Panax ginseng protects against copper sulfate-induced kidney toxicity in rats

Abstract

Objective: To assess the protective effects of Panax ginseng (PG) against copper sulfate (CuSO4)-induced kidney toxicity in rats.

Methods: The rats were randomly allocated into four groups: control, CuSO4, PG, and PG+CuSO4. The experiment continued for 14 days, during which CuSO4 was provided at a dosage of 100 mg/kg body weight per day and PG at 300 mg/kg body weight by oral gavage per day. Upon completion of the experiment, kidney sections were used for histological and histomorphometric analyses. The histochemical method was applied to ascertain the density of the glomerular mesangial matrix. The expressions of vascular endothelial growth factor (VEGF) and caspase-3 were examined using immunohistochemistry. The levels of malondialdehyde and glutathione, along with the activity of superoxide dismutase and catalase in the kidney, were measured.

Results: PG treatment exhibited a marked protective effect against CuSO4-induced renal damage, as evidenced by improved histopathological lesions, significantly reduced glomerular mesangial matrix density, VEGF in distal tubules, caspase-3 expression, and malondialdehyde levels in renal tissue, as well as enhanced superoxide dismutase and catalase activities.

Conclusions: PG treatment ameliorates CuSO4-induced kidney injury in rats. Further studies are warranted to verify its efficacy and elucidate the underlying mechanism of its nephroprotective action.

Keywords

Copper sulfate / Kidney / Panax ginseng / VEGF / Antioxidant

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research received no extramural funding.

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon request.

Authors’ contributions

OG, MB, AS, BD, and MY contributed to the methodology. OG, AS, and BD carried out the investigation and provided resources. The original draft of the manuscript was written by OG, AS, and BD. Review and editing of the manuscript were done by OG and MY Project administration was conducted by OG and MY. All authors read and approved the final version of the manuscript.

Publisher’s note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

[1] Focarelli F, Giachino A, Waldron KJ. Copper microenvironments in the human body define patterns of copper adaptation in pathogenic bacteria. PLoS Pathog 2022; 18(7). doi: 10.1371/journal.ppat.1010617.

[2] Wang Z, Jin D, Zhou S, Dong N, Ji Y, An P, et al. Regulatory roles of copper metabolism and cuproptosis in human cancers. Front Oncol 2023; 13. doi: 10.3389/fonc.2023.1123420.

[3] Firat O, Erol R, Firat O. Effects of individual and co-exposure of copper oxide nanoparticles and copper sulphate on Nile Tilapia Oreochromis niloticus: Nanoparticles enhance pesticide biochemical toxicity. Acta Chim Slov 2022; 69(1):81-90.

[4] El Sabry MI, Stino FKR, El-Ghany WAA. Copper: Benefits and risks for poultry, livestock, and fish production. Trop Anim Health Prod 2021; 53(5):487.

[5] Dai C, Liu Q, Li D, Sharma G, Xiong J, Xiao X. Molecular insights of copper sulfate exposure-induced nephrotoxicity: Involvement of oxidative and endoplasmic reticulum stress pathways. Biomolecules 2020; 10(7):1010.

[6] Hashem MA, Abd El Hamied SS, Ahmed EMA, Amer SA, Hassan AM. Alleviating effects of vitamins C and E supplementation on oxidative stress, hematobiochemical, and histopathological alterations caused by copper toxicity in broiler chickens. Animals (Basel) 2021; 11(6):1739.

[7] Failla CM, Carbone ML, Ramondino C, Bruni E, Orecchia A. Vascular endothelial growth factor (VEGF) family and the immune system: Activators or inhibitors? Biomedicines 2024; 13(1):6.

[8] Guo X, Yi H, Li TC, Wang Y, Wang H, Chen X. Role of vascular endothelial growth factor (VEGF) in human embryo implantation: Clinical implications. Biomolecules 2021; 11(2):253.

[9] Li J, Li XL, Li CQ. Immunoregulation mechanism of VEGF signaling pathway inhibitors and its efficacy on the kidney. Am J Med Sci 2023; 366(6):404-412.

[10] Rangaswamy D, Nagaraju SP, Bhojaraja MV, Swaminathan SM, Prabhu RA, Rao IR, et al. Ocular and systemic vascular endothelial growth factor ligand inhibitor use and nephrotoxicity: An update. Int Urol Nephrol 2024; 56(8):2635-2644.

[11] Yang N, Sun Q, Wang Y, Mei D, Wang X, Zhang J, et al. Endosomal disruption by co-encapsulating gentamicin in lipid nanoparticles for efficient siRNA delivery and cancer therapy. Asian J Pharm Sci 2025; 20(3):101011.

[12] Ratan ZA, Haidere MF, Hong YH, Park SH, Lee JO, Lee J, et al. Pharmacological potential of ginseng and its major component ginsenosides. J Ginseng Res 2021; 45(2):199-210.

[13] Alqahtani MS, Ali AHA, El Baz KR, Ibrahim SR, Albadrani AA, Alqasem S, et al. Protective effect of ginseng against the gentamicin-induced renal toxicity. Kurdish Stud 2024; 12(1):1778-1785.

[14] Yilmaz H, Karakoc Y, Tumkaya L, Mercantepe T, Sevinc H, Yilmaz A, et al. The protective effects of red ginseng and amifostine against renal damage caused by ionizing radiation. Hum Exp Toxicol 2022;41. doi: 10.1177/9603271221143029.

[15] Mostafa RE, Shaffie NM, Allam RM. Panax ginseng alleviates thioacetamide-induced liver injury in ovariectomized rats: Crosstalk between inflammation and oxidative stress. PLoS One 2021; 16(11). doi: 10.1371/journal.pone.0260507.

[16] Sarawi WS, Alhusaini AM, Fadda LM, Alomar HA, Albaker AB, Aljrboa AS, et al. Curcumin and nano-curcumin mitigate copper neurotoxicity by modulating oxidative stress, inflammation, and Akt/GSK-3β signaling. Molecules 2021; 26(18):5591.

[17] Selcuk ML, Tipirdamaz S. A morphological and stereological study on brain, cerebral hemispheres and cerebellum of New Zealand rabbits. Anat Histol Embryol 2020; 49(1):90-96.

[18] Kawilarang AP. Perbandingan pengecatan hematoxylin & eosin (HE) dan periodic acid Schiff (PAS) pada mucormycosis. JMKPM 2023; 2(1):1-5.

[19] Boyacioglu M, Gules O, Sahiner HS. Protective effect of sodium selenite on 4-nonylphenol-induced hepatotoxicity and nephrotoxicity in rats. Biol Trace Elem Res 2021; 199(8):3001-3012.

[20] Koc S, Kum S. vimentin, Investigation of IgG, CD 45 distribution, and density in mouse placenta at different periods of pregnancy. Turk J Vet Anim Sci 2022; 46:505-516.

[21] Yilgor A, Demir C. Determination of oxidative stress level and some antioxidant activities in refractory epilepsy patients. Sci Rep 2024; 14(1):6688.

[22] Sunil J, Manjubala M, Singh A. Parametric and non-parametric analysis. In: Mahapatra SK (ed.) Advances in agricultural research methodology. Odisha: S P Publishing; 2023, p. 60-68.

[23] Dai C, Li M, Liu Y, Tran DH, Jiang H, Tang S, et al. Involvement of the inhibition of mitochondrial apoptotic, p53, NF-κB pathways and the activation of Nrf2/HO-1 pathway in the protective effects of curcumin against copper sulfate-induced nephrotoxicity in mice. Ecotoxicol Environ Saf 2023; 249:114480.

[24] Owoeye O, Edem FV, Akinyoola BS, Arinola GO. Renal corpuscles were protected from Dichlorvos-induced morphological alterations in rats by antioxidant vitamins. Int J Morphol 2014; 32(2):475-480.

[25] Peng X, Dai C, Zhang M, Das Gupta S. Molecular mechanisms underlying protective role of quercetin on copper sulfate-induced nephrotoxicity in mice. Front Vet Sci 2021; 7:586033.

[26] Sailer J, Nagel J, Akdogan B, Jauch AT, Engler J, Knolle PA, et al. Deadly excess copper. Redox Biol 2024; 75:103256.

[27] Hajimohammadi S, Gharibi S, Pourbarkhordar V, Mousavi SR, Salmani Izadi H. Acute poisoning of copper sulfate: A case report and review of literature. Egypt J Intern Med 2022; 34:84.

[28] Park WH, Lee SK, Kim CH. A Korean herbal medicine, Panax notoginseng, prevents liver fibrosis and hepatic microvasculardysfunction in rats. Life Sci 2005; 76:1675-1690.

[29] Al-Jammas S, Al-Shibib AL, Taga GA, AL-Saraj A. The histological changes induced by Indian ginseng in kidneys, livers and brains of rats. Egypt J Histol 2023; 46(4):2148-2158.

[30] Ghonimi WAM, Alferah MAZ, Dahran N, El-Shetry ES. Hepatic and renal toxicity following the injection of copper oxide nanoparticles (CuO NPs) in mature male Westar rats: Histochemical and caspase 3 immunohistochemical reactivities. Environ Sci Pollut Res Int 2022; 29(54):81923-81937.

[31] Matos RC, Vieira C, Morais S, Pereira Mde L, Pedrosa J. Nephrotoxicity effects of the wood preservative chromium copper arsenate on mice: Histopathological and quantitative approaches. J Trace Elem Med Biol 2009; 23(3):224-230.

[32] Tomooka S, Border WA, Marshall BC, Noble NA. Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. Kidney Int 1992; 42:1462-1469.

[33] Sen S, Chen S, Feng B, Wu Y, Lui E, Chakrabarti S. Preventive effects of North American ginseng (Panax quinquefolium) on diabetic nephropathy. Phytomedicine 2012; 19(6):494-505.

[34] Borkow G, Melamed E. The Journey of copper-impregnated dressings in wound healing: From a medical hypothesis to clinical practice. Biomedicines 2025; 13(3):562.

[35] Wang F, Liu S, Sun Q, Zhang L, Song Y, Sheng W, et al. Urinary VEGF and PGE₂ levels and the association with arsenical metabolites in copper-smelting workers. Occup Environ Med 2014; 71(10):675-680.

[36] Ma C, Huang W, Wang H, Yao W, Liang M, Yu G, et al. Oxidized LDL promotes EMS-induced angiogenesis by increasing VEGF-A expression and secretion by endometrial cells. Mol Med 2022; 28(1):151.

[37] Shihab FS, Bennet WM, Isaac J, Yi H, Andoh T. Angiotensin II regulation of vascular endothelial growth factor and receptors Flt-1 and KDR/Flk-1 in cyclosporine nephrotoxicity. Kidney Int 2002; 62(2):422-433.

[38] Ogutmen B, Tuglular S, Cakalagaoglu F, Ozener C, Akoglu E. Transforming growth factor-beta1, vascular endothelial growth factor, and bone morphogenic protein-7 expression in tacrolimus-induced nephrotoxicity in rats. Transplant Proc 2006; 38(2):487-489.

[39] Wang YS, Chen C, Zhang SY, Li Y, Jin YH. Ginsenoside Rh 2 inhibits STAT3/VEGF signaling by targeting annexin A2. Int J Mol Sci 2021; 22(17):9289.

[40] Xie W, Zhou P, Qu M, Dai Z, Zhang X, Zhang C, et al. Ginsenoside Re attenuates high glucose-induced RF/6A injury via regulating PI3K/AKT inhibited HIF-1α/VEGF signaling pathway. Front Pharmacol 2020; 11:695.

[41] Park SK, Hyun SH, In G, Park CK, Kwak YS, Jang YJ, et al. The antioxidant activities of Korean Red Ginseng (Panax ginseng) and ginsenosides: A systemic review through in vivo and clinical trials. J Ginseng Res 2021; 45(1):41-47.

[42] Shibuya M. Vascular endothelial growth factordependent and-independent regulation of angiogenesis. BMB Rep 2008; 41(4):278-286.

[43] Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: Acritical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2001; 20:4368-4380.

[44] Elblehi SS, Hafez MH, El-Far AH. Panax ginseng ameliorates hepatorenal oxidative alterations induced by commercially used cypermethrin in male rats: Experimental and molecular docking approaches. Environ Sci Pollut Res Int 2023; 30(50);109702-109723.

[45] Yildiz M, Boyacioglu M, Avcioglu M, Elmas S. Changes induced by copper toxicity in the rat liver and the effects of Panax ginseng on these changes. Biol Bull 2023; 50(4):S694-S707.