Nephroprotective effect of Resveratrol against Methotrexate -induced renal toxicity in female rats

Year 2022, , 123 - 133, 26.08.2022

Şükriye Yeşilot , Meltem Özgöçmen

https://doi.org/10.24998/maeusabed.1136994

Cited By: 1

Abstract

The study purposed to appraise the nephroprotective effects of resveratrol-(RES) in relation to methotrexate-(MTX)-induced renal toxicity in female rats. The animals were allocated into three groups with six in each group: control, MTX:(15 mg/kg, only a dose, i.p), MTX+RES group: (15 mg/kg MTX, only a dose, i.p + 20 mg/kg RES, only a dose daily, oral gavage, 7 days). The nephroprotective efficacy was interpreted by measuring biochemical parameters such as serum renal function markers (uric acid, BUN and creatinine), total oxidant (TOS) and antioxidant status (TAS) in renal homogenates. Moreover, the effect of RES on kidneys was appraised by histopathological and immunohistochemical analyzes. In MTX-induced rats, RES treatment exhibited its nephroprotective effects with a significant increase in renal TAS as well as a significant decrease in serum BUN and renal TOS levels. In parallel with the biochemical data, it was observed that RES had a protective effect in the histological staining findings. Immunohistochemically, it was determined that TNF-α, one of the indicators of systemic inflammatory response, decreased with RES-treatment. The findings of the study show that RES administration 1 hour before MTX injection to rats has a curative effect on renal damage.

Keywords

Methotrexate, Resveratrol, Renal toxicity, female rats

Dişi sıçanlarda Resveratrol'ün Metotreksat ile indüklenen renal toksisiteye karşı nefroprotektif etkisi

Abstract

Reaktif oksijen türlerinin (ROS) güçlü bir temizleyicisi olan resveratrolün (RES), böbrek hastalıkları da dahil olmak üzere çeşitli metabolik bozukluklara karşı koruyucu etkisi olduğu bildirilmektedir. Bu çalışma, dişi sıçanlarda metotreksat (MTX) ile indüklenen renal toksisitede resveratrolün nefroprotektif etkilerini değerlendirmeyi amaçlamaktadır. Çalışma, her grupta altı adet rat olacak şekilde üç gruba ayrıldı: Kontrol, MTX: (15 mg/kg, tek doz, i.p), MTX + RES grubu: (15 mg/kg MTX, tek doz, i.p + 20 mg/ kg RES, günde tek doz, oral gavaj, 7 gün). Serum renal fonksiyon belirteçleri (ürik asit, BUN ve kreatinin), renal homojenatlarda toplam oksidan (TOS) ve antioksidan durumu (TAS) gibi biyokimyasal parametreler ölçülerek nefroprotektif etkinlik yorumlandı. Ayrıca RES'in böbrekler üzerindeki etkisi histopatolojik ve immünohistokimyasal analizlerle değerlendirildi. MTX ile indüklenen ratlarda RES tedavisi, serum BUN, kreatinin ve renal TOS düzeylerinde anlamlı azalmanın yanında renal TAS'ta anlamlı bir artışla nefro-koruyucu etkilerini gösterdi. Histolojik boyama bulgularında da biyokimyasal verilere paralel olarak, RES’in koruyucu etkisinin olduğu gözlendi. İmmünhistokimyasal olarak sistemik inflamatuar yanıtın göstergelerinden biri olan TNF-α'nın RES tedavisi ile azaldığı belirlendi. Araştırmanın bulguları, ratlara MTX enjeksiyonundan 1 saat önce RES uygulamasının böbrek hasarı üzerinde iyileştirici etkisi olduğunu göstermektedir.

Keywords

Metotreksat, Resveratrol, Böbrek toksisitesi, dişi sıçanlar

References

• Abdel-Raheem, I.T., Khedr, N.F., 2014. Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats, Naunyn Schmiedebergs Arch. Pharmacol. 387;341–353, http://dx.doi.org/10.1007/s00210-013-0949-x
• Abouelela, M.E., Orabi, M.A.A., Abdelhamid, R.A., Abdelkader, M.S., Madkor, H.R., Darwish, F.M.M., Hatano, T., Elsadek, B.E.M., 2020. Ethyl acetate extract of Ceiba pentandra (L.) Gaertn. reduces methotrexate-induced renal damage in rats via antioxidant, anti-inflammatory, and antiapoptotic actions. J Tradit Complement Med. 10(5):478-86. https://doi.org/10.1016/j.jtcme.2019.08.006
• Ahmed, W., Zaki, A.M.R. and Nabil, T., 2015. Prevention of methotrexate-induced nephrotoxicity by concomitantadministration of garlic aqueous extract in rat. Turkish Journal of Medical Sciences. 45(3) 1408-121.
• Akbel, E., Arslan-Acaroz, D., Demirel, H.H., Kucukkurt, I., Ince, S., 2018. The subchronic exposure to malathion, an organophosphate pesticide, causes lipid peroxidation, oxidative stress, and tissue damage in rats: the protective role of resveratrol, Toxicology Research. 7;3,503–512, https://doi.org/10.1039/c8tx00030a
• Armagan, I., Bayram, D., Candan, I.A., Yigit, A., Celik, E., Armagan, H.H. et al., 2015. Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats. Environ Toxicol Pharmacol, 39(3);1122-1131
• Asci, H., Ozmen, O., Ellidag, H.Y., 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.
• Baur, J., Sinclair, D., 2006. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5, 493–506. https://doi.org/10.1038/nrd2060
• Bay Karabulut A., 2008. Resveratrol and it's effects. Turkiye Klinikleri Journal of Medical Sciences. 28(Suppl):166-169
• Bedoui, Y., Guillot, X., Sélambarom, J., Guiraud, P., Giry, C., Jaffar-Bandjee, M.C., Ralandison, S., Gasque, P., 2019. Methotrexate an Old Drug with New Tricks. Int. J. Mol. Sci. 20(20):5023. doi: 10.3390/ijms20205023.
• Baud, L., Ardaillou, R., 1995. Tumor necrosis factor in renal injury. Miner Electrolyte Metab. 21:336–41.
• Braun, J., Rau, R., 2009. An update on methotrexate. Curr Opin Rheumatol. 21(3):216-23.
• Brown, V., K. Patel, M. Viskaduraki, et al . 2010. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics and effect on the insulin-like growth factor axis. Cancer Res. 70: doi. 10.1158/0008-5472.CAN-10-2364.
• Calamini, B., K. Ratia, M.G. Malkowski, et al . 2010. Pleiotropic mechanisms facilitated by resveratrol and its metabolites. Biochem. J. 429: 273– 282.
• Chan, E.S.L., Cronstein, B.N., 2013. Mechanisms of action of methotrexate. Bull. NYU Hosp. Jt. Dis. 71:S5–S8
• Çakır, T., Polat, C., Baştürk, A., Gül, M., Aslaner, A., Durgut, H., Şehirli, A.Ö., Aykaç, A., Bahar, Lç, Sabuncuoglu, M.Z., 2015. The effect of alpha lipoic acid on rat kidneys in methotrexate induced oxidative injury. Eur Rev Med Pharmacol Sci. 19(11):2132-9. PMID: 26125279.
• Drishya, S., Dhanisha, S. S., & Guruvayoorappan, C., 2022. Antioxidant-rich fraction of Amomum subulatum fruits mitigates experimental methotrexate-induced oxidative stress by regulating TNF-α, IL-1β, and IL-6 proinflammatory cytokines. Journal of Food Biochemistry. 46;e13855. https://doi.org/10.1111/jfbc.13855
• Elmarakby, A.A. and Sullivan, J.C., 2012. Relationship between Oxidative Stress and Inflammatory Cytokines in Diabetic Nephropathy. Cardiovascular Therapeutics, 30: 49-59. https://doi.org/10.1111/j.1755-5922.2010.00218.x
• Elmansy, R.A., Seleem, H.S., Mahmoud, A.R., Hassanein, E.H., Ali, F.E., 2021. Rebamipide potentially mitigates methotrexate-induced nephrotoxicity via inhibition of oxidative stress and inflammation: a molecular and histochemical study. Anat Rec. 304:647–661.
• El-Sheikh, A.A.K., Morsy, M.A. and Al-Taher, A.Y., 2016. Protective mechanisms of resveratrol against methotrexate-induced renal damage may involve BCRP/ABCG2. Fundam Clin Pharmacol, 30: 406-418. https://doi.org/10.1111/fcp.12205
• El-Sheikh, A.A., Morsy, M.A., Okasha, A.M., 2017. Inhibition of NF-kappaB/TNF-alpha pathway may be involved in the protective effect of resveratrol against cyclophosphamide-induced multi-organ toxicityImmunopharmacol. Immunotoxicol. 39 (4);180-187
• Erboga, M., Aktas, C., Fidanol Erboga, Z., Bozdemir Donmez, Y. & Gurel, A., 2015. Quercetin ameliorates methotrexate-induced renal damage, apoptosis and oxidative stress in rats, Renal Failure. 37:9, 1492-1497, DOI: 10.3109/0886022X.2015.1074521
• Fremont, L., 2000. Biological effects of resveratrol.Life Sci.66;663– 673
• Gaies, E., Jebabli, N., Trabelsi, S., Salouage, I., Charfi, R. et al., 2012. Methotrexate Side Effects: Review Article. J Drug Metab Toxicol 3:125. doi:10.4172/2157-7609.1000125
• Green, M.R., Chamberlain, M.C., 2009. Renal dysfunction during and after high-dose methotrexate. Cancer Chemother Pharmacol. 63, 599. https://doi.org/10.1007/s00280-008-0772-0
• Gunyeli, I., Saygin, M. & Ozmen, O.,2021. Methotrexate-induced toxic effects and the ameliorating effects of astaxanthin on genitourinary tissues in a female rat model. Arch Gynecol Obstet 304, 985–997 https://doi.org/10.1007/s00404-021-06000-2
• Heidari, R., Ahmadi, A., Mohammadi, H., Ommati, M.M., Azarpira, N., Niknahad, H., 2018. Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance, Biomedicine & Pharmacotherapy. 107;834-840.
• Hobl, E-L., Mader, R.M., Erlacher, L., Duhm, B., Mustak, M., Bröll, H., et al., 2011. The influence of methotrexate on the gene expression of the pro-inflammatory cytokine IL-12A in the therapy of rheumatoid arthritis. Clin Exp Rheumatol. 29:963–969
• Jang, I-A., Kim, E.N., Lim, J.H., Kim, M.Y., Ban, T.H., Yoon, H.E., Park, C.W., Chang, Y.S., Choi, B.S., 2018. Effects of Resveratrol on the Renin-Angiotensin System in the Aging Kidney. Nutrients. 10(11):1741. https://doi.org/10.3390/nu10111741
• Ju, HQ., Lin, JF., Tian, T. et al., 2020. NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Sig Transduct Target Ther 5, 231. https://doi.org/10.1038/s41392-020-00326-0
• Kandemir, F.M., Kucukler, S., Caglayan, C., Gur, C., Batil, A.A., Gülçin, İ., 2017. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 41:e12398.
• Kar, F., Hacioglu, C., Senturk, H. et al., 2020. The Role of Oxidative Stress, Renal Inflammation, and Apoptosis in Post Ischemic Reperfusion Injury of Kidney Tissue: the Protective Effect of Dose-Dependent Boric Acid Administration. Biol Trace Elem Res 195, 150–158. https://doi.org/10.1007/s12011-019-01824-1
• Kaundal, U., Khullar, A., Leishangthem, B., et al., 2021. The effect of methotrexate on neutrophil reactive oxygen species and CD177 expression in rheumatoid arthritis. Clinical and experimental rheumatology. 39(3):479-486.
• Khan, Z.A., Tripathi, R., Mishra, B., 2012. Methotrexate: a detailed review on drug delivery and clinical aspects, Expert Opin. Drug Deliv. 9(2);151–169, http://dx.doi.org/10.1517/17425247.2012.642362.
• Kitada, M., Koya, D., 2013. Renal protective effects of resveratrol. Oxid Med Cell Longev. 2013: 568093.
• Kocaman, N., Colakoglu, N., 2013. Effects of Repeated Doses Administration of Methotrexate on Rat Kidney Tissue. Firat Med J. 18(4):198–202
• Kremer, J.M., 2004. Toward a Better Understanding of Methotrexate. Arthritis Rheum. 50: 1370–1382
• Kwiatkowska, E., Domański, L., Dziedziejko, V., Kajdy, A., Stefańska, K., Kwiatkowski, S., 2021. The Mechanism of Drug Nephrotoxicity and the Methods for Preventing Kidney Damage. Int. J. Mol. Sci. 22, 6109. https://doi.org/10.3390/ijms22116109
• Malhotra, A., Bath, S., Elbarbry, F., 2015. An Organ System Approach to Explore the Antioxidative, Anti-Inflammatory, and Cytoprotective Actions of Resveratrol. Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 803971, 15 pages. https://doi.org/10.1155/2015/803971
• Navarro, J.F., Mora-Fernández, C., 2006. The role of TNF-α in diabetic nephropathy: Pathogenic and therapeutic implications, Cytokine & Growth Factor Reviews. 17(6);441-450
• Nunes, T., L. Almeida, J.F. Rocha, et al . 2009. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J. Clin. Pharmacol. 49: 1477– 1482.
• Özgöçmen, M. & Yeşilot, Ş., 2021. The role of resveratrol in hepatotoxicity caused by methotrexate . Veterinary Journal of Mehmet Akif Ersoy University , 6 (2) , 57-63 . DOI: 10.24880/maeuvfd.922106
• Perazella, M.A., 2009. Renal Vulnerability to Drug Toxicity. Clin J Am Soc Nephrol 4: 1275–1283. doi: 10.2215/CJN.02050309
• Refaiy, A., Muhammad, E., ElGanainy, E.O., 2011. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimens in cases of urinary bladder carcinoma. African J Urol. 17(1);6-10)
• Saldanha, J. F., Leal Vde, O., Stenvinkel, P., Carraro-Eduardo, J. C., & Mafra, D., 2013. Resveratrol: Why is it a promising therapy for chronic kidney disease patients? Oxidative Medicine and Cellular Longevity, 2013, 963217.
• Savran, M., Cicek, E., Doguc, D.K. et al., 2017. Vitamin C attenuates methotrexate-induced oxidative stress in kidney and liver of rats. Physiology International. 104 (2): 139–149.
• Sesti, F., Tsitsilonis, O.E., Kotsinas, A., Trougakos I.P., 2012. Oxidative stress-mediated biomolecular damage and inflammation in tumorigenesis In Vivo, 26;395-402
• Shah, V.V., Lin, E.J., Reddy, S.P., Wu, J.J., 2016. Chapter 4 - Methotrexate. In: Wu JJ, Feldman SR, Lebwohl MG (eds) Therapy for severe psoriasis. Elsevier, Philadelphia, pp 37–48
• Shahbazi, F., Farvadi, F., Dashti-Khavidaki, S. et al., 2020. Potential nephroprotective effects of resveratrol in drug induced nephrotoxicity: a narrative review of safety and efficacy data. Adv Tradit Med (ADTM) 20, 529–544. https://doi.org/10.1007/s13596-020-00432-y
• Silan, C., Uzun, O., Comunoglu, N.U., Gokcen, S., Bedirhan, S., Cengiz, M., 2007. Gentamicin-induced nephrotoxicity in rats ameliorated and healing effects of resveratrol. Biol Pharm Bull 30:79–83
• Singh, N.P., Ganguli, A., Prakash, A., 2003. Drug-induced kidney diseases. J Assoc Physicians India. 51:970-9. PMID: 14719587.
• Sotoudehmanesh, R., Anvari, B., Akhlaghi, M., Shahraeeni, S., & Kolahdoozan, S., 2010. Methotrexate hepatotoxicity in patients with rheumatoid arthritis. Middle East journal of digestive diseases, 2(2), 104–109.
• Soylu Karapinar, O., Pinar, N., Özcan, O, Özgür, T. & Dolapçıoğlu, K., 2017. Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats, Gynecological Endocrinology, 33:8, 653-659, DOI: 10.1080/09513590.2017.1306847
• Taghizadieh, M., Afshari, F., Shokri, N., & Hajipour, B., 2014. Protective Role of Vitamin E on Methotrexate Induced Renal Injury in Rabbits. Galen Medical Journal, 3(3), 194-99. https://doi.org/10.31661/gmj.v3i3.170
• Tambağ, A.K., Kazak, F., Peker Akalın, P., Kutlu, T., 2021. The protective effect of rutin against methotrexate-induced nephrotoxicity in rats. Turk J Nephrol. 30(3): 218-223.
• Tucker, P.S., Scanlan, A.T., Dalbo, V.J., 2015. Chronic Kidney Disease Influences Multiple Systems: Describing the Relationship between Oxidative Stress, Inflammation, Kidney Damage, and Concomitant Disease. Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 806358, 8 pages.. https://doi.org/10.1155/2015/806358
• Wang, M., Weng, X., Chen, H., Chen, Z., Liu X., 2020. Resveratrol inhibits tnf-α-induced inflammation to protect against renal ischemia/reperfusion injury in diabetic rats. Acta Cir. Bras. 35(5);1-8
• Wang, X., Meng, L., Zhao, L., et al., 2017. Resveratrol ameliorates hyperglycemia-induced renal tubular oxidative stress damage via modulating the SIRT1/FOXO3a pathway. Diabetes Res Clin Pract. 126: 172- 181.
• Widemann, B.C., Adamson, P.C., 2006. Understanding and managing methotrexate nephrotoxicity, Oncologist 11(6);694–703.
• Yeung, A.W.K., Aggarwal B.B. et al., 2019. Resveratrol, a popular dietary supplement for human and animal health: Quantitative research literature analysis - a review. Animal Science Papers and Reports, 37(2), 103–118.
• Yu, C., Shin, Y.G., Chow, A. et al., 2002. Human, Rat, and Mouse Metabolism of Resveratrol. Pharm Res 19, 1907–1914. https://doi.org/10.1023/A:1021414129280
• Yu, M., Xue, J., Li, Y. et al., 2013. Resveratrol protects against arsenic trioxide-induced nephrotoxicity by facilitating arsenic metabolism and decreasing oxidative stress. Arch Toxicol. 87, 1025–1035 https://doi.org/10.1007/s00204-013-1026-4
• Yuksel, Y., Yuksel, R., Yagmurca, M., et al., 2017. Effects of quercetin on methotrexate-induced nephrotoxicity in rats. Human & Experimental Toxicology. 51-61. doi:10.1177/0960327116637414
• Yuluğ, E., Türedi, S., Alver, A., Türedi, S., Kahraman, C., 2013. Effects of Resveratrol on Methotrexate-Induced Testicular Damage in Rats. The Scientific World Journal, vol. 2013, Article ID 489659, 6 pages, https://doi.org/10.1155/2013/489659
• Zhang, W., Liu, Y., Ge, M., Jing, J., Chen, Y., Jiang, H., Yu, H., Li, N., Zhang Z., 2014. Protective effect of resveratrol on arsenic trioxide-induced nephrotoxicity in rats Nutr. Res. Pract., 8, 220, 10.4162/nrp.2014.8.2.220