Effects of N-acetylcysteine on spexin immunoreactivity in kidney tissues of rats treated with adriamycin

Document Type : Original Article


1 Batman University, Health Services Vocational School, First and Emergency Program, Batman, Turkey

2 Firat University, Medicine Faculty, Department of Histology and Embryology, Elazığ, Turkey

3 Firat University, Medicine Faculty, Department of Medical Biology, Elazığ, Turkey


Objective(s): Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR.
Materials and Methods: A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15th day. 
Results: The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage.
Conclusion: Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage.


Main Subjects

Karna KK, Choi BR, You JH, Shin YS, Soni KK, Cui WS, et al. Cross-talk between ER stress and mitochondrial pathway-mediated adriamycin-induced testicular toxicity and DA-9401 modulate adriamycin-induced apoptosis in Sprague-Dawley rats. Cancer Cell Int 2019; 19: 1-11.
2.    Molehin OR, Adeyanju AA,  Adefega SA, Oyeyemi AO, Idowu KA. Protective mechanisms of protocatechuic acid against doxorubicin-induced nephrotoxicity in rat model. J Basic Clin Physiol Pharmacol 2019; 8:30:1–10.
3.    Mizutani H, Oikava ST, Hiraku Y, Kojima Y, Kawanishi S. Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sci 2005;76:1439–1453. 
4.    Sahyon HA, Al-Harbi SA. Chemoprotective role of an extract of the heart of the Phoenix dactylifera tree on adriamycin-induced cardiotoxicity and nephrotoxicity by regulating apoptosis, oxidative stress, and PD-1 suppression. Food Chem Toxicol 2020; 135:111045.
5.    Jambhulkar  S, Chen L, Lu Q, Sharma S, Li L, Morimoto S, et al. Quercetin attenuating doxorubicin ınduced hepatic , cardiac and renal toxicity in male albino Wistar rats. Br J Pharmacol 2014;171: 4440–4454.
6.    Hussain MA, Abogresha NM, AbdelKader G, Hassan R, Abdelaziz EZ, Greish SM. Anti-oxidant and anti-ınflammatory effects of crocin ameliorate doxorubicin-ınduced nephrotoxicity in rats. Oxid Med Cell Longev 2021; 2021: 1-12.
7.    Koc S, Aktas A, Sahin B, Ozkaraca M. Protective effect of melatonin and mycophenolate mofetil against nephrotoxicity ınduced by tacrolimus in wistar rats. Kafkas UnivVet Fak Derg 2022;28:67-74.
8.    Berthiaume JM, Wallace KB. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol  2007; 23:15–25. 
9.    Nagai K, Fukuno S, Otani K, Nagamine Y, Omotani S, Hatsuda Y, et al. Doxorubicin-ınduced renal toxicity by theanine in rats. Pharmacology 2018; 101:219–224. 
10.    Carvalho C, Santos RX, Cardosso S, Correia S, Oliveira PJ, Santos MS, et al. Doxorubicin: The good, the bad and the ugly effect. Curr Med Chem 2009; 16:3267–3285.  
11.    Alshabanah OA, Hafez MM, Al-Harbi MM, Hassan ZK, Rejaie SS, Asiri YA, et al. Doxorubicin toxicity can be ameliorated during anti-oxidant L-carnitine supplementation. Oxid Med Cell Longev 2010; 3:428–433.  
12.    Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine.  Biochim Biophys Acta 2013;1830:4117–4129.                                                                                     
13.    Abdel-Wahab WM, Moussa FI. Neuroprotective effect of N-acetylcysteine against cisplatin-induced toxicity in rat brain by modulation of oxidative stress and inflammation. Drug Des Devel Ther 2019; 13:1155–1162. 
14.    Giampreti A, Lonati D, Ragghianti B, Ronchi A, Petrolini VM, Vecchio S, Locatelli CA. N-Acetyl-cysteine as effective and safe chelating agent in metal-on-metal hip-ımplanted patients: two cases. Case Rep Orthop 2016; 2016: 1–7. 
15.    Shahripour RB, Harrigan MR, Alexandrov AV. N-acetylcysteine (NAC) in neurological disorders: Mechanisms of action and therapeutic opportunities. Brain Behav 2014;4:108–122. 
16.    Bhatti J, Nascimento B, Akhtar U, Rhind SG, Tien H, Nathens A, Luz LT.  Systematic review of human and animal studies examining the efficacy and safety of N-acetylcysteine (NAC) and N-Acetylcysteine Amide (NACA) in traumatic brain injury: Impact on neurofunctional outcome and biomarkers of oxidative stress and inflammation. Front Neurol  2018; 8:1-14. 
17.    Walewski JL, Ge F, Lobdel H, Levin N, Schwartz GJ, Vasselli JR, et al. Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity. Obesity 2014; 22:1643–1652. 
18.    Porzionato A, Rucinski M, Macchi V, Stecco C, Malendowicz LK, Caro RD. Spexin expression in normal rat tissues. J Histochem Cytochem 2010;58:825–837. 
19.    El-Saka MH,  El Gheit RA, El Saadany A, Alghazaly GM, Marea K, Madi NM. Effect of spexin on renal dysfunction in experimentally obese rats: Potential mitigating mechanisms via galanin receptor-2. Arch Physiol Biochem 2021; 25;1–10. 
20.    Oksay T,  Naziroglu M, Ergun O, Dogan S, Ozatik O, Armagan A, et al. N-acetyl cysteine attenuates diazinon exposure-induced oxidative stress in rat testis. Andrologia 2013; 45:171-177. 
21.    Zakaria N, Khalil SR, Awad A, Khairy GM. Quercetin reverses altered energy metabolism in the heart of rats receiving adriamycin chemotherapy. Cardiovasc Toxicol 2018;8:109-119.  
22.    Kaya S, Yalcin T, Boydak M, Donmez HH. Protective effect of N-Acetylcysteine against aluminum-ınduced kidney tissue damage in rats. Biol Trace Elem Res 2023; 201:1806-1815.
23.    Altinkaynak Y, Kural B, Akcan BA, Bodur A, Ozer S, Yulug E, et al. Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats. Biomed Pharmacother 2018; 108:1524–1534. 
24.    Ertik O, Magaji UF, Sacan O, Yanardag R. Effect of Moringa oleifera leaf extract on valproateinduced oxidative damage in muscle.  Drug Chem Toxicol 2022; 13:1-11.
25.    Oumayma B, Wahid K, Soumaya G, Olfa T, Rhouma KB, Mohsen S,  Dordaf H. Phycocyanin improved alcohol-induced hepatorenal toxicity and behavior impairment in Wistar rats. Drug ChemToxicol 2022; 7:1-6       
26.    Kaya S, Yalçın T, Kuloglu T. Resveratrol may reduce oxidative stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating meteorin-like and TRPM2 levels. Comp Clin Pathol 2023; 32:393-404.
27.    Yalçın T, Kaya S. Thymoquinone may alleviate cisplatin-induced muscle atrophy in rats by regulating mitofusin 2 and meteorin-like levels. Comp Clin Pathol 2023; 32:339-345.
28.    Yildirim SO, Colakoglu N, Kaya SO. Protective effects of L‐arginine against aluminium chloride‐induced testicular damage in rats. Andrologia 2022; 54:e14569.                
29.    Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behav Res Methods 2009; 41:1149-1160. 
30.    Liu X. Protection of Pifithrin-α and Melatonin against Doxorubicin-Induced, Cardiotoxicity. Doctor’s Degree Thesis, East Tennessee State University Biomedical Science. United States 2003.
31.    Minotti  G, Menna P, Salvatorelli E, Cairo G, Gianni L.  Anthracy-clines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004;56:185-229. 
32.    Amarasiri SS, Attanayake AP, Arawwawala LDAM, Jayatilaka KAPW, Mudduw LKB. Protective effects of three selected standardized medicinal plant extracts used in Sri Lankan traditional medicine in adriamycin induced nephrotoxic wistar rats. J Ethnopharmacol 2020; 259:112933.
33.    Liu LL, Li OX, Xia L, Li J, Shao L. Differential effects of dihydropyridine calcium antagonists on doxorubicin induced nephrotoxicity in rats. Toxicology 2007; 231:81-90.
34.    Zhao L, Qi Y, Xu L, Tao X, Han X, Yin L, Peng J. MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Redox Biol 2018; 15:284-296. 
35.    Lee T, Yun S, Jeong JH, Jung TW. Asprosin impairs insulin secretion in response to glucose and viability through TLR4/JNK-mediated inflammation. Mol Cell Endocrinol 2019; 486:96-104.
36.    Yalçın T, Kaya S. Resveratrol may reduce apoptosis due to doxorubicin-ınduced hepatotoxicity by regulating the bax/bcl2 ratio in male rats. Med J Health Sci 2023; 37:10-16.
37.    Zhang Z, Tan Y, Zhu L, Zhang B, Feng B, Gao E, et al. Asprosin improves the survival of mesenchymal stromal cells in myocardial infarction by inhibiting apoptosis via the activated ERK1/2-SOD2 pathway. Life Sci 2019; 231:116554. 
38.    Wang R, Lin P, Sun H, Hu W. Increased serum asprosin is correlated with diabetic nephropathy. Diabetol Metab Syndr 2021; 13:1-6.
39.    Kahraman H, Kurutas E, Tokur M, Bozkurt S, Cıralık H, Kabacı B, et al. Protective effects of erythropoietin and N-acetylcysteine on methotrexate- induced lung injury in rats. Balkan Med J 2013; 30: 99–104. 
40.    Yalçın T, Kaya S, Kuloğlu T, Yiğin A. N-Acetylcysteine may regulate altered meteorin-like levels in testicular tissue due to aluminum exposure. Biol Trace Elem Res 2023;  201, 5335–5345.
41.    Mansouri E, Assarehzadegan MA, Dehbashi FN, Kooti W. Effects of pravastatin in adriamycin-induced nephropathy in rats. Iran J Pharm Res 2018; 17:1413-1419.
42.    Kaymak E, Ozturk E, Akin AT, Karabulut D, Yakan B. Thymoquinone alleviates doxorubicin induced acute kidney injury by decreasing endoplasmic reticulum stress, inflammation and apoptosis. Biotech Histochem 2022; 97:622-634.                                                                                           
43.    Horenstein MS, Heide RSV, L’Ecuyer TJ. Molecular basis of anthracycline-induced cardiotoxicity and its prevention. Mol Genet Metab 2000;71:436–444. 
44.    Karabag F, Ozkan E. Investigation of boron effect on trace elements and anti-oxidant capacity in paracetamol-induced nephrotoxicity model. J Vet Med Ass 2020; 91:25–35.
45.    Chiribau CB, Gaccioli F, Huang CC, Yuan CL, Hatzoglou M. Molecular symbiosis of CHOP and C/EBPβ isoform LIP contributes to endoplasmic reticulum stress-induced apoptosis. Mol Cell Biol 2010; 30:3722–3731.
46.    Chen Y, He M, Lei MML, Ko WKW, Lin C, Bian Z, Wong AOL. Mouse Spexin: (III) differential regulation by glucose and ınsulin in glandular stomach and functional ımplication in feeding control. Front Endocrinol 2021;12:681648. 
47.    Gu X, Li H, Zhu X, Gu H, Chen J, Wang L, et al. Inverse correlation between plasma adropin and et-1 levels in essentialhy pertension: A cross-sectional study. a cross-sectional study. Medicine 2015; 94:1-5.
48.    Gambaro SE, Zubiría MG, Giordano AP, Portales AE, Alzamendi A, Rumbo M, Giovambattista A. Spexin ımproves adipose tissue ınflammation and macrophage recruitment in obese mice. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158700.
49.    Toll L, Khroyan TV, Sonmez K, Ozawa A, Lindberg  I, McLaughlin JP, et al. Peptides derived from the prohormone proNPQ/spexin are potent central modulators of cardiovascular and renal function and nociception. Faseb J 2012; 26: 947–954.
50.    Yazgan B, Avcı F, Memi G, Tastekin E. Inflammatory response and matrix metalloproteinases in chronic kidney failure: Modulation by adropin and spexin. Exp Biol Med (Maywood) 2021; 246: 1917-1927.