Abstract
Cadmium (Cd), a widely distributed heavy metal, is extremely toxic to the kidney. Vitamin E (VE) is an important antioxidant in the body. It is known that VE exerts a protective effect on renal oxidative damage caused by Cd, but the effect and mechanism of VE on apoptosis are not fully understood. Thus, we conducted this study to explore the protective effect of VE on Cd-induced renal apoptosis and to elucidate its potential mechanism. Thirty-two 9-week-old male Sprague-Dawley rats were randomly divided into four groups, namely control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl2), and VE + Cd (100 mg/kg VE + 5 mg/kg CdCl2), and received intragastric administration of Cd and/or VE for 4 weeks. The results showed that Cd exposure significantly reduced the weight of the body and kidney, elevated the accumulation of Cd in the kidney as well as the levels of BUN and Scr in serum, caused renal histological alterations, decreased the GSH and T-AOC contents and antioxidant enzyme (SOD, CAT, GSH-PX) activities, and increased renal MDA content. And the increased number of TUNEL-positive cells by Cd was accompanied by upregulated mRNA and protein expressions of apoptotic regulatory molecules (Bax, Caspase-3, GRP94, GRP78, Caspase-8) and downregulated Bcl-2 expressions. However, the combined treatment of Cd and VE could restore the above parameters to be close to those in the control rats. In conclusion, VE supplement could alleviate Cd-induced rat renal damage and oxidative stress through enhancing the antioxidant defense system and inhibiting apoptosis of renal cells.
Similar content being viewed by others
Data Availability
All data used to support the findings of this study are included within the article.
References
Bhattacharya S (2018) The role of medicinal plants and natural products in melioration of cadmium toxicity. Orient Pharm Exp Med 18(3):177–186. https://doi.org/10.1007/s13596-018-0323-0
Wang XY, Wang ZY, Zhu YS, Zhu SM, Fan RF, Wang L (2018) Alleviation of cadmium-induced oxidative stress by trehalose via inhibiting the Nrf2-Keap1 signaling pathway in primary rat proximal tubular cells. J Biochem Mol Toxicol 32(1):1–6. https://doi.org/10.1002/jbt.22011
Pallio G, Micali A, Benvenga S, Antonelli A, Marini HR, Puzzolo D, Macaione V, Trichilo V, Santoro G, Irrera N, Squadrito F, Altavilla D, Minutoli L (2019) Myo-inositol in the protection from cadmium-induced toxicity in mice kidney: an emerging nutraceutical challenge. Food Chem Toxicol 132:1–9. https://doi.org/10.1016/j.fct.2019.110675
Al Olayan EM, Aloufi AS, AlAmri OD, El-Habit OH, Abdel Moneim AE (2020) Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis. Sci Total Environ 723:137969. https://doi.org/10.1016/j.scitotenv.2020.137969
Shi L, Cao H, Luo J, Liu P, Wang T, Hu G, Zhang C (2017) Effects of molybdenum and cadmium on the oxidative damage and kidney apoptosis in duck. Ecotoxicol Environ Saf 145:24–31. https://doi.org/10.1016/j.ecoenv.2017.07.006
Mezynska M, Brzóska MM (2018) Environmental exposure to cadmium—a risk for health of the general population in industrialized countries and preventive strategies. Environ Sci Pollut Res 25(4):3211–3232. https://doi.org/10.1007/s11356-017-0827-z
Amanpour P, Khodarahmi P, Salehipour M (2019) Protective effects of vitamin E on cadmium-induced apoptosis in rat testes. Naunyn Schmiedeberg's Arch Pharmacol 393:349–358. https://doi.org/10.1007/s00210-019-01736-w
Gong ZG, Wang XY, Wang JH, Fan RF, Wang L (2019) Trehalose prevents cadmium-induced hepatotoxicity by blocking Nrf2 pathway, restoring autophagy and inhibiting apoptosis. J Inorg Biochem 192:62–71. https://doi.org/10.1016/j.jinorgbio.2018.12.008
Almeer RS, AlBasher GI, Alarifi S, Alkahtani S, Ali D, Abdel Moneim AE (2019) Royal jelly attenuates cadmium-induced nephrotoxicity in male mice. Sci Rep 9(1):5825. https://doi.org/10.1038/s41598-019-42368-7
Ge J, Zhang C, Sun YC, Zhang Q, Lv MW, Guo K, Li JL (2019) Cadmium exposure triggers mitochondrial dysfunction and oxidative stress in chicken (Gallus gallus) kidney via mitochondrial UPR inhibition and Nrf2-mediated antioxidant defense activation. Sci Total Environ 689:1160–1171. https://doi.org/10.1016/j.scitotenv.2019.06.405
Wang C, Nie G, Yang F, Chen J, Zhuang Y, Dai X, Liao Z, Yang Z, Cao H, Xing C, Hu G, Zhang C (2020) Molybdenum and cadmium co-induce oxidative stress and apoptosis through mitochondria-mediated pathway in duck renal tubular epithelial cells. J Hazard Mater 383:1–10. https://doi.org/10.1016/j.jhazmat.2019.121157
Zhuang J, Nie G, Yang F, Dai X, Cao H, Xing C, Hu G, Zhang C (2019) Cadmium induces cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells. Toxicol in Vitro 61:1–10. https://doi.org/10.1016/j.tiv.2019.104625
Fan R, Hu PC, Wang Y, Lin HY, Su K, Feng XS, Wei L, Yang F (2018) Betulinic acid protects mice from cadmium chloride-induced toxicity by inhibiting cadmium-induced apoptosis in kidney and liver. Toxicol Lett 299:56–66. https://doi.org/10.1016/j.toxlet.2018.09.003
Nishad P, Mohini (2017) Effect of vitamin E supplementation on heavy metal induced renal toxicity in rat model. Int J Food Sci Nutr 2(3):77–79.
Nair AR, DeGheselle O, Smeets K, Van Kerkhove E, Cuypers A (2013) Cadmium-induced pathologies: where is the oxidative balance lost (or not)? Int J Mol Sci 14(3):6116–6143. https://doi.org/10.3390/ijms14036116
Chen J, Shaikh ZA (2009) Activation of Nrf2 by cadmium and its role in protection against cadmium-induced apoptosis in rat kidney cells. Toxicol Appl Pharmacol 241(1):81–89. https://doi.org/10.1016/j.taap.2009.07.038
Rana SVS (2008) Metals and apoptosis: recent developments. J Trace Elem Med Biol 22(4):262–284. https://doi.org/10.1016/j.jtemb.2008.08.002
Biagioli M, Pifferi S, Ragghianti M, Bucci S, Rizzuto R, Pinton P (2008) Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis. Cell Calcium 43(2):184–195. https://doi.org/10.1016/j.ceca.2007.05.003
Kiran Kumar KM, Naveen Kumar M, Patil RH, Nagesh R, Hegde SM, Kavya K, Babu RL, Ramesh GT, Sharma SC (2016) Cadmium induces oxidative stress and apoptosis in lung epithelial cells. Toxicol Mech Methods 26(9):658–666. https://doi.org/10.1080/15376516.2016.1223240
Eder K, Siebers M, Most E, Scheibe S, Weissmann N, Gessner DK (2017) An excess dietary vitamin E concentration does not influence Nrf2 signaling in the liver of rats fed either soybean oil or salmon oil. Nutr Metab (Lond) 14(1):71. https://doi.org/10.1186/s12986-017-0225-z
Sen Gupta R, Sen Gupta E, Dhakal BK, Thakur AR, Ahnn J (2004) Vitamin C and vitamin E protect the rat testes from cadmium-induced reactive oxygen species. Mol Cell 17(1):132–974. https://doi.org/10.1242/jcs.00946
Ognjanović BI, Marković SD, Pavlović SZ, Zikić RV, Stajn AŠ, Saičić ZS (2006) Combined effects of coenzyme Q10 and vitamin E in cadmium induced alterations of antioxidant defense system in the rat heart. Environ Toxicol Pharmacol 22(2):219–224. https://doi.org/10.1016/j.etap.2006.03.008
Bolkent S, Koyuturk M, Bulan OK, Tunali S, Yanardag R, Tabakoglu AO (2007) The effects of combined alpha-tocopherol, ascorbic acid, and selenium against cadmium toxicity in rat intestine. J Environ Pathol Toxicol Oncol 26(1):21–27. https://doi.org/10.1615/JEnvironPatholToxicolOncol.v26.i1.30
Kara H, Cevik A, Konar V, Dayangac A, Servi K (2008) Effects of selenium with vitamin E and melatonin on cadmium-induced oxidative damage in rat liver and kidneys. Biol Trace Elem Res 125(3):236–244. https://doi.org/10.1007/s12011-008-8168-x
Nemmiche S, Chabane-Sari D, Guiraud P (2007) Role of α-tocopherol in cadmium-induced oxidative stress in Wistar rat's blood, liver and brain. Chem Biol Interact 170(3):221–230. https://doi.org/10.1016/j.cbi.2007.08.004
Weng D, Lu Y, Wei Y, Liu Y, Shen P (2007) The role of ROS in microcystin-LR-induced hepatocyte apoptosis and liver injury in mice. Toxicology 232(1):15–23. https://doi.org/10.1016/j.tox.2006.12.010
El-Demerdash FM, Yousef MI, Kedwany FS, Baghdadi HH (2004) Cadmium-induced changes in lipid peroxidation, blood hematology, biochemical parameters and semen quality of male rats: protective role of vitamin E and β-carotene. Food Chem Toxicol 42(10):1563–1571. https://doi.org/10.1016/j.fct.2004.05.001
Nazima B, Manoharan V, Miltonprabu S (2015) Grape seed proanthocyanidins ameliorates cadmium-induced renal injury and oxidative stress in experimental rats through the up-regulation of nuclear related factor 2 and antioxidant responsive elements. Biochim Biol Cell 93(3):210–226. https://doi.org/10.1139/bcb-2014-0114
Elkhadragy MF, Al-Olayan EM, Al-Amiery AA, Abdel Moneim AE (2017) Protective effects of Fragaria ananassa extract against cadmium chloride-induced acute renal toxicity in rats. Biol Trace Elem Res 181(2):378–387. https://doi.org/10.1007/s12011-017-1062-7
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254. https://doi.org/10.1006/abio.1976.9999
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 −ΔΔ C T method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262
Erboga M, Kanter M, Aktas C, Sener U, Fidanol Erboga Z, Bozdemir Donmez Y, Gurel A (2016) Thymoquinone ameliorates cadmium-induced nephrotoxicity, apoptosis, and oxidative stress in rats is based on its anti-apoptotic and anti-oxidant properties. Biol Trace Elem Res 170(1):165–172. https://doi.org/10.1007/s12011-015-0453-x
Bao RK, Zheng SF, Wang XY (2017) Selenium protects against cadmium-induced kidney apoptosis in chickens by activating the PI3K/AKT/Bcl-2 signaling pathway. Environ Sci Pollut Res 41:1–12. https://doi.org/10.1007/s11356-017-9422-6
Sanjeev S, Bidanchi RM, Murthy MK, Gurusubramanian G, Roy VK (2019) Influence of ferulic acid consumption in ameliorating the cadmium-induced liver and renal oxidative damage in rats. Environ Sci Pollut Res 26(1):20631–20653. https://doi.org/10.1007/s11356-019-05420-7
Wongmekiat O, Peerapanyasut W, Kobroob A (2018) Catechin supplementation prevents kidney damage in rats repeatedly exposed to cadmium through mitochondrial protection. Naunyn Schmiedeberg's Arch Pharmacol 391(4):385–394. https://doi.org/10.1007/s00210-018-1468-6
Rana MN, Tangpong J, Rahman MM (2018) Toxicodynamics of lead, cadmium, mercury and arsenic- induced kidney toxicity and treatment strategy: a mini review. Toxicol Rep 5:704–713. https://doi.org/10.1016/j.toxrep.2018.05.012
Rinaldi M, Micali A, Marini H, Adamo EB, Puzzolo D, Pisani A, Trichilo V, Altavilla D, Squadrito F, Minutoli L (2017) Cadmium, organ toxicity and therapeutic approaches. A review on brain, kidney and testis damage. Curr Med Chem 24(35):3879–3893. https://doi.org/10.2174/0929867324666170801101448
Rani A, Kumar A, Lal A, Pant M (2014) Cellular mechanisms of cadmium-induced toxicity: a review. Int J Environ Health Res 24(4):378–399. https://doi.org/10.1080/09603123.2013.835032
Sabolić I, Breljak D, Skarica M, Herak-Kramberger CM (2010) Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23(5):897–926. https://doi.org/10.1016/S0378-1127(01)00623-5
Prabu SM, Shagirtha K, Renugadevi J (2011) Reno-protective effect of naringenin in combination with vitamins C and E on cadmium induced oxidative nephrotoxicity in rats. J Pharm Res 325(6):1921–1926
El-Boshy ME, Risha EF, Abdelhamid FM, Mubarak MS, Hadda TB (2015) Protective effects of selenium against cadmium induced hematological disturbances, immunosuppressive, oxidative stress and hepatorenal damage in rats. J Trace Elem Med Biol 29:104–110. https://doi.org/10.1016/j.jtemb.2014.05.009
Adi PJ, Burra SP, Vataparti AR, Matcha B (2016) Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats. Toxicol Rep 3:591–597. https://doi.org/10.1016/j.toxrep.2016.07.005
Ognjanović BI, Marković SD, Pavlović SZ, Zikić RV, Stajn AS, Saicić ZS (2008) Effect of chronic cadmium exposure on antioxidant defense system in some tissues of rats: protective effect of selenium. Physiol Res 57(3):403–411. https://doi.org/10.1088/0967-3334/29/1/010
Evcimen M, Aslan R, Gulay MS (2018) Protective effects of polydatin and grape seed extract in rats exposed to cadmium. Drug Chem Toxicol 2:1–9. https://doi.org/10.1080/01480545.2018.1480629
Jihen EH, Imed M, Fatima H, Abdelhamid K (2008) Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver and kidney of the rat: histology and Cd accumulation. Food Chem Toxicol 46(11):3522–3527. https://doi.org/10.1016/j.fct.2008.08.037
Tripathi S, Srivastav AK (2011) Cytoarchitectural alterations in kidney of Wistar rat after oral exposure to cadmium chloride. Tissue Cell 43(2):131–136. https://doi.org/10.1016/j.tice.2011.01.001
Fujiwara Y, Lee J, Tokumoto M, Satoh M (2012) Cadmium renal toxicity via apoptotic pathways. Biol Pharm Bull 35(11):1892–1897. https://doi.org/10.1248/bpb.b212014
Loo DT (2011) In situ detection of apoptosis by the TUNEL assay: an overview of techniques. Methods Mol Biol 682:3–13. https://doi.org/10.1007/978-1-60327-409-8_1
Aktoz T, Kanter M, Uz YH, Aktaş C, Erboğa M, Atakan İH (2011) Protective effect of quercetin against renal toxicity induced by cadmium in rats. Balkan Med J 29(1):56–61. https://doi.org/10.5152/balkanmedj.2011.014
Aoyagi T, Hayakawa K, Miyaji K, Ishikawa H, Hata M (2003) Cadmium nephrotoxicity and evacuation from the body in a rat modeled subchronic intoxication. Int J Urol 10(6):332–338. https://doi.org/10.1046/j.1442-2042.2003.00627.x
Wang Y, Wu Y, Luo K, Liu Y, Zhou M, Yan S, Shi H, Cai Y (2013) The protective effects of selenium on cadmium-induced oxidative stress and apoptosis via mitochondria pathway in mice kidney. Food Chem Toxicol 58(6):61–67. https://doi.org/10.1016/j.fct.2013.04.013
Shao CC, Li N, Zhang ZW, Su J, Li S, Li JL, Xu SW (2014) Cadmium supplement triggers endoplasmic reticulum stress response and cytotoxicity in primary chicken hepatocytes. Ecotoxicol Environ Saf 106:109–114. https://doi.org/10.1016/j.ecoenv.2014.04.033
Liu G, Yuan Y, Long M, Luo T, Bian J, Liu X, Gu J, Zou H, Song R, Wang Y, Wang L, Liu Z (2017) Beclin-1-mediated autophagy protects against cadmium-activated apoptosis via the Fas/FasL pathway in primary rat proximal tubular cell culture. Sci Rep 7(1):977. https://doi.org/10.1038/s41598-017-00997-w
Slee EA, Adrain C, Martin SJ (2001) Executioner caspase-3, −6, and −7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 276(10):7320–7326. https://doi.org/10.1074/jbc.M008363200
Jing G, Wang JJ, Zhang SX (2012) ER stress and apoptosis: a new mechanism for retinal cell death. Exp Diabetes Res 2012:589589–589511. https://doi.org/10.1155/2012/589589
Palai TK, Mishra SR (2014) Caspases: an apoptosis mediator. J Adv Vet Anim Res 2(1):18–22. https://doi.org/10.5455/javar.2015.b52
Yokouchi M, Hiramatsu N, Hayakawa K, Kasai A, Takano Y, Yao J, Kitamura M (2007) Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response. Cell Death Differ 14(8):1467–1474. https://doi.org/10.1038/sj.cdd.4402154
Böhm V (2018) Vitamin E. Antioxidants 7(3):44. https://doi.org/10.3390/antiox7030044
Kim MJ, Hong JH, Rhee SJ (2003) Effect of vitamin E on cadmium accumulation and excretion in chronic cadmium poisoned rats. Korean J Nutr 36(7):691–698
Khalil MH, Helal AF, Abd elghfar AM (2017) Counteracting effect of selenium and vitamin E to cadmium toxicity in rats. Middle East J Appl Sci 7(4):681–702
Rambeck WA, Kollmer WE (2010) Modifying cadmium retention in chickens by dietary supplements. J Anim Physiol Anim Nutr 63(1–5):66–74. https://doi.org/10.1111/j.1439-0396.1990.tb00118.x
Tandon SK, Singh S, Dhawan M (1992) Preventive effect of vitamin E in cadmium intoxication. Biomed Environ Sci 5(1):39–45
Kandeil MAM, Hassanin KMAA, Mohammed ET, Safwat GM, Mohamed DS (2018) Pumpkin and vitamin E as potent modulators of apoptosis in gentamicin-induced rat nephrotoxicity. Asian J Biochem 13(1):1–8. https://doi.org/10.3923/ajb.2018.1.8
Kandeil MAM, Hassanin KMA, Mohammed ET, Safwat GM, Mohamed DS (2018) Wheat germ and vitamin E decrease BAX/BCL-2 ratio in rat kidney treated with gentamicin. Beni-Suef Univ J Basic Appl Sci 7(3):257–262. https://doi.org/10.1016/j.bjbas.2018.02.001
Rahimi Anbarkeh F, Nikravesh MR, Jalali M, Sadeghnia HR, Sargazi Z (2019) The effect of diazinon on cell proliferation and apoptosis in testicular tissue of rats and the protective effect of vitamin E. Int J Fertil Steril 13(2):154–160. https://doi.org/10.22074/ijfs.2019.5612
Acknowledgements
This work was supported by the National Key Research and Development Project (2018YFD0501800), the Sichuan Science and Technology Program (2018NZ0002, 2019YFQ0012), and the Sichuan beef cattle innovation team of National Modern Agricultural Industry Technology System (SCCXTD-2020-13).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Fang, J., Xie, S., Chen, Z. et al. Protective Effect of Vitamin E on Cadmium-Induced Renal Oxidative Damage and Apoptosis in Rats. Biol Trace Elem Res 199, 4675–4687 (2021). https://doi.org/10.1007/s12011-021-02606-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-021-02606-4