:

Glutathione

MPTP:

Mitochondrial permeability transition pore

MEG3:

Maternally expressed gene 3

References

  • Ahmadvand H, Yalameha B, Adibhesami G, Nasri M, Naderi N, Babaeenezhad E, Nouryazdan N (2019) The protective role of gallic acid pretreatment on renal ischemia-reperfusion injury in rats. Rep Biochem Mol Biol 8(1):42–48

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akomolafe SF, Akinyemi AJ, Anadozie SO (2014) Phenolic acids (gallic and tannic acids) modulate antioxidant status and cisplatin-induced nephrotoxicity in rats. Int Sch Res Notices 11(2014):984709. https://doi.org/10.1155/2014/984709

    Article  Google Scholar 

  • Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A, Badavi M (2019a) 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

    Article  PubMed  Google Scholar 

  • Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A (2019b) Badavi M (2019b) The renoprotective effects of naringin and trimetazidine on renal ischemia/reperfusion injury in rats through inhibition of apoptosis and downregulation of micoRNA-10a. Biomed Pharmacother 112(7):108568. https://doi.org/10.1016/j.biopha.2019.01.029

    Article  CAS  PubMed  Google Scholar 

  • Bai J, Zhang Y, Tang C, Hou Y, Ai X, Chen X, Zhang Y, Wang X, Meng X (2021) Gallic acid: pharmacological activities and molecular mechanisms involved in inflammation-related diseases. Biomed Pharmacother. 133:110985

    Article  CAS  PubMed  Google Scholar 

  • Bär C, Chatterjee S, Thum T (2016) Long noncoding RNAs in cardiovascular pathology, diagnosis, and therapy. Circulation 134(19):1484–1499

    Article  PubMed  CAS  Google Scholar 

  • Barabas K, Milner R, Lurie D, Adin C (2008) Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 6(1):1–18

    Article  CAS  PubMed  Google Scholar 

  • Baradaran A, Nasri H, Rafieian-Kopaei M (2015) Protection of renal tubular cells by antioxidants: current knowledge and new trends. Cell J (Yakhteh). 16(4):568–71

    PubMed Central  Google Scholar 

  • Belayev LY, Palevsky PM (2014) The link between AKI and CKD. Curr Opin Nephrol Hyper 23(2):149–154

    Article  CAS  Google Scholar 

  • Borkan SC (2016) The role of BCL-2 family members in acute kidney injury. Semin Nephrol 36(3):237–250. https://doi.org/10.1016/j.semnephrol.2016.04.001

    Article  CAS  PubMed  Google Scholar 

  • Cadenas S (2018) ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med 117:76–89

    Article  CAS  PubMed  Google Scholar 

  • Canbek M, Ustuuml MC, Kabay S, Uysal O, Ozden H, Sentuuml H, Ozbayar C, Ustuuml D, Degirmenci I (2011) The effect of gallic acid on kidney and liver after experimental renal ischemia/reperfusion injury in the rats. Afr J Pharmacy Pharmacol 5(8):1027–1033

    CAS  Google Scholar 

  • Canbek M, Bayramoglu G, Senturk H, Ap OV, Uyanoglu M, Ceyhan E, Ozen A, Durmus B, Kartkaya K, Kanbak G (2014) The examination of protective effects of gallic acid against damage of oxidative stress during induced-experimental renal ischemia-reperfusion in experiment. Bratisl Lek Listy. 115(9):557–62

    CAS  PubMed  Google Scholar 

  • Chowdhury S, Sinha K, Banerjee S, Sil PC (2016) Taurine protects cisplatin-induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses. BioFactors 42(6):647–664

    Article  CAS  PubMed  Google Scholar 

  • Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A (2006) Biomarkers of oxidative damage in human disease. Clin Chem 52(4):601–623

    Article  CAS  PubMed  Google Scholar 

  • De Mendonça A, Vincent JL, Suter P, Moreno R, Dearden N, Antonelli M, Takala J, Sprung C, Cantraine F (2000) Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med 26(7):915–921

    Article  PubMed  Google Scholar 

  • Doi K, Rabb H (2016) Impact of acute kidney injury on distant organ function: recent findings and potential therapeutic targets. Kidney Int. 89(3):555–64

    Article  PubMed  Google Scholar 

  • Fuschi P, Carrara M, Voellenkle C, Garcia-Manteiga JM, Righini P, Maimone B, Sangalli E, Villa F, Specchia C, Picozza M (2017) Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. Aging (albany, NY) 9(12):2559–2586

    Article  CAS  Google Scholar 

  • Gaschler MM, Stockwell BR (2017) Lipid peroxidation in cell death. Biochem Biophys Res Commun 482(3):419–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghafouri-Fard S, Shoorei H, Taheri M (2020) Non-coding RNAs are involved in the response to oxidative stress. Biomed Pharmacother. 127:110228

    Article  CAS  PubMed  Google Scholar 

  • Gholamine B, Houshmand G, Hosseinzadeh A, Kalantar M, Mehrzadi S, Goudarzi M (2021) Gallic acid ameliorates sodium arsenite-induced renal and hepatic toxicity in rats. Drug Chemi Toxicol 44(4):341–352

    Article  CAS  Google Scholar 

  • Hanigan MH, Devarajan P (2003) Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 1:47

    PubMed  PubMed Central  Google Scholar 

  • Harries LW (2012) Long non-coding RNAs and human disease. Bioch Soc Trans 40(4):902–906

    Article  CAS  Google Scholar 

  • Havasi A, Borkan SC (2011) Apoptosis and acute kidney injury. Kidney Int 80(1):29–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jassem W, Fuggle SV, Rela M, Koo DD, Heaton ND (2002) The role of mitochondria in ischemia/reperfusion injury. Transplantation 73(4):493–499

    Article  CAS  PubMed  Google Scholar 

  • Jayle C, Favreau F, Zhang K, Doucet C, Goujon JM, Hebrard W, Carretier M, Eugene M, Mauco G, Tillemen JP (2007) Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model. Am J Physiol Renal Physiol 292(3):F1082–F1093

    Article  CAS  PubMed  Google Scholar 

  • Jeong HJ, Koo HN, Na HJ, Kim MS, Hong SH, Eom JW, Kim KS, Shin TY, Kim HM (2002) Inhibition of TNF-α and IL-6 production by aucubin through blockade of NF-κB activation in RBL-2H3 mast cells. Cytokine 18(5):252–259

    Article  CAS  PubMed  Google Scholar 

  • Jing X, Han J, Zhang J, Chen Y, Yuan J, Wang J, Neo S, Li S, Yu X, Wu J (2021) Long non-coding RNA MEG3 promotes cisplatin-induced nephrotoxicity through regulating AKT/TSC/mTOR-mediated autophagy. Int J Biol Sci 17(14):3968–3980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kölling M, Genschel C, Kaucsar T, Hübner A, Rong S, Schmitt R, Sörensen-Zender I, Haddad G, Kistler A, Seeger H, Kielstein JT, Fliser D, Haller H, Wüthrich R, Zörnig M, Thum T, Lorenzen JJ (2018) Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury. Sci Rep 8:3438

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu Z, Wang X, Wang Y, Zhao M (2017) NLRP3 inflammasome activation regulated by NF-κB and DAPK contributed to paraquat-induced acute kidney injury. Immunol Res 65(3):687–698

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Wang Y, Shu S, Cai J, Tang C, Dong Z (2019) Non-coding RNAs in kidney injury and repair. Am J Physiol Cell Physiol 317(2):C177–C188

    Article  CAS  PubMed  Google Scholar 

  • Long J, Badal SS, Ye Z, Wang Y, Ayanga BA, Galvan DL, Green NH, Chang BH, Overbeek PA, Danesh FR (2016) Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy. J Clin Invest 126(11):4205–4218

    Article  PubMed  PubMed Central  Google Scholar 

  • Lorenzen JM, Thum T (2016) Long noncoding RNAs in kidney and cardiovascular diseases. Nat Rev Nephrol. 12(6):360–73

    Article  CAS  PubMed  Google Scholar 

  • Maiorino M, Conrad M, Ursini F (2018) GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxid Redox Sign 29(1):61–74

    Article  CAS  Google Scholar 

  • Mansouri MT, Farbood Y, Sameri MJ, Sarkaki A, Naghizadeh B, Rafeirad M (2013) Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Food Chem 138(2–3):1028–1033

    Article  CAS  PubMed  Google Scholar 

  • Nouri A, Heibati F, Heidarian E (2021) Gallic acid exerts anti-inflammatory, anti-oxidative stress, and nephroprotective effects against paraquat-induced renal injury in male rats. Naunyn Schmiedeberg’s Arch Pharmacol 394(1):1–9

    Article  CAS  Google Scholar 

  • Okusa MD, Jaber BL, Doran P, Duranteau J, Yang L, Murray PT, Mehta RL, Ince C (2013) Physiological biomarkers of acute kidney injury: a conceptual approach to improving outcomes. Contrib Nephrol 182:65–81

    Article  PubMed  Google Scholar 

  • Olayinka E, Ore A, Adeyemo O, Ola O (2016) Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity and nephrotoxicity in rat. J Xenobiot 6(1):14–18

    Article  Google Scholar 

  • Ozkok A, Edelstein CL (2014) Pathophysiology of cisplatin-induced acute kidney injury. Bio Med Res Int 2014:967826. https://doi.org/10.1155/2014/967826

    Article  CAS  Google Scholar 

  • Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73(9):994–1007

    Article  CAS  PubMed  Google Scholar 

  • Perazella MA, Moeckel GW (2010) Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy. Semin Nephrol 30(6):570–81

    Article  CAS  PubMed  Google Scholar 

  • Priscilla DH, Prince PSM (2009) Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats. Chem Biol Interact 179(2–3):118–124

    Article  CAS  PubMed  Google Scholar 

  • Ramesh G, Reeves WB (2004) Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-α. Kidney Int 65(2):490–498

    Article  CAS  PubMed  Google Scholar 

  • Reckziegel P, Dias VT, Benvegnu DM, Boufleur N, Barcelos RCS, Segat HJ, Pase CS, Dos Santos CMM, Flores ÉMM, Bürger ME (2016) Antioxidant protection of gallic acid against toxicity induced by Pb in blood, liver and kidney of rats. Toxicol Rep 3:351–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su S, Liu J, He K, Zhang M, Feng C, Peng F, Li B, Xia X (2016) Overexpression of the long noncoding RNA TUG 1 protects against cold-induced injury of mouse livers by inhibiting apoptosis and inflammation. The FEBS J 283(7):1261–1274

    Article  CAS  PubMed  Google Scholar 

  • Xu Jj, Zhen Jt, Tang L, Qm Lin (2017) Intravenous injection of Xuebijing attenuates acute kidney injury in rats with paraquat intoxication. World J Emerg Med. 8(1):61

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Deng W, Zhang W (2018) Long non-coding RNA TUG1 protects renal tubular epithelial cells against injury induced by lipopolysaccharide via regulating microRNA-223. Biomed Pharmacother 104:509–519

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Niu Y, Li H (2020) Pan G (2020) Downregulation of lncRNA TUG1 attenuates inflammation and apoptosis of renal tubular epithelial cell induced by ischemia-reperfusion by sponging miR-449b-5p via targeting HMGB1 and MMP2. Inflammation 43(4):1362–1374

    Article  CAS  PubMed  Google Scholar 

  • Yang B, Jain S, Ashra SY, Furness PN, Nicholson ML (2006) Apoptosis and caspase-3 in long-term renal ischemia/reperfusion injury in rats and divergent effects of immunosuppressants. Transplantation 81(10):1442–1450

    Article  CAS  PubMed  Google Scholar 

  • Yu W, Sheng M, Xu R, Yu J, Cui K, Tong J, Shi L, Ren H, Du H (2013) Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. J Transl Med 11(1):1–10

    Article  CAS  Google Scholar 

  • Zhang J, Zhu Y, Wang R (2018) Long noncoding RNAs in respiratory diseases. Histol Histopathol 33(8):747–756

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to express their gratitude for the assistance of the Persian Gulf Physiology Research Center of Ahvaz Jundishapur University of Medical Sciences.

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Negin Amini, Mohammad Badavi, Seyyed Ali Mard & Mahin Dianat

  2. The Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Negin Amini, Mohammad Badavi, Seyyed Ali Mard & Mahin Dianat

  3. Department of Anatomical Science, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mahin Taheri Moghadam

  4. Fertility, Infertility and Perinatology Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mahin Taheri Moghadam

Authors
  1. Negin Amini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Badavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seyyed Ali Mard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahin Dianat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahin Taheri Moghadam
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NA designed the study, performed the experiments, analyzed the data, and wrote the manuscript; MB designed and edited the study; MD edited the manuscript; AM performed the molecular parameters; MT performed the histopathological assay. All authors read and approved the manuscript and all data were generated in-house and no paper mill was used (APRC-9907).

Corresponding author

Correspondence to Mohammad Badavi.

Ethics declarations

Ethics approval

The whole protocol of the research was approved by the Ahvaz Jundishapur University of Medical Sciences (IR.AJUMS.ABHC.REC.1399.044).

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 11 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amini, N., Badavi, M., Mard, S.A. et al. The renoprotective effects of gallic acid on cisplatin-induced nephrotoxicity through anti-apoptosis, anti-inflammatory effects, and downregulation of lncRNA TUG1. Naunyn-Schmiedeberg's Arch Pharmacol 395, 691–701 (2022). https://doi.org/10.1007/s00210-022-02227-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-022-02227-1

Keywords

Search

Navigation