The Effects of Quercetin on Apoptosis and Antioxidant Activity in a Renal Ischemia/Reperfusion Injury Animal Model

Abstract

Renal ischemia-reperfusion injury (IRI) is considered as one of the most prevalent causes of acute kidney injury (AKI), which can happen in various clinical situations including hypovolemic shock, injury, thrombo-embolism, and after a kidney transplant. This paper aims to evaluate the reno-protective effects of Quercetin in induced ischemia/reperfusion injury by regulating apoptosis-related proteins, inflammatory cytokines, MMP-2, MMP-9, and nuclear factor kappa-light-chain-enhancer inactivated B cells (NF-kB) in rats. The male Wistar rats (n=32) were randomly divided into Sham, untreated IR, and Quercetin-treated IR (gavage and intraperitoneal). Quercetin was given orally and intraperitoneally one hour before inducing ischemia-reperfusion injury . After reperfusion, blood samples and kidneys were collected to assess renal function and inflammatory cytokines, apoptotic signaling proteins, and antioxidants. Urea, creatinine, and MDA levels improved in Quercetin-treated groups with different administration methods. In addition, the activities of other antioxidant in Quercetin-treated rats were higher than those in the IR group. Further, Quercetin inhibited NF-kB signaling, apoptosis-associated factors and produced matrix metalloproteinase protein in the kidneys of rats. Based on the findings, the antioxidant, anti-inflammatory, and anti-apoptotic effects of the Quercetin diminished renal ischemia-reperfusion injury in the rats significantly. It is suggested that a single dosage of Quercetin have a reno-protective impact in the case of renal I/R injury.

Keywords

Quercetin - acute renal injury - ischemia-reperfusion - oxidative stress - apoptosis

Publication History

Received: 06 September 2022

Accepted: 12 December 2022

Article published online:
27 March 2023

• References

• 1 Kalogeris T, Baines CP, Krenz M. et al. “Cell biology of ischemia/reperfusion injury”. International review of cell and molecular biology 2012; 298: 229-317
• 2 Nadereh R, Hassan A, Amir G. et al. “C-reactive protein level following treatment and withdrawal of lovastatin in diabetic nephropathy,”. 2009
• 3 Malek M, Nematbakhsh M. “Renal ischemia/reperfusion injury; from pathophysiology to treatment”. Journal of renal injury prevention 2015; 4: 20-27
• 4 Rovcanin B, Medic B, Kocic G. et al. “Molecular dissection of renal ischemia-reperfusion: oxidative stress and cellular events”. Current medicinal chemistry 2016; 23: 1965-1980
• 5 Granger DN, Kvietys PR. “Reperfusion injury and reactive oxygen species: the evolution of a concept”. Redox biology 2015; 6: 524-551
• 6 Fathi E, Farahzadi R. “Zinc sulphate mediates the stimulation of cell proliferation of rat adipose tissue-derived mesenchymal stem cells under high intensity of EMF exposure”. Biological trace element research 2018; 184: 529-535
• 7 Saliani N, Montazersaheb S, Kouhsari SM. “Micromanaging glucose tolerance and diabetes”. Advanced pharmaceutical bulletin 2017; 7: 547
• 8 Ornellas FM, Ornellas DS, Martini SV. et al. “Bone Marrow–Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules”. Cellular Physiology and Biochemistry 2017; 41: 1736-1752
• 9 Fathi E, Charoudeh HN, Sanaat Z. et al. “Telomere shortening as a hallmark of stem cell senescence”. Stem cell investigation 2019; 6: 7-7
• 10 Nakhlband A, Omidi Y. “Barrier functionality of porcine and bovine brain capillary endothelial cells”. BioImpacts: BI 2011; 1: 153
• 11 Bagheri Y, Aghajani S, Hosseinzadeh M. et al. “Protective effects of Gamma Oryzanol on distant organs after kidney ischemia-reperfusion in rats: A focus on liver protection”. Human & Experimental Toxicology 2021; 40: 1022-1030
• 12 Malekinejad Z, Aghajani S, Jeddi M. et al. “Prazosin Treatment Protects Brain and Heart by Diminishing Oxidative Stress and Apoptotic Pathways After Renal Ischemia Reperfusion”. Drug Research. 2022
• 13 Rahimi M, Bagheri A, Bagheri Y. et al. “Renoprotective effects of prazosin on ischemia-reperfusion injury in rats”. Human & Experimental Toxicology 2021; 40: 1263-1273
• 14 Ganea E, Trifan M, Laslo A. et al. “Matrix metalloproteinases: useful and deleterious”. Biochemical Society Transactions 2007; 35: 689-691
• 15 Liu W, Yu W, Carling T. et al. “Regulation of gp330/megalin expression by vitamins A and D”. European journal of clinical investigation 1998; 28: 100-107
• 16 Bagheri Y, Barati A, Nouraei S. et al. “Comparative study of gavage and intraperitoneal administration of gamma-oryzanol in alleviation/attenuation in a rat animal model of renal ischemia/reperfusion-induced injury”. Iranian Journal of Basic Medical Sciences 2021; 24: 175
• 17 Gholampour F, Sadidi Z. “Hepatorenal protection during renal ischemia by quercetin and remote ischemic perconditioning”. journal of surgical research 2018; 231: 224-233
• 18 Rodrigo R, Retamal C, Schupper D. et al. “Antioxidant Cardioprotection against Reperfusion Injury: Potential Therapeutic Roles of Resveratrol and Quercetin”. Molecules 2022; 27: 2564
• 19 Cui Z, Zhao X, Amevor FK. et al “Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism”. Front Immunol 2022; 13: 943321
• 20 Özsoy Gökbilen S, Becer E, Vatansever HS. “Senescence-mediated anticancer effects of quercetin”. Nutr Res 2022; 104: 82-90
• 21 Gu Y-Y, Zhang M, Cen H. et al “Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study”. PLoS One 2021; 16: e0245209
• 22 Ali AM, Gabbar MA, Abdel-Twab SM. et al “Antidiabetic potency, antioxidant effects, and mode of actions of Citrus reticulata fruit peel hydroethanolic extract, hesperidin, and quercetin in nicotinamide/streptozotocin-induced Wistar diabetic rats”. Oxidative medicine and cellular longevity. 2020 2020.
• 23 Yamada S, Shirai M, Inaba Y. et al. “Effects of repeated oral intake of a quercetin-containing supplement on allergic reaction: a randomized, placebo-controlled, double-blind parallel-group study”. Eur Rev Med Pharmacol Sci 2022; 26: 4331-4345
• 24 Bondonno NP, Bondonno CP, Ward NC. et al. “Enzymatically modified isoquercitrin improves endothelial function in volunteers at risk of cardiovascular disease”. Br J Nutr 2020; 123: 182-189
• 25 Casanova AG, Prieto M, Colino CI. et al “A micellar formulation of quercetin prevents cisplatin nephrotoxicity”. International Journal of Molecular Sciences 2021; 22: 729
• 26 Rahdar A, Hasanein P, Bilal M. et al. “Quercetin-loaded F127 nanomicelles: Antioxidant activity and protection against renal injury induced by gentamicin in rats”. Life Sciences 2021; 276: 119420
• 27 Wang Y, Quan F, Cao Q. et al. “Quercetin alleviates acute kidney injury by inhibiting ferroptosis”. Journal of advanced research 2021; 28: 231-243
• 28 Liu X, Sun N, Mo N. et al. “Quercetin inhibits kidney fibrosis and the epithelial to mesenchymal transition of the renal tubular system involving suppression of the Sonic Hedgehog signaling pathway”. Food & function 2019; 10: 3782-3797
• 29 Li D, Jiang C, Mei G. et al. “Quercetin alleviates ferroptosis of pancreatic β cells in type 2 diabetes”. Nutrients 2020; 12: 2954
• 30 Yang H, Yang T, Heng C. et al. “Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice”. Phytotherapy Research 2019; 33: 3140-3152
• 31 Zargar S, Wani TA. “Protective Role of Quercetin in Carbon Tetrachloride Induced Toxicity in Rat Brain: Biochemical, Spectrophotometric Assays and Computational Approach”. Molecules 2021; 26
• 32 Yang B, Zheng CY, Zhang R. et al. “Quercetin Efficiently Alleviates TNF-α-Stimulated Injury by Signal Transducer and Activator of Transcription 1 and Mitogen-Activated Protein Kinase Pathway in H9c2 Cells: A Protective Role of Quercetin in Myocarditis”. J Cardiovasc Pharmacol 2021; 77: 570-577
• 33 Tong F, Liu S, Yan B. et al. “Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium”. International Journal of Nanomedicine 2017; 12: 7799
• 34 Hosseinzadeh H, Sadeghnia HR, Ziaee T. et al. “Protective effect of aqueous saffron extract (Crocus sativus L.) and crocin, its active constituent, on renal ischemia-reperfusion-induced oxidative damage in rats”. J Pharm Pharm Sci 2005; 8: 387-393
• 35 Inal M, Altinişik M, Bilgin MD. “The effect of quercetin on renal ischemia and reperfusion injury in the rat”. Cell Biochemistry and Function: Cellular biochemistry and its modulation by active agents or disease 2002; 20: 291-296
• 36 Kristensen MLV, Kierulf-Lassen C, Nielsen PM. et al “Remote ischemic perconditioning attenuates ischemia/reperfusion-induced downregulation of AQP2 in rat kidney”. Physiological reports 2016; 4: e12865
• 37 Lanzotti V. “The analysis of onion and garlic”. Journal of chromatography A 2006; 1112: 3-22
• 38 Rivera L, Morón R, Sánchez M. et al. “Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats”. Obesity 2008; 16: 2081-2087
• 39 Boots AW, Drent M, de Boer VC. et al. “Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis”. Clinical Nutrition 2011; 30: 506-512
• 40 Kaşıkcı MB, Bağdatlıoğlu N. “Bioavailability of quercetin”. Current research in nutrition and food science journal 2016; 4: 146-151
• 41 Ghosh A, Mandal AK, Sarkar S. et al. “Nanoencapsulation of quercetin enhances its dietary efficacy in combating arsenic-induced oxidative damage in liver and brain of rats”. Life sciences 2009; 84: 75-80
• 42 Y. Gu, X. Huang, Y. Wu, X. Liu, and H. Lan, “QUERCETIN ALLEVIATES CISPLATIN-INDUCED ACUTE KIDNEY INJURY BY REBALANCING TGF-BETA/SMAD SIGNALLING,” in NEPHROLOGY, 2020, 15–15
• 43 Suzuki S, Maruyama S, Sato W. et al “Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70”. Kidney International 2005; 67: 2210-2220
• 44 Ali BR. “Renal Protective Effect of Quercetin on Cisplatin-Induced on Some Blood Parameters and Nephrotoxicity in Male Rats”. Indian Journal of Public Health Research & Development 2019; 10
• 45 Adegoke AO, Njoku R, Bamigbowu OE. et al. “Effect of Quercetin on Liver Oxidative Stress Parameters Induced by Butylparaben in Male Wistar Rats”. International Journal of Medical and Health Sciences Research 2021; 8: 1-7
• 46 Kaya C, Karabulut R, Turkyilmaz Z. et al. “Lycopene has reduced renal damage histopathologically and biochemically in experimental renal ischemia-reperfusion injury”. Renal failure 2015; 37: 1390-1395
• 47 Zhang J, Tang L, Li GS. et al. “The anti-inflammatory effects of curcumin on renal ischemia-reperfusion injury in rats”. Renal Failure 2018; 40: 680-686
• 48 Kim J, Jang H-S, Park KM. “Reactive oxygen species generated by renal ischemia and reperfusion trigger protection against subsequent renal ischemia and reperfusion injury in mice”. American Journal of Physiology-Renal Physiology 2010; 298: F158-F166
• 49 Zizzi HC, Zibari GB, Granger DN. et al. “Quantification of P-selectin expression after renal ischemia and reperfusion”. Journal of Pediatric Surgery 1997; 32: 1010-1013
• 50 Bagheri Y, Fathi E, Maghoul A. et al. “Effects of Achillea tenuifolia Lam. hydro-alcoholic extract on anxiety-like behavior and reproductive parameters in rat model of chronic restraint stress”. Human & Experimental Toxicology 2021; 40: 1852-1866
• 51 Bolann B, Ulvik R. “Improvement of a direct spectrophotometric assay for routine determination of superoxide dismutase activity”. Clinical chemistry 1991; 37: 1993-1999
• 52 Marklund S, Marklund G. “Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase”. European journal of biochemistry 1974; 47: 469-474
• 53 Claiborne A. “Handbook of methods for oxygen radical research, ed. R. Greenwald,” ed. CRC Press; Florida: 1985
• 54 Uchiyama M., Mihara M. “Determination of malonaldehyde precursor in tissues by thiobarbituric acid test”. Analytical biochemistry 1978; 86: 271-278
• 55 Seyfizadeh N, Tazehkand M, Palideh A. et al. “Is arbutin an effective antioxidant for the discount of oxidative and nitrosative stress in Hep-G2 cells exposed to tert-butyl hydroperoxide?”. Bratislavske lekarske listy 2019; 120: 569-575
• 56 Jafari S, Lavasanifar A, Hejazi MS. et al. “STAT3 inhibitory stattic enhances immunogenic cell death induced by chemotherapy in cancer cells”. DARU Journal of Pharmaceutical Sciences 2020; 28: 159-169
• 57 Barati A, Rahbar Saadat Y, Meybodi SM. et al. “Eplerenone reduces renal ischaemia/reperfusion injury by modulating Klotho, NF-κB and SIRT1/SIRT3/PGC-1α signalling pathways”. Journal of Pharmacy and Pharmacology. 2022
• 58 Patschan D, Patschan S, Müller G. “Inflammation and microvasculopathy in renal ischemia reperfusion injury”. Journal of transplantation. 2012 2012.
• 59 Gwon M-G, Gu H, Leem J. et al. “Protective effects of 6-Shogaol, an active compound of ginger, in a murine model of cisplatin-induced acute kidney injury”. Molecules 2021; 26: 5931
• 60 Wei W, Ma N, Fan X. et al. “The role of Nrf2 in acute kidney injury: Novel molecular mechanisms and therapeutic approaches”. Free Radical Biology and Medicine 2020; 158: 1-12
• 61 Hui D, Rui-Zhi T, Jian-Chun L. et al. “Astragalus propinquus Schischkin and Panax notoginseng (A&P) compound relieved cisplatin-induced acute kidney injury through inhibiting the mincle maintained macrophage inflammation”. Journal of ethnopharmacology 2020; 252: 112637
• 62 Marefati N, Ghorani V, Shakeri F. et al. “A review of anti-inflammatory, antioxidant, and immunomodulatory effects of Allium cepa and its main constituents”. Pharmaceutical biology 2021; 59: 287-302
• 63 Coppolino G, Leonardi G, Andreucci M. et al. “Oxidative stress and kidney function: a brief update”. Current pharmaceutical design 2018; 24: 4794-4799
• 64 Canuto JA, Sampaio TL, d. Silva ME. et al. “Protective Effect of Quercetin on Renal Tubular Cells and the Involvement with the Renin-Angiotensin-Aldosterone Axis”. Brazilian Archives of Biology and Technology 2022; 64
• 65 Altintas R, Ciftci O, Aydin M. et al. “Quercetin prevents docetaxel-induced testicular damage in rats”. Andrologia 2015; 47: 248-256
• 66 Lin R, Piao M, Song Y. et al. “Quercetin suppresses AOM/DSS-induced colon carcinogenesis through its anti-inflammation effects in mice”. Journal of Immunology Research. 2020 2020.
• 67 Zhang Y-M, Zhang Z-Y, Wang R-X. “Protective mechanisms of quercetin against myocardial ischemia reperfusion injury”. Frontiers in Physiology 2020; 11: 956
• 68 Sanchez-Gonzalez PD, Lopez-Hernandez FJ, Perez-Barriocanal F. et al. “Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity”. Nephrology Dialysis Transplantation 2011; 26: 3484-3495
• 69 de Oliveira MR, Nabavi SM, Braidy N. et al. “Quercetin and the mitochondria: a mechanistic view”. Biotechnology advances 2016; 34: 532-549
• 70 Kuhar M, Sen S, Singh N. “>Role of Mitochondria in Quercetin-enhanced Chemotherapeutic Response in Human Non-small Cell Lung Carcinoma H-520 Cells”. Anticancer research 2006; 26: 1297-1303
• 71 Cui L, Li Z, Chang X. et al. “Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission”. Vascular pharmacology 2017; 88: 21-29
• 72 Anuar NN, Zulkafali NIN, Ugusman A. “Modulation of matrix metalloproteinases by plant-derived products”. Current Cancer Drug Targets 2021; 21: 91-106
• 73 Jacob-Ferreira AL, Kondo MY, Baral PK. et al “Phosphorylation status of 72 kDa MMP-2 determines its structure and activity in response to peroxynitrite”. PLoS One 2013; 8: e71794
• 74 Zhang Z, Amorosa LF, Coyle SM. et al “Proteolytic cleavage of AMPKα and intracellular MMP9 expression are both required for TLR4-mediated mTORC1 activation and HIF-1α expression in leukocytes”. The Journal of Immunology 2015; 195: 2452-2460
• 75 Sbai O, Ould-Yahoui A, Ferhat L. et al “Differential vesicular distribution and trafficking of MMP-2, MMP-9, and their inhibitors in astrocytes”. Glia 2010; 58: 344-366
• 76 Sans-Fons MG, Sole S, Sanfeliu C. et al. “Matrix metalloproteinase-9 and cell division in neuroblastoma cells and bone marrow macrophages”. The American journal of pathology 2010; 177: 2870-2885
• 77 Watanabe T, Sato K. “Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis”. Nutrition, Metabolism and Cardiovascular Diseases 2020; 30: 889-895
• 78 Ahmadian E, Eftekhari A, Kavetskyy T. et al. “Effects of quercetin loaded nanostructured lipid carriers on the paraquat-induced toxicity in human lymphocytes”. Pesticide biochemistry and physiology 2020; 167: 104586