Nephroprotective Effects of Citrus spp. Fruit-Cuticle Extracts, Melatonin, and Hydrochlorothiazide on HgCl₂-Induced Acute Renal Failure in Albino Rats
DOI:
https://doi.org/10.31530/cjnst.2026.2.2.4Keywords:
Mercury Chloride, Nephrotoxicity, Kidney failure, Rat, Citrus sinensis, Citrus limon, Melatonin, HydrochlorothiazideAbstract
Background: The management of renal failure is a global challenge and roles of medicinal plants in treating acute renal failure (ARF) are still under consideration. Most research focused on their benefits in chronic kidney disease (CKD), leaving a gap in how these natural remedies could help in ARF management.
Aim: To find out how Citrus sinensis, Citrus limon fruit cuticles and melatonin protect the kidneys from HgCl2-induced nephrotoxicity at rat model and comparing them with routine-diuretic thiazide drug.
Patients and Methods: Thirty-six healthy male Wistar rats were evenly allocated into six groups (n=6): Control, Model (ARF), Citrus limon Extract (CLE), Citrus sinensis Extract (CSE), Melatonin (MEL), and Hydrochlorothiazide (HCTZ). The rats were provided with regular food and water ad libitum. except for the control group, both the model and treatment groups were injected with HgCl2 every 72 hours for a duration of three weeks to induce ARF. Treatment protocols were assigned to the treatment groups throughout the trial duration. At the end of the study, serum renal biomarkers including Urea, Creatinine, Uric acid, Electrolytes (Na+, K+, and Cl-), Packed Cell Volume, and Malondialdehyde (MDA) were quantified from blood samples.
Result: HgCl2-treated animals exhibited a substantial elevation (p<0.05) in serum urea, creatinine, and MDA levels, alongside a non-significant reduction in serum Na+ and PCV levels, indicating HgCl2-induced renal impairment in comparison to control rats. Moreover, treatments of CLE and CSE, MEL and HCTZ in conjunction with HgCl2 significantly (P<0.05) ameliorated HgCl2-induced nephrotoxicity, in comparison to model rats, indicating a reduction in HgCl2's toxic effects and safeguarding of renal tubules from oxidative stress.
Conclusion: All treatments from the current study showed a mild renal protective effect across biomarkers of urea, creatinine and MDA and CSE showed most significant potential effect.
Downloads
References
[1] M. Ostermann, N. Lumlertgul, R. Jeong, E. See, M. Joannidis, and M. James, “Acute kidney injury,” The Lancet, vol. 405, no. 10474, pp. 241–256, 2025:
https://doi.org/10.1016/S0140-6736(24)02385-7.
[2] X. Xu et al., "Acute kidney injury: pathogenesis and therapeutic interventions," Molecular biomedicine, vol. 6, no. 1, p. 61, 2025: https://doi.org/10.1186/s43556-025-00293-4.
[3] D. Ponce, N. Kazan, A. Pereira, and A. Balbi, "Acute kidney injury: risk factors and management challenges in low-and middle-income countries," NEPHROLOGY, vol. 8, no. 1, pp. 60-67, 2020: https://doi.org/10.2147/IJNRD.S104209.
[4] A. Zuk and J. V. Bonventre, "Acute kidney injury," Annual review of medicine, vol. 67, no. 1, pp. 293-307, 2016: https://doi.org/10.1146/annurev-med-050214-013407.
[5] P. Lentini, L. Zanoli, A. Granata, S. S. Signorelli, P. Castellino, and R. Dellaquila, "Kidney and heavy metals-The role of environmental exposure," Molecular medicine reports, vol. 15, no. 5, pp. 3413-3419, 2017: https://doi.org/10.3892/mmr.2017.6389
[6] C. G. Y. Paul B Tchounwou, Anita K Patlolla, and Dwayne J Sutton, "Heavy Metals Toxicity and the Environment," NIH, vol. 1, pp. 1-26, 2012, doi: https://doi.org/10.1007/978-3-7643-8340-4_6.
[7] C. Caglayan, F. M. Kandemir, S. Yildirim, S. Kucukler, and G. Eser, "Rutin protects mercuric chloride‐induced nephrotoxicity via targeting of aquaporin 1 level, oxidative stress, apoptosis and inflammation in rats," Journal of Trace Elements in Medicine and Biology, vol. 54, pp. 69-78, 2019/07/01/ 2019, doi: https://doi.org/10.1016/j.jtemb.2019.04.007.
[8] V. Unsal, "Natural Phytotherapeutic Antioxidants in the Treatment of Mercury Intoxication-A Review," (in eng), Adv Pharm Bull, vol. 8, no. 3, pp. 365-376, Aug 2018, doi: https://doi.org/10.15171/apb.2018.043.
[9] M. A. Alam, N. Subhan, M. M. Rahman, S. J. Uddin, H. M. Reza, and S. D. Sarker, "Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action," (in eng), Adv Nutr, vol. 5, no. 4, pp. 404-17, Jul 2014, doi: https://doi.org/10.3945/an.113.005603.
[10] M. Markowska, S. Niemczyk, and K. Romejko, "Melatonin Treatment in Kidney Diseases," (in eng), Cells, vol. 12, no. 6, Mar 8 2023, doi: https://doi.org/10.3390/cells12060838.
[11] A. Tarocco et al., "Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care," Cell Death & Disease, vol. 10, no. 4, p. 317, 2019/04/08 2019, doi: https://doi.org/10.1038/s41419-019-1556-7.
[12] W. Jo, E. S. Koh, and S. Chung, "Therapeutic roles of thiazides and loop diuretics in blood pressure control and renal protection against chronic kidney disease," Clin Hypertens, vol. 29, no. 1, 0/ 2023, doi: https://doi.org/10.1186/s40885-023-00238-5.
[13] Z. H. Ibrahim, "Anti-obesity effects of Arum maculatum, Nasturtium officinale plant extracts and exercise in high fat diet-induced obese rats," Kurdistan Journal of Applied Research, vol. 6, no. 2, pp. 190-198, 2021: https://doi.org/10.24017/science.2021.2.18.
[14] N. Bennour, H. Mighri, H. Eljani, T. Zammouri, and A. Akrout, "Effect of solvent evaporation method on phenolic compounds and the antioxidant activity of Moringa oleifera cultivated in Southern Tunisia," South African Journal of Botany, vol. 129, pp. 181-190, 2020: https://doi.org/10.1016/j.sajb.2019.05.005.
[15] K. Mahmood and S. Kadir, "Protective Effects of Exogenous Melatonin on Cisplatin-Induced Acute Nephrotoxicity in Rats," Journal of Zankoy Sulaimani-Part A, vol. 19, no. 1, pp. 17-26, 2017: https://doi.org/10.17656/jzs.10581.
[16] P. R. Augusti et al., "Effect of lycopene on nephrotoxicity induced by mercuric chloride in rats," Basic & clinical pharmacology & toxicology, vol. 100, no. 6, pp. 398-402, 2007: https://doi.org/10.1111/j.1742-7843.2007.00067.x.
[17] Z. O. Khudhur and I. M. Maulood, "Lead acetate deteriorates the improvement effect of L-arginine and tetrahydrobiopterin on endothelin-1 receptors activity in rat aorta," Baghdad Science Journal, vol. 20, no. 5, p. 43, 2023: https://doi.org/10.21123/bsj.2023.7594
[18] E. C. de Almeida et al., "Metalloproteomic Investigation of Hg-Binding Proteins in Renal Tissue of Rats Exposed to Mercury Chloride," International Journal of Molecular Sciences, vol. 25, no. 1, p. 164, 2023: https://doi.org/10.3390/ijms25010164.
[19] S. E. Orr and C. C. Bridges, "Chronic kidney disease and exposure to nephrotoxic metals," International journal of molecular sciences, vol. 18, no. 5, p. 1039, 2017: https://doi.org/10.3390/ijms18051039.
[20] E. Onan, S. Ulu, and Ö. Güngör, "Heavy Metals and Kidney," Turk J Nephrol, vol. 33, no. 3, pp. 244-251, 2024: https://doi.org/10.5152/turkjnephrol.2024.22497.
[21] R. S. Almeer, G. Albasher, F. Alotibi, S. Alarifi, D. Ali, and S. Alkahtani, "Ziziphus spina-christi Leaf Extract Suppressed Mercury Chloride‐Induced Nephrotoxicity via Nrf2‐Antioxidant Pathway Activation and Inhibition of Inflammatory and Apoptotic Signaling," Oxidative medicine and cellular longevity, vol. 2019, no. 1, p. 5634685, 2019: https://doi.org/10.1155/2019/5634685.
[22] C. C. Bridges and R. K. Zalups, "Mechanisms involved in the transport of mercuric ions in target tissues," Archives of toxicology, vol. 91, no. 1, pp. 63-81, 2017: https://doi.org/10.1007/s00204-016-1803-y.
[23] M. Kahramanoğullari, M. Erişir, M. Yaman, and T. Parlak Ak, "Effects of naringenin on oxidative damage and apoptosis in liver and kidney in rats subjected to chronic mercury chloride," Environmental Toxicology, vol. 39, no. 5, pp. 2937-2947, 2024:
https://doi.org/10.1002/tox.24164.
[24] A. M. Mahmoud, R. J. Hernandez Bautista, M. A. Sandhu, and O. E. Hussein, "Beneficial effects of citrus flavonoids on cardiovascular and metabolic health," Oxidative medicine and cellular longevity, vol. 2019, no. 1, p. 5484138, 2019:
https://doi.org/10.1155/2019/5484138.
[25] A. Abd-Eltawab Tammam et al., "Hesperidin protects rats’ liver and kidney from oxidative damage and physiological disruption induced by nickel oxide nanoparticles," Frontiers in Physiology, vol. 13, p. 912625, 2022, doi:
https://doi.org/10.3389/fphys.2022.912625.
[26] A. Ota-Kontani, H. Hirata, M. Ogura, Y. Tsuchiya, and M. Harada-Shiba, "Comprehensive analysis of mechanism underlying hypouricemic effect of glucosyl hesperidin," Biochemical and biophysical research communications, vol. 521, no. 4, pp. 861-867, 2020: https://doi.org/10.1016/j.bbrc.2019.10.199
[27] N. J. Frenkel et al., "Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2," Journal of Hypertension, vol. 33, no. 3, pp. 627-633, 2015, doi: https://doi.org/10.1097/hjh.0000000000000423.
[28] Y. Zhao et al., "Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases," Nature Communications, vol. 15, no. 1, p. 7006, 2024, doi: https://doi.org/10.1038/s41467-024-51381-y.
[29] R. Vinodhini and M. Narayanan, "The impact of toxic heavy metals on the hematological parameters in common carp (Cyprinus carpio L.)," Journal of Environmental Health Science & Engineering, vol. 6, no. 1, pp. 23-28, 2009, doi: https://doi.org/10.5555/20093168474.
[30] G. Şener, A. Ö. Şehirli, and G. Ayanogˇlu‐Dülger, "Melatonin protects against mercury (II)‐induced oxidative tissue damage in rats," Pharmacology & toxicology, vol. 93, no. 6, pp. 290-296, 2003, doi: https://doi.org/10.1111/j.1600-0773.2003.pto930607.x.
[31] R. Kołodziejska et al., "Melatonin—A Powerful Oxidant in Neurodegenerative Diseases," Antioxidants, vol. 14, no. 7, p. 819, 2025, doi: https://doi.org/10.3390/antiox14070819.
[32] X. Lu, C. Zhao, H. Shi, Y. Liao, F. Xu, H. Du, H. Xiao, and J. Zheng, “Nutrients and bioactives in citrus fruits: Different citrus varieties, fruit parts, and growth stages,” Critical Reviews in Food Science and Nutrition, vol. 63, no. 14, pp. 2018–2041, 2023. doi: https://doi.org/10.1080/10408398.2021.1969891.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Charmo Journal of Natural Sciences and Technologies

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.


