Drug-induced nephrotoxicity – a review of therapeutic activity of selenium and zinc in preclinical studies
DOI:
https://doi.org/10.15584/ejcem.2026.1.1Keywords:
drugs nephrotoxicity, selenium nephroprotection, zinc nephroprotectionAbstract
Introduction and aim. Certain drugs cause nephrotoxicity and renal dysfunction through induction of oxidative stress and activation of inflammatory and apoptotic signaling pathways within the renal tissue. To mitigate drug nephrotoxicity, the therapeutic potential of trace elements such as selenium (Se) and zinc (Zn) has been experimentally explored. The current knowledge and mechanisms are hereby summarized in this review.
Material and methods. This narrative review was carried out through a critical assessment of relevant articles published in scientific databases like Google Scholar, PubMed, Scopus, and Web of Science.
Analysis of the literature. The antioxidant, antiapoptotic and anti-inflammatory properties of Se and Zn culminate in their therapeutic activity against drugs nephrotoxicity. The nephroprotective effect of Se and Zn has been characterized with suppression of renal oxidative stress (reduced malondialdehyde, protein cabonyl and elevated levels of superoxide dismutase, glutathione, glutathione peroxidase, catalase, total antioxidant capacity levels); upregulation of anti-apoptotic and anti-inflammatory markers (Bcl-2, heme oxygenase-1, factor related to nuclear factor erythroid 2; downregulation of pro-apoptotic and pro-inflammatory like inducible nitric oxide synthase, nitric oxide, tumor necrosis factor-α, interleukin-6, nuclear factor kappa light chain enhancer of activated B cells NF-κB, and Bax, leading to reparation of renal histomorphology and improved renal function (indicated by reduced serum creatinine, urea, BUN levels).
Conclusion. The therapeutic activity of Se and Zn against drugs nephrotoxicity underscores their potential role in the management of nephrotoxicity due to pharmacotherapy.
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References
Sembulingam K, Sembulingam P. Essentials of Medical Physiology. 5th ed. Jaypee Brothers Medical Publishers Ltd; 2010:288.
Al-Naimi MS, Rasheed HA, Hussien NR, Al-Kuraishy HM, Al-Gareeb AI. Nephrotoxicity: role and significance of renal biomarkers in the early detection of acute renal injury. J Adv Pharm Technol Res. 2019;10(3):95-99. doi:10.4103/japtr.JAPTR_336_18
Omotoso DR, Lawal OS, Olatomide OD, Okojie IG. Nephroprotective effect of Cissampelos owariensis extract on renal histomorphology of Wistar rats during exposure to carbon tetrachloride-induced nephropathy. Asia J Biol. 2019;8(4):1-10. doi:10.9734/AJOB/2019/v8i430071
Molaei E, Molaei A, Abedi F, Hayes WA, Karimi G. Nephroprotective activity of natural products against chemical toxicants: the role of Nrf2/ARE signaling pathway. Food Sci Nutr. 2021;9(6):3362-3384. doi:10.1002/fsn3.2320
Okwuonu UC, Omotoso DR, Bienonwu EO, Adagbonyin O, Dappa J. Histomorphological profile of liver and kidney tissues of albino Wistar rats following exposure to cadmium-induced damage and ascorbic acid supplementation. Acad Anat Int. 2020;6(1):15-19. doi:10.21276/aanat.2020.6.1.5
Yadav R, Kumar D, Singh J, Jangra A. Environmental toxicants and nephrotoxicity: implications on mechanisms and therapeutic strategies. Toxicol. 2024;504:153784. doi:10.1016/j.tox.2024.153784
Omotoso DR, Olajumoke JM. Ameliorative effects of ascorbic acid and Allium sativum (garlic) ethanol extract on renal parenchyma of gentamicin-induced nephropathic rats. J Complement Alt Med Res. 2020;9(4):1-8. doi:10.9734/JOCAMR/2020/V9I430146
Omotoso DR, Owonikoko WM, Ehiemere WP. Comparative amelioration of renal histomorphology by ascorbic acid and Camellia sinensis extract in Wistar rats exposed to lead-induced nephropathy. Ann Med Res. 2020;27(8):2161-2165. doi:10.5455/annalsmedres.2020.02.105
Xu M, Xu S, Yi X. A comparative analysis of drug-induced kidney injury adverse reactions between cyclosporine and tacrolimus based on the FAERS database. BMC Immunol. 2025;26:35. doi:10.1186/s12865-025-00714-7
Pazhayattil GS, Shirali AC. Drug-induced impairment of renal function. Int J Nephrol Renovasc Dis. 2014;7:457-468. doi:10.2147/IJNRD.S39747
Kim SY, Moon A. Drug-induced nephrotoxicity and its biomarkers. Biomol Ther (Seoul). 2012;20(3):268-272. doi:10.4062/biomolther.2012.20.3.268
Al-Naimi MS, Rasheed HA, Hussien NR, Al-Kuraishy HM, Al-Gareeb AI. Nephrotoxicity: Role and significance of renal biomarkers in the early detection of acute renal injury. J Adv Pharm Technol Res. 2019;10(3):95-99. doi:10.4103/japtr.JAPTR_336_18
Islam MR, Akash S, Jony MH, et al. Exploring the potential function of trace elements in human health: a therapeutic perspective. Mol Cell Biochem. 2023;478:2141-2171. doi:10.1007/s11010-022-04638-3
Jahankhani K, Taghipour N, Mashhadi Rafiee M, Nikoonezhad M, Mehdizadeh M, Mosaffa N. Therapeutic effect of trace elements on multiple myeloma and mechanisms of cancer process. Food Chem Toxicol. 2023;179:113983. doi:10.1016/j.fct.2023.113983
Barker T. Vitamins and human health: systematic reviews and original research. Nutrients. 2023;15(13):2888. doi:10.3390/nu15132888
Zhang FF, Barr SI, McNulty H, Li D, Blumberg JB. Health effects of vitamin and mineral supplements. BMJ. 2020;369:m2511. doi:10.1136/bmj.m2511
Rai SN, Singh P, Steinbusch HWM, Vamanu E, Ashraf G, Singh MP. The role of vitamins in neurodegenerative disease: an update. Biomed. 2021;9(10):1284. doi:10.3390/biomedicines9101284
Barnett LMA, Cummings BS. Cellular and molecular mechanisms of kidney toxicity. Semin Nephrol. 2019;39(2):141-151. doi:10.1093/toxsci/kfy159
Reis AMM. Drug-induced nephrotoxicity. In: Braund R, ed. Renal Medicine and Clinical Pharmacy. Vol 1. Cham, Switzerland: Springer; 2020. doi:10.1007/978-3-030-37655-0_6
Çoban FK, İnce S, Demirel HH, İslam İ, Aytuğ H. Acetaminophen-induced nephrotoxicity: suppression of apoptosis and endoplasmic reticulum stress using boric acid. Biol Trace Elem Res. 2023;201(1):242-249. doi:10.1007/s12011-022-03114-9
Aktas Senocak E, Utlu N, Kurt S, Kucukler S, Mehmet F. Sodium pentaborate prevents acetaminophen-induced hepatorenal injury by suppressing oxidative stress, lipid peroxidation, apoptosis, and inflammatory cytokines in rats. Biol Trace Elem Res. 2024;202:1164-1173. doi:10.1007/s12011-023-03755-4
Ozatik FY, Teksen Y, Kadioglu E, Ozatik O, Bayat Z. Effects of hydrogen sulfide on acetaminophen-induced acute renal toxicity in rats. Int Urol Nephrol. 2019;51(4):745-754. doi:10.1007/s11255-018-2053-0
Shi J, Peng X, Huang J, Zhang M, Wang Y. Dihydromyricetin alleviated acetaminophen-induced acute kidney injury via nrf2-dependent anti-oxidative and anti-inflammatory effects. Int J Mol Sci. 2025;26(5):2365. doi:10.3390/ijms26052365
Volarevic V, Djokovic B, Jankovic MG, et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci. 2019;26:25. doi:10.1186/s12929-019-0518-9
Tang C, Livingston MJ, Safirstein R, Dong Z. Cisplatin nephrotoxicity: new insights and therapeutic implications. Nat Rev Nephrol. 2023;19:53-72. doi:10.1038/s41581-022-00631-7
El-Rhman RH, El-Naga RN, Gad AM, Tadros MG, Hassaneen SK. Dibenzazepine attenuates against cisplatin-induced nephrotoxicity in rats: involvement of NOTCH pathway. Front Pharmacol. 2020;11:567852. doi:10.3389/fphar.2020.567852
Shinde SD, Jain PG, Cheke RS, Surana SJ, Gunjegaonkar SM. Abrogation of cisplatin-induced nephrotoxicity in rats and HEK-293 cell lines by formononetin: in vivo and in vitro study. Comp Clin Pathol. 2021;30:617-625. doi:10.1007/s00580-021-03252-x
Qi J, Gao L. Linarin protects against cisplatin-induced nephrotoxicity via subsiding proinflammatory and oxidative stress biomarkers in male Wistar rats. Pharmacognosy Mag. 2024;0(0). doi:10.1177/09731296241297432
Famurewa AC, Akunna GG, Nwafor J, Chukwu OC, Ekeleme-Egedigwe CA, Oluniran JN. Nephroprotective activity of virgin coconut oil on diclofenac-induced oxidative nephrotoxicity is associated with antioxidant and anti-inflammatory effects in rats. Avicenna J Phytomed. 2020;10(3):316-324
Moradi A, Abolfathi M, Javadian M, et al. Gallic Acid Exerts Nephroprotective, Anti-Oxidative Stress, and Anti-Inflammatory Effects Against Diclofenac-Induced Renal Injury in Male rats. Arch Med Res. 2021;52(4):380-388. doi:10.1016/j.arcmed.2020.12.005
Karimi-Matloub S, Namavari R, Hatefi-Hesari F, et al. The nephroprotective effect of ellagic acid against diclofenac-induced renal injury in male rats: role of Nrf2/HO-1 and NF-κB/TNF-α pathways. Biologia 2022;77:3633-3643. doi:10.1007/s11756-022-01217-1
Alorabi M, Cavalu S, Al-Kuraishy HM, et al. Pentoxifylline and berberine mitigate diclofenac-induced acute nephrotoxicity in male rats via modulation of inflammation and oxidative stress. Biomed Pharmacother. 2022;152:113225. doi:10.1016/j.biopha.2022.113225
Comez M, Cellat M, Kuzu M, et al. The effect of tyrosol on diclofenac sodium-induced acute nephrotoxicity in rats. J Biochem Mol Toxicol. 2024;38(1):e23582. doi:10.1002/jbt.23582
Mansoure AN, Elshal M, Helal MG. Inhibitory effect of diacerein on diclofenac-induced acute nephrotoxicity in rats via modulating SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes. Int Immunopharmacol. 2024;131:111776. doi:10.1016/j.intimp.2024.111776
Lu C, Wei J, Gao C, et al. Molecular signaling pathways in doxorubicin-induced nephrotoxicity and potential therapeutic agents. Int Immunopharmacol. 2025;144:113373. doi:10.1016/j.intimp.2024.113373
Ikewuchi CC, Ifeanacho MO, Ikewuchi JC. Moderation of doxorubicin-induced nephrotoxicity in Wistar rats by aqueous leaf-extracts of Chromolaena odorata and Tridax procumbens. Porto Biomed J. 2021;6(1):e129. doi:10.1097/j.pbj.0000000000000129
Afsar T, Razak S, Almajwal A, Al-Disi D. Doxorubicin-induced alterations in kidney functioning, oxidative stress, DNA damage, and renal tissue morphology; improvement by Acacia hydaspica tannin-rich ethyl acetate fraction. Saudi J Biol Sci. 2020;27(9):2251-2260. doi:10.1016/j.sjbs.2020.07.011
Altinkaynak Y, Kural B, Akcan BA, et al. Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats. Biomed Pharmacother. 2018;108:1524-1534. doi:10.1016/j.biopha.2018.09.171
Hekmat AS, Chenari A, Alipanah H. et al. Protective effect of alamandine on doxorubicin induced nephrotoxicity in rats. BMC Pharmacol Toxicol. 2021;22:31 doi:10.1186/s40360-021-00494-x
Al Suleimani Y, Al Maskari R, Ali BH, et al. Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats. Toxicol Rep. 2023;11:460-468. doi:10.1016/j.toxrep.2023.11.005
Famurewa AC, Aja PM, Balogun ME, et al. Prophylactic administration of naringin prevents anticancer drug 5-fluorouracil-induced hepatorenal toxicity via suppressing lipid peroxidation and oxidative stress in rats. Pharmacol Res Nat Prod. 2025;6:100137. doi:10.1016/j.prenap.2024.100137
Mansoori R, Kazemi S, Almasi D, et al. Therapeutic benefit of melatonin in 5-fluorouracil-induced renal and hepatic injury. Basic Clin Pharmacol Toxicol. 2023;134(3):397-411. doi:10.1111/bcpt.13976
El-Gendy HF, El-Bahrawy MM, Mansour DA, et al. Unraveling the potential of Saccharum officinarum and Chlorella vulgaris towards 5-fluorouracil-induced nephrotoxicity in rats. Pharmaceutics. 2024;17(7):885. doi:10.3390/ph17070885
Althagafy HS, Hassanein EHM. Morin Mitigates 5-Fluorouracil-Induced Nephrotoxicity by Activating Nrf2/HO-1 and FXR, and Suppressing ERK/VCAM-1 and NF-κB Pathways. Int Immunopharmacol. 2025;148:114092. doi:10.1016/j.intimp.2025.114092
Albadrani GM, Altyar AE, Kensara OA, et al. Lycopene alleviates 5-fluorouracil-induced nephrotoxicity by modulating PPAR-γ, Nrf2/HO-1, and NF-κB/TNF-α/IL-6 signals. Renal Failure. 2024;46(2). doi:10.1080/0886022X.2024.2423843
Al-Ghamdi AH, Mohamed MZ, Elbadry RM, Fouad AA. Kidney protective effect of sitagliptin in 5-fluorouracil-challenged rats. Pharmacia. 2024;71:1-5. doi:10.3897/pharmacia.71.e114441
Akila AA, Gad RA, Ewees MGED, Abdul-Hamid M, Abdel-Reheim ES. Clopidogrel protects against gentamicin-induced nephrotoxicity through targeting oxidative stress, apoptosis, and coagulation pathways. Naunyn Schmiedebergs Arch Pharmacol. 2025;398:2609-2625. doi:10.1007/s00210-024-03380-5
Abukhalil MH, Al-Alami Z, Altaie HAA, et al. Galangin prevents gentamicin-induced nephrotoxicity by modulating oxidative damage, inflammation, and apoptosis in rats. Naunyn Schmiedebergs Arch Pharmacol. 2025;398:3717-3729. doi:10.1007/s00210-024-03449-1
Saeedavi M, Goudarzi M, Fatemi I, et al. Gentisic acid mitigates gentamicin-induced nephrotoxicity in rats. Tissue Cell. 2023;84:102191. doi:10.1016/j.tice.2023.102191
Dik B, Hatipoglu D, Ates MB. Potential effects of Resatorvid and alpha lipoic acid on gentamicin-induced nephrotoxicity in rats. Pharmacol Res Persp.2024;12(4):e1222. doi:10.1002/prp2.1222
Nadeem RI, Aboutaleb AS, Younis NS, Ahmed HI. Diosmin mitigates gentamicin-induced nephrotoxicity in rats: insights on miR-21 and -155 expression, Nrf2/HO-1 and p38-MAPK/NF-κB pathways. Toxics. 2023;11(1):48. doi:10.3390/toxics11010048
Rafique Z, Aabid M, Nadeem H, et al. Nephroprotective Potential of 1,3,4-Oxadiazole Derivative Against Methotrexate-Induced Nephrotoxicity in Rats by Upregulating Nrf2 and Downregulating NF-κB and TNF-α Signaling Pathways. J Biochem Mol Toxicol. 2024;38(12):e70084. doi:10.1002/jbt.70084
Mishriki AA, Khalifa AK, Ibrahim DA, et al. Empagliflozin mitigates methotrexate-induced nephrotoxicity in male albino rats: insights on the crosstalk of AMPK/Nrf2 signaling pathway. Futur J Pharm Sci. 2024;10:95. doi:10.1186/s43094-024-00669-3
Morsy MA, El-Sheikh AAK, Abdel-Hafez SMN, Kandeel M, Abdel-Gaber SA. Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway. Front Pharmacol. 2022;13: 774387. doi:10.3389/fphar.2022.774387
Wasfey EF, Shaaban M, Essam M, et al. Infliximab Ameliorates Methotrexate-Induced Nephrotoxicity in Experimental Rat Model: Impact on Oxidative Stress, Mitochondrial Biogenesis, Apoptotic and Autophagic Machineries. Cell Biochem Biophys. 2023;81(4):717-726. doi:10.1007/s12013-023-01168-7
Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin I. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017;41(5):e12398. doi:10.1111/jfbc.12398
Gunes S, Sahinturk V, Uslu S, Ayhanci A, Kacar S, Uyar R. Protective effects of selenium on cyclophosphamide-induced oxidative stress and kidney injury. Biol Trace Elem Res. 2018;185(1):116-123. doi:10.1007/s12011-017-1231-8
Adikwu E, Ezerioha CE, Biradee I. Selenium Protects against Tenofovir/Lamivudine/Efavirenz-Induced Nephrotoxicity in Rats. J Nat Sci Med. 5(2):157-162. doi:10.4103/jnsm.jnsm_153_20
Mehanna ET, Khalaf SS, Mesbah NM, Abo-Elmatty DM, Hafez MM. Anti-oxidant, anti-apoptotic, and mitochondrial regulatory effects of selenium nanoparticles against vancomycin induced nephrotoxicity in experimental rats. Life Sci. 2022;288:120098. doi:10.1016/j.lfs.2021.120098
Wu Q, Wang X, Nepovimova E, Wang Y, Yang H, Kuca K. Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings. Food Chem Toxicol. 2018;118:889-907. doi:10.1016/j.fct.2018.06.054
Bai S, Zhang M, Tang S, et al. Effects and impact of selenium on human health, A review. Molecules. 2024;30(1):50. doi:10.3390/molecules30010050
Genchi G, Lauria G, Catalano A, Sinicropi MS, Carocci A. biological activity of selenium and its impact on human health. Int J Mol Sci. 2023;24(3):2633. doi:10.3390/ijms24032633
Bjørklund G, Shanaida M, Lysiuk R, et al. Selenium: an antioxidant with a critical role in anti-aging. Molecules. 2022;27(19):6613. doi:10.3390/molecules27196613
Randjelovic P, Veljkovic S, Stojiljkovic N, et al. Protective effect of selenium on gentamicin-induced oxidative stress and nephrotoxicity in rats. Drug Chem Toxicol. 2011;35(2):141-148. doi:10.3109/01480545.2011.589446
Aksoy A, Karaoglu A, Akpolat N, Naziroglu M, Ozturk T, Karagoz ZK. Protective role of selenium and high dose vitamin E against cisplatin - induced nephrotoxicty in rats. Asian Pac J Cancer Prev. 2015;16(16):6877-6882. doi:10.7314/apjcp.2015
Al-Fartusie FS, Mohssan SN. Essential trace elements and their vital roles in human body. Ind J Adv Chem Sci. 2017;5(3):127-136. doi:10.22607/IJACS.2017.503003
Kloubert V, Rink L. Zinc as a micronutrient and its preventive role of oxidative damage in cells. Food Func. 2015;6:3195-3204. doi:10.1039/c5fo00630a
Lahhoba QR, Al-sanafd AE, Mohammede NY, et al. Mineral and trace elements, dietary sources, biological effects, deficiency, and toxicity: A review. Eurasian Chem Commun. 2023;5:536-555. doi:10.22034/ecc.2023.381964.1594
Tuzcu M, Sahin N, Dogukan A, et al. Protective role of zinc picolinate on cisplatin-induced nephrotoxicity in rats. J Ren Nutr. 2010;20(6):398-407. doi:10.1053/j.jrn.2010.04.002
Kone SD, Gnahoue G, Yapi FH. Evaluation of preventive effects of zinc, vitamin D and their combination against nephrotoxicity induced by gentamicin in rats. Eur J Biotechnol Biosci. 2019;7(2):23-29.
Choopani S, Kasaei S, Talebi A, et al. Cyclosporine-A induced nephrotoxicity in male and female rats: Is zinc a suitable protective supplement? Biomed Res Ther. 5(12): 2888-2897. doi:10.15419/bmrat.v5i12.507
Elgohary A, Metwalli F, Mostafa NY, Reffat M, El-Khawaga OY. Zinc oxide nanoparticles regulate NF-kB expression and restrict inflammation response in doxorubicin-induced kidney injury in rats. Toxicol Environ Health Sci. 2023;15:437-448. doi:10.1007/s13530-023-00194-5
Barakat LAA, Barakat N, Zakaria MM, Khirallah SM. Protective role of zinc oxide nanoparticles in kidney injury induced by cisplatin in rats. Life Sci. 2020;262:118503. doi:10.1016/j.lfs.2020.118503
Vinceti M, Filippini T, Jablonska E, Saito Y, Wise LA. Safety of selenium exposure and limitations of selenoprotein maximization: Molecular and epidemiologic perspectives. Environ Res. 2022;211:113092. doi:10.1016/j.envres.2022.113092
Schoofs H, Schmit J, Rink L. Zinc toxicity: understanding the limits. Molecules. 2024;29(13):3130. doi:10.3390/molecules29133130.
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