Melatonin alleviates oxidative stress, inflammation, apoptosis, and DNA damage in acrylamide-induced nephrotoxicity in rats

Abstract

Objective: To investigate the effects of melatonin on renal inflammation, oxidative stress, apoptosis, as well as DNA and tissue damage in acrylamide-induced nephrotoxicity in rats. Methods: Fifty male rats were randomly divided into five groups. The control group received distilled water by gastric lavage for 11 days and the acrylamide group was administered acrylamide (50 mg/kg, i.g.) for 11 days. The MEL10+ACR and MEL20+ACR groups received intraperitoneal melatonin 10 and 20 mg/kg, respectively, for 11 days, and acrylamide (50 mg/kg, i.g.) was administered 1 h after melatonin injection. The MEL20 group was injected with melatonin (20 mg/kg) for 11 days. Kidney function tests were performed and biochemical and inflammatory parameters were determined. In addition, histopathological, immunohistochemical, and immunofluorescence examinations were carried out. Results: Melatonin significantly abated acrylamide-induced rise in serum urea and creatinine levels. Acrylamide caused oxidative stress, inflammation, apoptosis, as well as DNA and tissue damage in the kidneys. Melatonin treatment alleviated acrylamide-induced renal damage by exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, melatonin significantly ameliorated acrylamide-caused histopathological changes in kidney tissue. Conclusions: Melatonin attenuates acrylamide-induced renal oxidative stress, inflammation, apoptosis, and DNA damage in rats.

Keywords

Acrylamide / Apoptosis / Inflammation / Melatonin / Nephrotoxicity / Oxidative stress / Rat

Conflict of interest statement

The authors declare that they have no conflict of interest.

Funding

This research was supported by Atatürk University Scientific Research Projects Coordinatorship (BAP) with the project code 2021-8836.

Authors’ contributions

HA, EŞ, FI, and SY contributed to experimental design and experiment implementation. EŞ and FI performed biochemical analyses and evaluations. SY performed the histopathological, immunohistochemical, and immunofluorescent examination. HA, EŞ, SY, and FI contributed to the writing and editing of the article and read and approved the final text.

References

[1] Tareke E, Rydberg P, Karlsson P, Eriksson S, Tornqvist M. Analysis of acrylamide, a carcinogen formed in heated foodstuffs. J Agric Food Chem 2002; 50(17): 4998-5006.

[2] Reynolds T. Acrylamide and cancer: Tunnel leak in Sweden prompted studies. J Nati Cancer Inst 2002; 94: 876-878.

[3] Sumner SCJ, Williams CC, Snyder RW, Krol WL, Asgharian B, Fennell TR. Acrylamide: A comparison of metabolism and hemoglobin adducts in rodents following dermal, intraperitoneal, oral, or inhalation exposure. Toxicol Sci 2003; 75: 260-270.

[4] Gur C, Kandemir FM, Darendelioglu E, Caglayan C, Kucukler S, Kandemir O, et al. Morin protects against acrylamide-induced neurotoxicity in rats: An investigation into different signal pathways. Environ Sci Pollut Res 2021; 28(36): 49808-49819.

[5] Yesildag K, Eroz R, Genc A, Dogan T, Satici E. Evaluation of the protective effects of morin against acrylamide-induced lung toxicity by biomarkers of oxidative stress, inflammation, apoptosis, and autophagy. J Food Biochem 2022; 46(7): e14111.

[6] Dearfield KL, Douglas GR, Ehling UH, Moore MM, Sega GA, Brusick DJ. Acrylamide-a review of its genotoxicity and an assessment of heritable genetic risk. Mutat Res Fund Mol Mech Mutagen 1995; 330(1-2): 71-99.

[7] Kucukler S, Caglayan C, Darendelioglu E, Kandemir FM. Morin attenuates acrylamide-induced testicular toxicity in rats by regulating the NF-κB, Bax/Bcl-2 and PI3K/Akt/mTOR signaling pathways. Life Sci 2020; 261: 118301.

[8] Friedman M, Levin CE. Review of methods for the reduction of dietary content and toxicity of acrylamide. J Agric Food Chem 2008; 56(15): 6113-6140.

[9] Gelen V, Yıldırım S, Şengül E, Çınar A, Çelebi F, Küçükkalem M, et al. Naringin attenuates oxidative stress, inflammation, apoptosis, and oxidative DNA damage in acrylamide-induced nephrotoxicity in rats. Asian Pac J Trop Biomed 2022; 12(5): 223-232.

[10] Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, et al. Regulation of antioxidant enzymes: A role for melatonin. J Pineal Res 2004; 36: 1-9.

[11] Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int J Endocrinol 2017; 13.

[12] Kilic U, Kilic E, Tuzcu Z, Tuzcu M, Ozercan IH, Yilmaz O, et al. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf2/HO-1 pathway. Nutr Metab 2013; 10(1): 1-8.

[13] Jamshidi K, Zahedi A. Acrylamide-induced acute nephrotoxicity in rats. Int J Sci Res Sci Technol 2015; 1(5): 286-293.

[14] Tapias V, Cannon JR, Greenamyre JT. Melatonin treatment potentiates neurodegeneration in a rat rotenone Parkinson’s disease model. J Neurosci Res 2010; 88: 420-427.

[15] Sengul E, Gelen V, Yildirim S, Tekin S, Dag Y. The effects of selenium in acrylamide-induced nephrotoxicity in rats: Roles of oxidative stress, inflammation, apoptosis, and DNA damage. Biol Trace Elem Res 2021; 199: 173-184.

[16] Aksu DS, Sağlam YS, Yildirim S, Aksu T. Effect of pomegranate (Punica granatum L.) juice on kidney, liver, heart and testis histopathological changes, and the tissues lipid peroxidation and antioxidant status in lead acetate-treated rats. Cell Mol Biol 2017; 63(10): 33-42.

[17] Belhan S, Yıldırım S, Karasu A, Kömüroğlu AU, Özdek U. Investigation of the protective role of chrysin within the framework of oxidative and inflammatory markers in experimental testicular ischaemia/reperfusion injury in rats. Andrologia 2020; 52(9): e13714.

[18] Sulukan E, Ghosigharehagaji A, Baran A, Yildirim S, Bolat I, Ceyhun SB. A versatile toxicity evaluation of ethyl carbamate (urethane) on zebrafish embryos: Morphological, physiological, histopathological, immunohistochemical, transcriptional and behavioral approaches. Toxicol Lett 2021; 353: 71-78.

[19] Ghorbel I, Elwej A, Fendri N, Mnif H, Jamoussi K, Boudawara T, et al. Olive oil abrogates acrylamide induced nephrotoxicity by modulating biochemical and histological changes in rats. Ren Fail 2017; 39(1): 236-245.

[20] Alwan NA, Alkalby J, Al-Masoudi EA. Ameliorative effect of melatonin, vit. C alone and their combination on liver and kidney functions in acrylamide intoxicated of adult male rats. Basrah J Vet Res 2016; 15: 3.

[21] Kara A, Gedikli S, Sengul E, Gelen V, Ozkanlar S. Oxidative stress and autophagy. In: Rizwan A (ed.) Free radicals and diseases. IntechOpen: E-Publishing Inc; 2016, p. 69-86.

[22] Catalgol B, Ozhan G, Alpertunga B. Acrylamide-induced oxidative stress in human erythrocytes. Hum Exp Toxicol 2009; 28: 611-617.

[23] Asaduzzaman Khan M, Tania M, Zhang DZ, Chen HC. Antioxidant enzymes and cancer. Chinese J Cancer Res 2010; 22(2): 87-92.

[24] Aslankoç R, Demirci D, Ümmahan İ, Yıldız M, Öztürk A, Çetin M, et al. Role of antioxidant enzymes in oxidative stress-Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Med J SDU 2019; 26: 362-369.

[25] Tozan-Beceren A, Sehirli A, Eksioglu-Demiralp E, Sener G, Omurtag G. Melatonin protects against acrylamide-induced oxidative tissue damage in rats. Marmara Pharm J 2012; 16(3): 213-221.

[26] Ali BH, Abdelrahman A, Al Suleimani Y, Manoj P, Ali H, Nemmar A, et al. Effect of concomitant treatment of curcumin and melatonin on cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother 2020; 131: 110761.

[27] Sahin K, Tuzcu M, Sahin N, Ali S, Kucuk O. Nrf2/HO-1 signaling pathway may be the prime target for chemoprevention of cisplatin-induced nephrotoxicity by lycopene. Food Chem Toxicol 2010; 48(10): 2670-2674.

[28] Shelton LM, Park BK, Copple IM. Role of Nrf2 in protection against acute kidney injury. Kidney Int 2013; 84: 1090-1095.

[29] Nath M, Agarwal A. New insights into the role of heme oxygenase-1 in acute kidney injury. Kidney Res Clinl Pract 2020; 39(4): 387.

[30] Gur C, Kandemir FM, Caglayan C, Seller E. Chemopreventive effects of hesperidin against paclitaxel-induced hepatotoxicity and nephrotoxicity via amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways. Chem Biol Interact 2022; 365: 110073.

[31] Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci 2019; 20(23): 6008.

[32] Lin YF, Jamison S, Lin WS. Interferon-gamma activates nuclear factor-kappa B in oligodendrocytes through a process mediated by the unfolded protein response. PLoS One 2012; 7(5): 36408.

[33] Wang P, Wu P, Siegel MI, Egan RW, Billah MM. Interleukin (Il)-10 inhibits nuclear factor kappa-B (Nf-kappa-B) activation in human monocytes-Il-10 and Il-4 suppress cytokine synthesis by different mechanisms. J Biol Chem 1995; 270(16): 9558-9563.

[34] Cano Barquilla P, Pagano ES, Jiménez-Ortega V, Fernández-Mateos P, Esquifino AI, Cardinali DP. Melatonin normalizes clinical and biochemical parameters of mild inflammation in diet-induced metabolic syndrome in rats. J Pineal Res 2014; 57(3): 280-290.

[35] Wang Y, Zhao TT, Zhao HY, Wang H. Melatonin protects methotrexate-induced testicular injury in rats. Eur Rev Med Pharmacol Sci 2018; 22(21): 7517-7525.

[36] Heming M, Gran S, Jauch SL, Fischer-Riepe L, Russo A, Klotz L, et al. Peroxisome proliferator-activated receptor-gamma modulates the response of macrophages to lipopolysaccharide and glucocorticoids. Front Immunol 2018; 9: 893.

[37] Badawy AM, El-Naga RN, Gad AM, Tadros MG, Fawzy HM. Wogonin pre-treatment attenuates cisplatin-induced nephrotoxicity in rats: Impact on PPAR-γ, inflammation, apoptosis and Wnt/β-catenin pathway. Chem Biol Interact 2019; 308: 137-146.

[38] Le PH, Kuo CJ, Cheng HT, Wu RC, Chen TH, Lin CJ, et al. Melatonin attenuates acute pancreatitis-induced liver damage through Akt-dependent PPAR-γ pathway. J Surg Res 2019; 236: 311-318.

[39] Tekin S, Dag Y, Bolat M, Sengul E. Effects of p-coumaric acid on kidney injury molecule-1 in bisphenol A-induced nephrotoxicity in rats. J Lab Anim Sci Pract 2021; 1(1): 1-7.

[40] Potić M, Ignjatović I, Ničković VP, Živković JB, Krdžić JD, Mitić JS, et al. Two different melatonin treatment regimens prevent an increase in kidney injury marker-1 induced by carbon tetrachloride in rat kidneys. Can J Physiol Pharmacol 2019; 97(5): 422-428.

[41] Erdemli ME, Zayman E, Erdemli Z, Gul M, Gul S, Gozukara BH. Protective effects of melatonin and vitamin E in acetamiprid-induced nephrotoxicity. Environ Sci Pollut Res 2020; 27(9): 9202-9213.

[42] Li ZY, Piao FY, Liu SA, Wang Y, Qu SX. Subchronic exposure to arsenic trioxide-induced oxidative DNA damage in kidney tissue of mice. Exp Toxicol Pathol 2010; 62: 543-547.

[43] Mercantepe F, Mercantepe T, Topcu A, Yılmaz A, Tumkaya L. Protective effects of amifostine, curcumin, and melatonin against cisplatin-induced acute kidney injury. Naunyn Schmiedebergs Arch Pharmacol 2018; 391(9): 915-931.

[44] Ibrahim YF, Hammady SH, Rifaai RA, Waz S, Ibrahim MA, Hafez HM. Dose-dependent ameliorating effect of lipoxin A4 on gentamicin-induced nephrotoxicity in rats: The role of TNFα, TGF-β, ICAM-1, and JNK signaling. Chem Biol Interact 2022; 366: 110139.

[45] Alotaibi MR, Hassan ZK, Al-Rejaie SS, Alshammari MA, Almutairi MM, Alhoshani AR, et al. Characterization of apoptosis in a breast cancer cell line after IL-10 silencing. Asian Pac J Cancer Prev 2018; 19(3): 777-783.