Histopathological and immunohistochemical evaluation of renal tissue in rats following chronic low-dose cadmium exposure and the nephroprotective potential of N-acetylcysteine
DOI:
https://doi.org/10.31210/spi2026.29.01.42Keywords:
cadmium nephrotoxicity, N-acetylcysteine, renal histopathology, oxidative stress, rat model, immunohistochemistry, tubular injury, interstitial fibrosis, apoptosis, cellular proliferation.Abstract
Cadmium is a nephrotoxic heavy metal that progressively accumulates within renal tissue, inducing structural injury. This study evaluated the histopathological, morphometric, and immunohistochemical effects of chronic low-dose cadmium exposure on rat kidneys and investigated the nephroprotective potential of N-acetylcysteine. Thirty adult male Sprague-Dawley rats were divided into three groups: control; cadmium chloride (0.5 mg/kg orally twice weekly for eight weeks); and cadmium chloride concurrently with N-acetylcysteine (150 mg/kg/day intraperitoneally). Renal sections were processed for hematoxylin-eosin, Periodic Acid–Schiff, and Masson’s trichrome staining, and for immunohistochemical localization of Caspase-3 and Ki-67. Quantitative morphometric analysis demonstrated that chronic cadmium exposure increased the kidney-to-body weight ratio by 29.6 %, reduced mean glomerular diameter by 22 % (82.4±3.1 versus 105.6±4.2 micrometers; p=0.004), caused a 38 % decrease in tubular lumen area (p<0.001), and triggered a 4.1-fold expansion of interstitial fibrosis (15.8 ± 1.2% versus 3.9±0.5 %; p=0.001). Immunohistochemical data revealed that cadmium provoked a 3.2-fold elevation in Caspase-3 expression (18.2±2.1 % versus 5.6±1.0 %; p=0.002) and a 45% suppression of the Ki-67 proliferative labeling index (9.3±1.4 % versus 17.0±1.8 %; p=0.008), indicating accelerated apoptosis and compromised regeneration. A strong positive correlation was identified between interstitial fibrosis and Caspase-3 expression (Pearson r = 0.89, p<0.001). Co-administration of N-acetylcysteine significantly attenuated these alterations: interstitial fibrosis was reduced by 62% (6.7±0.9 %; p=0.003), mean glomerular diameter was partially restored to 96.1±3.8 micrometers, tubular lumen area recovered to 61.2±2.9 % (p=0.02), Caspase-3 expression decreased to 8.3±1.2 % (p=0.01), and the Ki-67 labeling index rose to 13.5±1.3 % (p=0.04). Collectively, these findings prove that chronic cadmium exposure induces apoptosis-driven fibrosis, whereas N-acetylcysteine provides substantial nephroprotection by suppressing cell death, preventing fibrosis, and partial restoring proliferative capacity.
References
1. Odewumi, C. O., Badisa, V. L., Le, U. T., Latinwo, L. M., Ikediobi, C. O., Badisa, R. B., & Darling-Reed, S. F. (2011). Protective effects of N-acetylcysteine against cadmium-induced damage in cultured rat normal liver cells. International Journal of Molecular Medicine, 27 (2), 243–248. https://doi.org/10.3892/ijmm.2010.564
2. Wang, J., Zhu, H., Liu, X., & Liu, Z. (2014). N-acetylcysteine protects against cadmium-induced oxidative stress in rat hepatocytes. Journal of Veterinary Science, 15 (4), 485. https://doi.org/10.4142/jvs.2014.15.4.485
3. Yang, Y., Hassan, M. F., Ali, W., Zou, H., Liu, Z., & Ma, Y. (2025). Effects of cadmium pollution on Human Health: A narrative review. Atmosphere, 16 (2), 225. https://doi.org/10.3390/atmos16020225
4. Zhou, J., Huang, Y., Li, G., Zhao, Z., Deng, Y., Xian, S., Hu, Y., Yi, M., & Liu, L. (2026). Cadmium exposure induces renal fibrosis by inhibiting hsa_circ_0075684/miR-363-3p/KLF4 signaling pathway. Scientific Reports, 16 (1), 8754. https://doi.org/10.1038/s41598-026-39715-w
5. Wong, V. Y., Keller, P. M., Nuttall, M. E., Kikly, K., DeWolf, W. E., Lee, D., Ali, S. M., Nadeau, D. P., Grygielko, E. T., Laping, N. J., & Brooks, D. P. (2001). Role of caspases in human renal proximal tubular epithelial cell apoptosis. European Journal of Pharmacology, 433 (2-3), 135–140. https://doi.org/10.1016/s0014-2999(01)01517-5
6. Liu, Q., Zhang, R., Wang, X., Shen, X., Wang, P., Sun, N., Li, X., Li, X., & Hai, C. (2019). Effects of sub-chronic, low-dose cadmium exposure on kidney damage and potential mechanisms. Annals of Translational Medicine, 7 (8), 177. https://doi.org/10.21037/atm.2019.03.66
7. Prozialeck, W. C., & Edwards, J. R. (2010). Early biomarkers of cadmium exposure and nephrotoxicity. BioMetals, 23 (5), 793–809. https://doi.org/10.1007/s10534-010-9288-2
8. Sonpol, H. M. A., Taha, M., Bedeer, R. F., Ali, L. S., Baokbah, T. A. S., Farage, A. E., Elsisy, R. A., & Abdelkareem, M. A. (2021). Ameliorating effect of N-acetylcysteine on iron toxicity of the liver and pancreas in albino rats: Histochemical and ultrastructural study. European Journal of Anatomy, 25 (4), 385–396.
9. Safari Maleki, A., Hayes, A. W., & Karimi, G. (2024). Enhancing renal protection against cadmium toxicity: the role of herbal active ingredients. Toxicology Research, 13 (6). https://doi.org/10.1093/toxres/tfae222
10. Bautista, C. J., Arango, N., Plata, C., Mitre-Aguilar, I. B., Trujillo, J., & Ramírez, V. (2024). Mechanism of cadmium-induced nephrotoxicity. Toxicology, 502, 153726. https://doi.org/10.1016/j.tox.2024.153726
11. Ren, Z., Zheng, Y., Liu, J., Liu, Z., Chen, J., Liu, H., Qi, R., & Ma, H. (2025). Cadmium induces the secretion of SASP factors regulated by MAPK and NF-κB signaling pathways in HEK293 cells: A possible mechanism of acute kidney damage induced by cadmium. Toxicology, 515, 154166. https://doi.org/10.1016/j.tox.2025.154166
12. Dong, W., Zhang, K., Gong, Z., Luo, T., Li, J., Wang, X., Zou, H., Song, R., Zhu, J., Ma, Y., Liu, G., & Liu, Z. (2023). N-acetylcysteine delayed cadmium-induced chronic kidney injury by activating the sirtuin 1–P53 signaling pathway. Chemico-Biological Interactions, 369, 110299. https://doi.org/10.1016/j.cbi.2022.110299
13. Farjad, E., & Momeni, H. R. (2018). Silymarin ameliorates oxidative stress and enhances antioxidant defense system capacity in cadmium-treated mice. Cell Journal, 20 (3), 422–426. https://doi.org/10.22074/cellj.2018.5355
14. Nair, A., DeGheselle, O., Smeets, K., Van Kerkhove, E., & Cuypers, A. (2013). Cadmium-induced pathologies: Where is the oxidative balance lost (or not)? International Journal of Molecular Sciences, 14 (3), 6116–6143. https://doi.org/10.3390/ijms14036116
15. Renugadevi, J., & Milton Prabu, S. (2010). Quercetin protects against oxidative stress-related renal dysfunction by cadmium in rats. Experimental and Toxicologic Pathology, 62 (5), 471–481. https://doi.org/10.1016/j.etp.2009.06.006
16. Satarug, S., Garrett, S. H., Sens, M. A., & Sens, D. A. (2010). Cadmium, environmental exposure, and health outcomes. Environmental Health Perspectives, 118 (2), 182–190. https://doi.org/10.1289/ehp.0901234
17. Genchi, G., Sinicropi, M. S., Lauria, G., Carocci, A., & Catalano, A. (2020). The effects of cadmium toxicity. International Journal of Environmental Research and Public Health, 17 (11), 3782. https://doi.org/10.3390/ijerph17113782
18. Jaishankar, M., Tseten, T., Anbalagan, N., Mathew, B. B., & Beeregowda, K. N. (2014). Toxicity, mechanism and health effects of some heavy metals. Interdisciplinary Toxicology, 7 (2), 60–72. https://doi.org/10.2478/intox-2014-0009
19. Johri, N., Jacquillet, G., & Unwin, R. (2010). Heavy metal poisoning: the effects of cadmium on the kidney. BioMetals, 23 (5), 783–792. https://doi.org/10.1007/s10534-010-9328-y
20. Thévenod, F. (2009). Cadmium and cellular signaling cascades: To be or not to be? Toxicology and Applied Pharmacology, 238 (3), 221–239. https://doi.org/10.1016/j.taap.2009.01.013
21. Brzóska, M. M., Rogalska, J., Galażyn-Sidorczuk, M., Jurczuk, M., Roszczenko, A., Kulikowska-Karpińska, E., & Moniuszko-Jakoniuk, J. (2007). Effect of zinc supplementation on bone metabolism in male rats chronically exposed to cadmium. Toxicology, 237 (1-3), 89–103. https://doi.org/10.1016/j.tox.2007.05.001
22. Wang, B., & Du, Y. (2013). Cadmium and its neurotoxic effects. Oxidative Medicine and Cellular Longevity, 2013, 1–12. https://doi.org/10.1155/2013/898034
23. Patra, R. C., Rautray, A. K., & Swarup, D. (2011). Oxidative stress in lead and cadmium toxicity and its amelioration. Veterinary Medicine International, 2011, 1–9. https://doi.org/10.4061/2011/457327
24. Almansour, M. I., Alferah, M. A., Shraideh, Z. A., & Jarrar, B. M. (2017). Zinc oxide nanoparticles hepatotoxicity: Histological and histochemical study. Environmental Toxicology and Pharmacology, 51, 124–130. https://doi.org/10.1016/j.etap.2017.02.015
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