Iranian Journal of Nuclear Medicine

Iranian Journal of Nuclear Medicine

Evaluation of preventive effect of quercetin on doxorubicin-induced nephrotoxic rat model by [99mTc]Tc-DMSA renal cortical scintigraphy and biochemical methods

Document Type : Original Article

Authors
Reyhan Köroğlu 1
Serdar Savaş Gül 2
Hatice Aygun 3
1 Department of Nuclear Medicine, Sultan 2 Abdülhamid Han Training and Research Hospital, Istanbul, Turkey
2 Department of Nuclear Medicine, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey
3 Department of Physiology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey
10.22034/irjnm.2023.129042.1536
Abstract
Introduction: The purpose of this study was to evaluate possible preventive role of quercetin on doxorubicin (DOX) induced kidney toxicity using Tc-99m Dimercaptosuccinic Acid ([99mTc]Tc-DMSA) renal cortical scintigraphy and biochemical approaches.
Methods: 28 Male Wistar rats were separated into four groups. First group was intraperitoneally (i.p.) injected saline and regarded as the control group; second one was received 18 mg/kg/i.p doxorubicin for three days at a 24 h interval; the third and last group received 10 mg/kg and  100 mg/kg quercetin for 21 days and for the last 3 days doxorubicin and quercetin were administrated together at the same time. On the 22 th day of the experiment, [99mTc]Tc-DMSA renal cortikal scintigraphy and biochemical parameters were measured.
Results:DOX administration significantly increased blood urea nitrogen (845%) and creatinine (702%) levels in serum; nitric oxide (158%), plasma tumor necrosis factor-alpha (233%) and interleukin-6 (191%) levels in kidney tissue, and also reduced [99mTc]Tc-DMSA uptake by 29% in the kidneys as well. Pre-treatment with quercetin mitigated such alterations in all mentioned parameters.
Conclusion: All data indicate that oxidative stress and inflammatory processes are involved in DOX-induced nephrotoxicity, which might be decreased by quercetin.In addition, [99mTc]Tc-DMSA scintigraphic may be a good method for demonstrating doxorobucin-induced renal injury.
Keywords
Doxorubicin
Kidney
Quercetin
Nephrotoxicity
[99mTc]Tc-DMSA
Subjects
  1. Chmielewska M, Symonowicz K, Pula B, Owczarek T, Podhorska-Okolow M, Ugorski M, Dziegiel P. Expression of metallothioneins I and II in kidney of doxorubicin-treated rats. Exp Toxicol Pathol. 2015 Apr;67(4):297-303.
  2. Khames A, Khalaf MM, Gad AM, Abd El-Raouf OM. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats. Eur J Pharmacol. 2017 Jun 15;805:118-24. 
  3. Altınkaynak Y, Kural B, Akcan BA, Bodur A, Özer S, Yuluğ E, Munğan S, Kaya C, Örem A. Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats. Biomed Pharmacother. 2018 Dec;108:1524-34.
  4. Cardoso DF, Coriolano HA, Duarte JA. Regular voluntary running has favorable histological effects on doxorubicin-induced kidney toxicity in Wistar rats. Cell Tissue Res. 2018 Oct;374(1):177-87.
  5. Fadillioglu E, Oztas E, Erdogan H, Yagmurca M, Sogut S, Ucar M, Irmak MK. Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats. J Appl Toxicol. 2004 Jan-Feb;24(1):47-52.
  6. Aluise CD, Miriyala S, Noel T, Sultana R, Jungsuwadee P, Taylor TJ, Cai J, Pierce WM, Vore M, Moscow JA, St Clair DK, Butterfield DA. 2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med. 2011 Jun 1;50(11):1630-8.
  7. Zordoky BN, Anwar-Mohamed A, Aboutabl ME, El-Kadi AO. Acute doxorubicin toxicity differentially alters cytochrome P450 expression and arachidonic acid metabolism in rat kidney and liver. Drug Metab Dispos. 2011 Aug;39(8):1440-50.
  8. Zhang Y, Xu Y, Qi Y, Xu L, Song S, Yin L, Tao X, Zhen Y, Han X, Ma X, Liu K, Peng J. Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation. Toxicology. 2017 Mar 1;378:53-64.
  9. Tu Y, Sun W, Wan YG, Che XY, Pu HP, Yin XJ, Chen HL, Meng XJ, Huang YR, Shi XM. Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, ameliorates adriamycin-induced renal inflammation and glomerular injury via inhibiting p38MAPK signaling pathway activity in rats. J Ethnopharmacol. 2013 May 20;147(2):311-20.
  10. Ren X, Bo Y, Fan J, Chen M, Xu D, Dong Y, He H, Ren X, Qu R, Jin Y, Zhao W, Xu C. Dalbergioidin Ameliorates Doxorubicin-induced renal fibrosis by suppressing the TGF-β signal pathway. Mediators Inflamm. 2016;2016:5147571.
  11. Prša P, Karademir B, Biçim G, Mahmoud H, Dahan I, Yalçın AS, Mahajna J, Milisav I. The potential use of natural products to negate hepatic, renal and neuronal toxicity induced by cancer therapeutics. Biochem Pharmacol. 2020 Mar;173:113551.
  12. Aygun H, Gul SS. Protective effect of melatonin and agomelatine on adriamycin-induced nephrotoxicity in rat model: a renal scintigraphy and biochemical study. Bratisl Lek Listy. 2019;120(2):113-8. 
  13. Aygun H, Gul SS. Cardioprotective effect of melatonin and agomelatine on doxorubicin-induced cardiotoxicity in a rat model: an electrocardiographic, scintigraphic and biochemical study. Bratisl Lek Listy. 2019;120(4):249-55.
  14. Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med. 2004 Apr 1;36(7):838-49.
  15. Chen X. Protective effects of quercetin on liver injury induced by ethanol. Pharmacogn Mag. 2010 Apr;6(22):135-41.
  16. Heeba GH, Mahmoud ME. Dual effects of quercetin in doxorubicin-induced nephrotoxicity in rats and its modulation of the cytotoxic activity of doxorubicin on human carcinoma cells. Environ Toxicol. 2016 May;31(5):624-36.
  17. Sánchez-González PD, López-Hernández FJ, Dueñas M, Prieto M, Sánchez-López E, Thomale J, Ruiz-Ortega M, López-Novoa JM, Morales AI. Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues. Food Chem Toxicol. 2017 Sep;107(Pt A):226-36.
  18. Jackson JK, Higo T, Hunter WL, Burt HM. The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis. Inflamm Res. 2006 Apr;55(4):168-75.
  19. Mandell GA, Eggli DF, Gilday DL, Heyman S, Leonard JC, Miller JH, Nadel HR, Treves ST. Procedure guideline for renal cortical scintigraphy in children. Society of Nuclear Medicine. J Nucl Med. 1997 Oct;38(10):1644-6.
  20. Rezaei M, Papie M, Cheki M, Mansi L, Kitson S, Ahmadi A. The Screening of Renoprotective Agents by 99mTc-DMSA: A Review of Preclinical Studies. Curr Radiopharm. 2019;12(3):211-9.
  21. Su Z, Ye J, Qin Z, Ding X. Protective effects of madecassoside against Doxorubicin induced nephrotoxicity in vivo and in vitro. Sci Rep. 2015 Dec 14;5:18314.
  22. Rehman MU, Tahir M, Khan AQ, Khan R, Oday-O-Hamiza, Lateef A, Hassan SK, Rashid S, Ali N, Zeeshan M, Sultana S. D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NFκB in kidneys of Wistar rats. Exp Biol Med (Maywood). 2014 Apr;239(4):465-76. 
  23. Deepa PR, Varalakshmi P. Influence of a low-molecular-weight heparin derivative on the nitric oxide levels and apoptotic DNA damage in adriamycin-induced cardiac and renal toxicity. Toxicology. 2006 Jan 16;217(2-3):176-83.
  24. Amir O, Paz H, Rogowski O, Barshai M, Sagiv M, Shnizer S, Reznick AZ, Amir RE. Serum oxidative stress level correlates with clinical parameters in chronic systolic heart failure patients. Clin Cardiol. 2009 Apr;32(4):199-203.
  25. Yang W, Wang J, Shi L, Yu L, Qian Y, Liu Y, Wang W, Cheng S. Podocyte injury and overexpression of vascular endothelial growth factor and transforming growth factor-beta 1 in adriamycin-induced nephropathy in rats. Cytokine. 2012 Aug;59(2):370-6
  26. Wei MG, He WM, Lu X, Ni L, Yang YY, Chen L, Xiong PH, Sun W. JiaWeiDangGui Decoction Ameliorates Proteinuria and Kidney Injury in Adriamycin-Induced Rat by Blockade of TGF-β/Smad Signaling. Evid Based Complement Alternat Med. 2016;2016:5031890.
  27. Hosten AO. BUN and creatinine. Walker HK, Hall WD, Hurst JW, editors. Clinical methods: the history, physical, and laboratory examinations. 3rd ed. Boston: Butterworths; 1990.
  28. Uchino S, Bellomo R, Goldsmith D. The meaning of the blood urea nitrogen/creatinine ratio in acute kidney injury. Clin Kidney J. 2012 Apr;5(2):187-191.
  29. Devi PS, Shyamala DC. Protective effect of quercetin in cisplatin-induced cell injury in the rat kidney. Indian J. Pharmacol.1999 Oct 1;31(6):422.
  30. Behling EB, Sendão MC, Francescato HD, Antunes LM, Costa RS, Bianchi Mde L. Comparative study of multiple dosage of quercetin against cisplatin-induced nephrotoxicity and oxidative stress in rat kidneys. Pharmacol Rep. 2006 Jul-Aug;58(4):526-32.
  31. Almaghrabi OA. Molecular and biochemical investigations on the effect of quercetin on oxidative stress induced by cisplatin in rat kidney. Saudi J Biol Sci. 2015 Mar;22(2):227-31
  32. Liu CM, Sun YZ, Sun JM, Ma JQ, Cheng C. Protective role of quercetin against lead-induced inflammatory response in rat kidney through the ROS-mediated MAPKs and NF-κB pathway. Biochim Biophys Acta. 2012 Oct;1820(10):1693-703.
  33. Faddah LM, Abdel Baky NA, Al-Rasheed NM, Al-Rasheed NM, Fatani AJ, Atteya M. Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats. BMC Complement Altern Med. 2012 May 2;12:60.
  34. Fatemikia H, Seyedabadi M, Karimi Z, Tanha K, Assadi M, Tanha K. Comparison of 99mTc-DMSA renal scintigraphy with biochemical and histopathological findings in animal models of acute kidney injury. Mol Cell Biochem. 2017 Oct;434(1-2):163-9.
  35. Yamada M. [Assessment of 99mTc-DMSA renography and uptake compared with creatinine clearance in rats with drug-induced nephrotoxicity--I. Gentamicin-induced nephrotoxicity]. Kaku Igaku. 1991 Apr;28(4):339-45. Japanese
  36. Hosseinimehr SJ, Asadian R, Naghshvar F, Azizi S, Jafarinejad M, Noaparast Z, Abedi SM, Hosseini SA. Protective effects of thymol against nephrotoxicity induced by cisplatin with using 99mTc-DMSA in mice. Ren Fail. 2015 Mar;37(2):280-4.
  37. Salihoglu YS, Elri T, Gulle K, Can M, Aras M, Ozacmak HS, Cabuk M. Evaluation of the protective effect of agmatine against cisplatin nephrotoxicity with 99mTc-DMSA renal scintigraphy and cystatin-C. Ren Fail. 2016 Oct;38(9):1496-502.
  38. Yagmurca M, Yasar Z, Bas O. Effects of quercetin on kidney injury induced by doxorubicin. Bratisl Lek Listy. 2015;116(8):486-9.
  39. Kocahan S, Dogan Z, Erdemli E, Taskin E. Protective effect of quercetin against oxidative stress-induced toxicity associated with Doxorubicin and Cyclophosphamide in rat kidney and liver tissue. Iran J Kidney Dis. 2017 Mar;11(2):124-31.
  40. Córdoba-Adaya JC, Oros-Pantoja R, Torres-García E, Morales-Ávila E, Aranda-Lara L, Santillán-Benítez JG, Hernández-Herrera NO, Otero G, Isaac-Olivé K. Evaluation of doxorubicin-induced early multi-organ toxicity in male CD1 mice by biodistribution of 18F-FDG and 67Ga-citrate. Pilot study. Toxicol Mech Methods. 2021 Sep;31(7):546-58.