Abstract
Cadmium (Cd), an environmental and industrial pollutant, generates free radicals responsible for oxidative stress. Cd can also lead to various renal toxic damage such as the proximal tubules and glomerulus dysfunction. Thymoquinone (TQ) is the main constituent of the essential oil obtained from black seeds (Nigella sativa) and has various pharmacological effects. The aim of the present study was to examine the nephroprotective, anti-oxidant, and anti-apoptotic effect of the TQ against Cd-induced nephrotoxicity. A total of 24 male Wistar albino rats were divided into three groups: control, Cd-treated, and Cd-treated with TQ; each group contain eight animals. The Cd-treated group was injected subcutaneously with CdCl2 dissolved in saline in the amount of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in TQ-treated groups were given TQ (50 mg/kg body weight) once a day orally together with first Cd injection during the study period. The histopathological studies in the kidney of rats also showed that TQ markedly reduced the toxicity of Cd and preserved the normal histological architecture of the renal tissue. Immunohistochemical analysis revealed that TQ significantly decreased the Cd-induced over expression of nuclear factor-κB in renal tissue. Furthermore, TQ treatment resulted in decreased the number of apoptotic cells. TQ significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses (reduced superoxide dismutase, glutathione peroxidase and catalase activities) in renal tissue resulted from Cd administration. These findings suggest that the nephroprotective potential of TQ in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced nephrotoxicity.
Similar content being viewed by others
References
Long C, Juan Z, Wei G, Ying-Zi J (2003) Action of NO and TNF-α release of rats with cadmium loading in malfunction of multiple system organs. Acta Physiologica Sinica 55(5):535–540
Kaplan M, Atakan IH, Aydogdu N, et al. (2008) Influence of N-acetylcysteine on renal toxicity of cadmium in rats. Pediatr Nephrol 23:233–241
Chowdhury MJ, McDonald DG, Wood CM (2004) Gastrointestinal uptake and fate of cadmium in rainbow trout acclimated to sublethal diatary cadmium. Aquat Toxicol 691:49–163
Agency for Toxic Substances and Disease Registry (1989) Decision guide for identifying substance specific data needs related to toxicological profiles. Agency for Toxic Substances and Disease Registry, Division of Toxicology, Atlanta, GA
Goyer R (1996) Toxic effect of metals. In: Casarett and Doull’s Toxicology. Mc-Graw and Hill, Inc, 699-701.
Rehm S, Waalkes MP (1990) Acute cadmium chloride-induced renal toxicity in the Syrian hamster. Toxicol Appl Pharmacol 104:94–105
Agirdir BV, Bilgen I, Dinc O, et al. (2002) Effect of zinc ion on cadmium induced auditory changes. Biol Trace Elem Res 88(2):153–163
Thijssen S, Cuypers A, Maringwa J, et al. (2007) Low cadmium exposure triggers a biphasic oxidative stress response in mice kidneys. Toxicology 236:29–41
Chaieb K, Kouidhi B, Jrah H, Mahdouani K, Bakhrouf A (2011) Antibacterial activity of thymoquinone, an active principle of Nigella sativa and its potency to prevent bacterial biofilm formation. BMC Complement Altern Med 11:29–35
Kanter M, Coskun O, Uysal H (2006) The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage. Arch Toxicol 80(4):217–224
Jafri SH, Glass J, Shi R, et al. (2010) Thymoquinone and cisplatin as a therapeutic combination in lung cancer: in vitro and in vivo. J Exp Clin Cancer Res 29:87–98
Sayed-Ahmed MM, Aleisa AM, Al-Rejaie SS, et al. (2010) Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. Oxidative Med Cell Longev 3(4):254–261
Oguz S, Kanter M, Erboga M, Erenoglu C (2012) Protective effects of thymoquinone against cholestatic oxidative stress and hepatic damage after biliary obstruction in rats. J Mol Histol 43(2):151–159
Badary OA, Nagi MN, Al-Shabanah OA, et al. (1997) Thymoquinone ameliorates the nephrotoxicity induced by cisplatin in rodents and potentiates its antitumor activity. Can J Physiol Pharmacol 75:1356–1361
Badary OA, Abdel-Naim AB, Abdel-Wahab MH, et al. (2000) The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. Toxicology 143:219–226
Nagi MN, Mansour MA (2000) Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity in rats: a possible mechanism of protection. Pharmacol Res 41:283–289
El-Abhar HS, Abdallah DM, Saleh S (2003) Gastroprotective activity of Nigella sativa oil and its constituent, thymoquinone, against gastric mucosal injury induced by ischaemia/reperfusion in rats. J Ethnopharmacol 84:251–258
Aktoz T, Kanter M, Uz YH, et al. (2012) Protective effect of quercetin against renal toxicity induced by cadmium in rats. Balkan Med J 29:56–61
Hsu SM, Raine L (1981) Fanger H (1981) Use of avidinbiotin-peroxidase complex (ABC) in immunperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580
Fouad AA, Jresat I (2011) Protective effect of telmisartan against cadmium-induced nephrotoxicity in mice. Life Sci 89:29–35
Jawan B, Goto S, Pan TL, et al. (2003) The protective mechanism of magnolol, a Chinese herb drug, against warm ischemia- reperfusion injury of rat liver. J Surg Res 110:378–382
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Buege AJ, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310
Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500
Aebi H (1974) Catalase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York
Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterisation of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169
Chargui A, Zekri S, Rubera GCI (2011) Cadmium-induced autophagy in rat kidney: an early biomarker of subtoxic exposure. Toxicol Sci 121(1):31–42
Tripathi S, Srivastav AK (2011) Cytoarchitectural alterations in kidney of Wistar rat after oral exposure to cadmium chloride. Tissue Cell 43(2):131–136
Prozialeck WC, Edwards JR (2007) Cell adhesion molecules in chemically induced renal injury. Pharmacol Ther 114:74–93
Boroushaki MT, Mollazadeh H, Rajabian A, Dolati K, Hoseini A, Paseban M, Farzadnia M (2014) Protective effect of pomegranate seed oil against mercuric chloride-induced nephrotoxicity in rat. Ren Fail 36(10):1581–1586
Renugadevi J, Milton Prabu S (2009) Naringenin protects against cadmium-induced oxidative renal dysfunction in rats. Toxicology 256:128–134
Jung HY, Seo DW, Hong CO, Kim JY, Yang SY, Lee KW (2015) Nephroprotection of plantamajoside in rats treated with cadmium. Environ Toxicol Pharmacol 39(1):125–136
Ojo OA, Ajiboye BO, Oyinloye BE, Ojo AB, Olarewaju OI (2014) Protective effect of Irvingia gabonensis stem bark extract on cadmium-induced nephrotoxicity in rats. Interdiscip Toxicol 7(4):208–214
Jeffery TK, Morrell NW (2002) Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 45(3):173–202
Haddad JJ, Abdel-Karim NE (2011) NF-κB cellular and molecular regulatory mechanisms and pathways: therapeutic pattern or pseudoregulation? Cell Immunol 271(1):5–14
Kim SF (2011) The role of nitric oxide in prostaglandin biology; update. Nitric Oxide 25:255–264
Queisser N, Schupp N (2012) Aldosterone, oxidative stress, and NF-κB activation in hypertension-related cardiovascular and renal diseases. Free Radic Biol Med 15;53(2):314–327
Bhatt SR, Lokhandwala MF, Banday AA (2014) Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B. Clin Exp Hypertens 36(6):367–373
Xie J, Shaikh ZA (2006) Cadmium-induced apoptosis in rat kidney epithelial cells involves decrease in nuclear factor-kappa B activity. Toxicol Sci 91(1):299–308
Walker NI, Harmon BV, Gobe GC, Kerr JFR (1988) Patterns of cell death. Meth Archiev Exp Pathol 13:18–54
Wang L, Cao J, Chen D, et al. (2009) Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium. Biol Trace Elem Res 127:53–68
Gobe G, Crane D (2010) Mitochondria, reactive oxygen species and cadmium toxicity in the kidney. Toxicol Lett 198:49–55
Yuan G, Dai S, Yin Z, et al. (2014) Sub-chronic lead and cadmium co-induce apoptosis protein expression in liver and kidney of rats. Int J Clin Exp Pathol 7(6):2905–2914
Liu L, Yang B, Cheng Y, Lin H (2015) Ameliorative effects of seleniumon cadmium-induced oxidative stress and endoplasmic reticulum stress in the chicken kidney. Biol Trace Elem. doi:10.1007/s12011-015-0314-7
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 10:332–338
Kobroob A, Chattipakorn N, Wongmekiat O (2012) Caffeic acid phenethyl ester ameliorates cadmium-induced kidney mitochondrial injury. Chem Biol Interact 200(1):21–27
Hagar H, Al Malki W (2014) Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: role of oxidative stress and caspase-3. Environ Toxicol Pharmacol 37(2):803–811
Li M, Xia T, Jiang CS, et al. (2003) Cadmium directly induced the opening of membrane permeability pore of mitochondria which possibly involved in cadmium-triggered apoptosis. Toxicology 194:19–33
Cannino G, Ferruggia E, Luparello C, Rinaldi AM (2009) Cadmium and mitochondria. Mitochondrion 9:377–384
Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208
Gawel S, Wardas M, Niedworok E, Wardas P (2004) Malondialdehyde (MDA) as a lipid peroxidation marker. Wiad Lek 57(9–10):453–455
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
Morales AI, Vicente-Sánchez C, Sandoval JM, et al. (2006) Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties. Food Chem Toxicol 44(12):2092–2100
Shaikh ZA, Zaman K, Tang W, Vu T (1999) Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine. Toxicol Lett 104:137–142
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 125:236–244
Conflict of Interest
The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Erboga, M., Kanter, M., Aktas, C. et al. 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, 165–172 (2016). https://doi.org/10.1007/s12011-015-0453-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-015-0453-x