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Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice
G Model ETP 50973 No. of Pages 5
Experimental and Toxicologic Pathology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Experimental and Toxicologic Pathology journal homepage: www.elsevier.de/etp
Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice Hamid Reza Momeni, Ph.D., Associated Professor* , Najmeh Eskandari, M.Sc. Biology Department, Faculty of Science, Arak University, Arak 38156-8-8349, Iran
A R T I C L E I N F O
Article history: Received 26 July 2016 Accepted 22 August 2016 Keywords: Adult mouse Antioxidant capacity Curcumin Kidney Malondialdehyde Sodium arsenite
A B S T R A C T
Sodium arsenite is an environmental pollutant with the ability to generate free radicals and curcumin acts as a potent antioxidant. This study investigates the effect of curcumin on kidney histopathology, lipid peroxidation and antioxidant capacity of serum in the mice treated with sodium arsenite. Adult male mice were divided into four groups: control, sodium arsenite, curcumin and curcumin + sodium arsenite. The treatments were delivered for 5 weeks. After the treatment period, blood samples were collected and the concentrations of malondialdehyde (MDA) and total antioxidant capacity of serum were determined. Left kidney was dissected, weighed and used for histopathological and histomorphometrical studies. Sodium arsenite-treated mice showed a significant decrease in the diameter of glomerulus and proximal tubule, glomerular area, total antioxidant capacity of serum as well as a significant increase in serum concentration of MDA compared to the control group. However, no significant difference was found in kidney weight, area and diameter of Bowman's capsule as well as the diameter of distal tubule in mice treated with sodium arsenite compared to the control. In curcumin + sodium arsenite group, curcumin significantly reversed the adverse effects of sodium arsenite on the diameter of glomerulus and proximal tubule, glomerular area, total antioxidant capacity of serum and serum concentration of MDA compared to the sodium arsenite group. The application of curcumin alone significantly increased the total antioxidant capacity of serum compared to the control. Curcumin compensated the adverse effects of sodium arsenite on kidney tissue, lipid peroxidation and total antioxidant capacity of serum. ã 2016 Elsevier GmbH. All rights reserved.
1. Introduction Environmental pollution is one of the greatest threats to human health. Human activity releases toxic heavy metals such as arsenic. Arsenic mobilization in the environment is enhanced by microorganisms but human intervention also affects the natural equilibrium of the ecosystems (Akter et al., 2005). Arsenic compounds are used to make special glass types, wood preservatives, herbicides, insecticides (Kannan and Flora, 2004) as well as medicines for the treatment of blood cancer (Hu et al., 2005). The main source of arsenic exposure is via the use of arsenic-contaminated foods and water that endangers health (Ayotte et al., 2003; Karagas et al., 2002). Arsenic poisoning has adverse effects on human health (Ahmad et al., 2001; Rossman,
* Corresponding author. E-mail addresses: [email protected] (H.R. Momeni), [email protected] (N. Eskandari).
2003) and damages all the target organs including kidney (Blanca et al., 2007). Decrease in tubular volume (Rubatto Birri et al., 2010) and lumen (Ferzand et al., 2008), the shrinkage of the glomerulus (Roy and Bhattacharya, 2006), increase in the Bowman's space, acute tubular and glomerular degeneration (Ferzand et al., 2008) and increase in blood creatinine and urea (Rizwan et al., 2014) are some kidney complications associated with arsenic exposure. Several lines of evidence have shown that arsenic exerts its toxicity through reactive oxygen species (ROS) and generation of free radicals (Gurr et al., 2003; Shi et al., 2004). Arsenic is able to induce lipid peroxidation in the membranes (Gupta and Flora, 2005), leading to apoptosis in a wide variety of cells (Das et al., 2009). Therefore, the application of antioxidants, particularly the antioxidants which are derived from medical plants, can be a possible strategy for protecting cellular damages against arsenic toxicity. Antioxidants are known as free radical scavenger and reduce the impact of the free radicals created by oxidative stress (Bengmark, 2006).
http://dx.doi.org/10.1016/j.etp.2016.08.006 0940-2993/ã 2016 Elsevier GmbH. All rights reserved.
Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
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Curcumin is a polyphenol compound derived from the tumeric with powerful anti inflammatory and antioxidant properties (ElWakf et al., 2011). In addition, the presence of methoxy groups on the phenyl ring increases curcumin activity (Priyadarsini, 2013). Curcumin is shown to inhibit ROS formation and scavenge free radicals in pathological conditions, resulting in the protection of vital cellular components such as lipids, proteins and DNA (ElWakf et al., 2011). Previous studies have shown the adverse effects of sodium arsenite on kidney. To our knowledge, however, no study has examined the effect of curcumin on sodium arsenite mediated toxicity in kidney histopathological changes and serum antioxidant capacity of adult mice. The present study was therefore conducted to investigate the effect of curcumin on kidney histopathology and histomorphometry, lipid peroxidation index and total antioxidant capacity of serum in adult mice treated by sodium arsenite. 2. Material and methods 2.1. Animals and treatments In this experimental study adult male NMRI mice (32 5 gr) were purchased from Pasture's Institute, Tehran, Iran. The animals were housed in plastic cages at 12-h light/dark cycle, 24 2 C with water and food available ad libitum. The mice were divided into four groups (n = 6 for each group): control, sodium arsenite (5 mg/kg, Sigma, USA), curcumin (100 mg/kg, Sigma, USA) and curcumin + sodium arsenite. The treatments were delivered by intraperitoneal injection for five weeks (Chinoy et al., 2004). The experiments were approved by the local ethical committee at Arak University. Sodium arsenite and curcumin were dissolved in distilled water and dimethyl sulfoxide (DMSO) respectively. Based on the solvants, two control groups were selected; distilled water and DMSO. Since no significant difference was found between the results of the controls, distilled water data was considered as control group. At the end of the treatments, the animals were weighed and anesthetized. Blood samples were collected from the heart and centrifuged, and serum samples were stored at 80 C for biochemical analysis. Left kidney was dissected, decapsulated, weighed and fixed for the histopathological and histomorphometrical studies. 2.2. Tissue preparation for histopathological and histomorphometrical evaluation
Table 1 Kidney weight in mice treated with sodium arsenite and curcumin. Weight (g)
Control
Kidney
0.232 0.02 0.245 0.01 0.215 0.01 0.231 0.02
Curcumin
Sodium arsenite
Curcumin + Sodiumarsenite
Mean SD, n = 6 per group. ANOVA, Tukey’s test, p < 0.05.
concentration was calculated by its molar extinction coefficient 1.56 105M 1 cm 1and expressed as nmol/ml. 2.4. Assessment of total antioxidant capacity of serum The ferric reducing antioxidant power assay (FRAP) is a routine method for estimating total antioxidant capacity. The principle of this method is based on the reduction of Fe3+ to Fe2+due to the action of antioxidants. Interaction of Fe2+with 2,4,6-tri(2-pyridyl)1,3,5-triazine (TPTZ) provides a maximum absorption at 593 nm (Emin et al., 2010). Briefly, 900 ml of freshly prepared and pretempered (37 C) FRAP reagent (300 mM acetate buffer, pH 3.6 with 10 mM TPTZ solution in 40 mM HCl and 20 mM FeCl3 solution in ratio10:1:1 respectively) was added to 100 ml of serum (previously diluted 1:1 with distilled water) which was then incubated for 4 min at 37 C. The absorbance was determined at 593 nm by a spectrophotometer. Different concentrations of FeSO47H2O were used for the preparation of standard curve preparation. The total antioxidant capacity of the samples was then calculated using regression equation obtained from the standard curve and expressed in mmol/l. 2.5. Statistical analysis Results were expressed as mean standard deviation (SD) for six animals per group. One-way analysis of variance (ANOVA) followed by Tukey's test was used to assess the statistical significance of data. p < 0.05 was considered significant. 3. Results 3.1. Kidney weight No significant difference was found in kidney weight among the four groups (p > 0.05) (Table 1). 3.2. Kidney histopathology
The kidneys were fixed in Bouin's fixative for 36 h. They were subsequently dehydrated, embedded in paraffin, sectioned at 5 mm and stained via Heidenhain’s Azan method (Mehranjani et al., 2009). The sections were then examined and photographed under an optical microscope. Motic Image 2000 Software was used to measure the area and the diameter of glomerulus, Bowman's capsule as well as distal and proximal tubules. 2.3. Assessment of serum malondialdehyde Malondialdehyde (MDA) is an end-product of lipid peroxidation during oxidative stress and is frequently used as an indicator of lipid peroxidation. The amount of serum MDA was measured using the thiobarbituric acid (TBA) assay according to the method described by Turki and Moayad Naji (Turki and Moayad Naji, 2011). In brief, 1000 ml of trichloroacetic acid, thiobarbituric acid and hydrochloric acidreagent (TCA15% w/v, TBA 0.375% w/v and HCl0.25 N) was added to 500 ml of serum sample and heated for 15 min in boiling water bath. The samples were then cooled and centrifuged at 1000g for 10 min. The absorbance of the supernatant was determined using a spectrophotometer at 535 nm. The MDA
The control and curcumin groups (Fig. 1a–d respectively) displayed an expected structure of renal tubules, glomeruli and Bowman's capsule. Shrinkage of glomerulus, increase in the Bowman's space, vacuolation of tubular epithelium and acute tubular and glomerular degeneration were observed in the sodium arsenite group (Fig. 1b). In addition, degenerated epithelial cells were extruded into tubular lumen in this group. Curcumin compensated for the adverse effect of sodium arsenite in the curcumin + sodium arsenite group compared to the sodium arsenite group (Fig. 1c). 3.3. Kidney histomorphometry The histomorphometrical analysis of the kidney (Table 2) showed a significant decrease in the diameter of glomerulus and proximal tubule (p < 0.001) as well as glomerular area (p < 0.01) in the sodium arsenite group compared to the control. Curcumin significantly reversed the adverse effect of sodium arsenite on the diameter of glomerulus and proximal tubule (p < 0.001) as well as glomerular area (p < 0.05) in the curcumin + sodium arsenite group
Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
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Fig. 1. Kidney tissue in mice treated with sodium arsenite and curcumin. a, c, d: Glomerulus and Bowman's capsule with regular arrangement of renal tubules in control, sodium arsenite + curcumin and curcumin (100 mg/kg) groups respectively; b: glomerular atrophy (1), extrusion of degenerated epithelial cells into tubular lumen (2), the vacuolation of tubular epithelium (3) and increase in Bowman's space (* 4) in sodium arsenite group (5 mg/kg). Heidenhain’s Azan staining. Scale bar: 50 mm.
as compared with the sodium arsenite group. However, sodium arsenite had no significant effect on the area and the diameter of Bowman's capsule and the diameter of distal tubule compared to the control (p > 0.05). Animals treated with curcumin showed no significant difference in the histomorphometrical parameters compared to the control. 3.4. Serum malondialdehyde Fig. 2 shows that sodium arsenite induced a significant (p < 0.001) increase in serum MDA compared to the control. In the sodium arsenite + curcumin group, curcumin significantly (p < 0.001) reversed serum MDA compared to the sodium arsenite
group. No significant difference was found in serum MDA among the curcumin and the control groups (Fig. 2). 3.5. Total antioxidant capacity of serum Total antioxidant capacity of serum was significantly (p < 0.001) decreased in the sodium arsenite group compared to the control. The administration of curcumin significantly (p < 0.001) ameliorated the total antioxidant capacity of serum in the curcumin + sodium arsenite group when compared to the sodium arsenite group. In addition, the application of curcumin alone significantly (p < 0.001) increased the total antioxidant capacity of serum compared to the control (Fig. 3).
Table 2 Kidney histomorphometrical parameters in mice treated with sodium arsenite and curcumin. Histomorphometrical parameters
Control
Curcumin
Sodium arsenite
Curcumin + Sodium arsenite
Glomerular diameter (mm) Glomerular area (mm2) Bowman's capsule diameter (mm) Bowman's capsule area (mm2) Proximal tubule diameter (mm) Distal tubule diameter (mm)
54.27 5.95 b 2364.62 165.77b 64.11 10.04 a 3922.01 764.26 a 35.97 1.09 b 22.68 1.36 a
53.28 7.09 b 2413.27 244.30b 64.42 2.08 a 3775.66 463.34 a 34.84 1.49 b 23.79 2.93 a
40.83 2.87 a 1962.13 168.60a 55.10 6.53 a 3370.74 477.23a 30.72 0.64a 23.64 0.85a
55.12 3.16 b 2325.03 286.31 63.06 7.51 a 3784.70 596.59 35.45 2.76 b 24.09 1.03 a
b
a
Mean SD, n = 6 per group. Means with the same superscripts do not differ significantly. ANOVA, Tukey’s test,p < 0.05.
Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
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b
4.5 Serum MDA (nmol/ml)
4 3.5 3
a
a
2.5
a
2 1.5 1 0.5 0
Control
Sodium arsenite Curcumin + sodium arsenite
Curcumin
Fig. 2. Evaluation of serum malondialdehyde (MDA) in mice treated with sodium arsenite and curcumin. Mean SD, n = 6 per group. Means with the same superscripts do not differ significantly. ANOVA, Tukey's test, p < 0.05.
4. Discussion The present study showed the toxic effects of sodium arsenite on histopathologic and histomorphometric changes of kidney tissue and the ameliorating effect of curcumin on sodium arsenite toxicity in adult mice. No significant difference was found in kidney weight in sodium arsenite-treated mice. Our results were consistent with previous studies (El-Demerdash et al., 2009; Yu and Beynen, 2001). This might be due to the fact that toxic effect of sodium arsenite depends on dose and/or treatment period (Chattopadhyay et al., 2001).In agreement with previous findings (Ferzand et al., 2008; Roy and Bhattacharya, 2006), sodium arsenite led to the shrinkage (atrophy) of the glomerulus, a reduction in glomerular area and diameter as well as an increase in the Bowman's space (but not the area and diameter of Bowman's capsule) compared to the control group. Increase in the Bowman's space may occur as a consequence of glomerular atrophy. The structural integrity of the glomerulus is associated with the integrity of membrane in this organ. Collagen is the most abundant protein component of glomerular basement membrane and is required to maintain glomerular integrity (Miner, 2012). Arsenic affects cell antioxidant defense system to induce lipid peroxidation and the disruption of cell membrane polyunsaturated fatty acid (Shi et al., 2004). On the other hand, arsenic inhibits protein synthesis (Liao et al., 2004). This pollutant with its electrophilic nature readily interferes with the cellular
Total anoxidant capacity of serum (μmol/l)
0.9
a
0.8 0.7
c
a b
0.6
metabolism through interaction with thiol and sulfhydryl groups in proteins to inhibit their enzymatic activity (Das et al., 2009). Arsenic also triggers the dysfunction of proteins by binding to the protein carbonyl groups (Manna et al., 2008) and the inhibition of protein synthesis by the prevention of transcription factor activity (Liao et al., 2004). Animals exposed to sodium arsenite showed a reduction in the diameter of proximal tubule of the nephrons. In addition, vacuolation and acute degeneration of these tubules were abundant. However, no significant change was observed in the diameter of distal tubule in this group. Arsenic accumulation in the kidney caused histopathological changes including tubular disruption (Tsukamoto et al., 1983). The epithelial cells of proximal tubule are more susceptible than distal tubule due to their high mitochondrial content and are the primary targets of renal injury due to arsenic toxicity (Hall et al., 2009). One possibility for sodium arsenite-induced nephrotoxicity is shown to be related to metabolic changes in proximal tubule cells (Rizwan et al., 2014). Furthermore, sodium arsenite can cause mitochondrial membrane depolarization (Peraza et al., 2003) and affect cell viability which may itself lead to proximal tubule injury. Cytoplasmic vacuolation might be due to the degradation of cytoplasmic material especially the denaturation of proteins components which produce vacuoles in the cytoplasm (Ferzand et al., 2008). Kidney is rich in phospholipids and very susceptible to oxidative damage. ROS produced by arsenic (Shi et al., 2004) and/or reduction in cell antioxidant defense system (Das et al., 2009) attacks unsaturated fatty acids in the cell membrane of this organ which in turn causes lipid peroxidation. We hypothesized that kidney histopathological and histomorphometrical changes induced by sodium arsenite might be due to the ability of this toxicant in the induction of oxidative stress. To test this hypothesis, we assessed the concentration of MDA and total antioxidant capacity in serum. Sodium arsenite-treated mice showed a significant increase in the serum concentration of MDA and a significant decrease in the total antioxidant capacity of serum compared to the control. Such oxidative stress markers could be strong evidence for the induction of oxidative stress by sodium arsenite in the kidney. We also used a potent antioxidant, curcumin, in combination with sodium arsenite to provide further evidence for this hypothesis. In curcumin + sodium arsenite group, curcumin reversed the adverse effects of sodium arsenite on renal histopathological and histomorphometrical changes. Furthermore, this antioxidant increased the concentration of serum MDA and decreased the total antioxidant capacity of serum. Curcumin as a polyphenolic compound with methoxyl group is a powerful free radical scavenger that suppresses lipid peroxidation (Priyadarsini, 2013). Interestingly, the use of curcumin alone significantly increased the total antioxidant capacity of serum compared to the control. In addition to its direct antioxidant activity, curcumin may function indirectly as an antioxidant by enhancing the synthesis of glutathione (Dabidi Roshan et al., 2012) and improve antioxidant defense system. 5. Conclusion
0.5 0.4
Since kidney is a main target of arsenic toxicity, the present study was conducted to evaluate the protective effect of curcumin on sodium arsenite nephrotoxicity. Curcumin as an antioxidant compensated for adverse effects of sodium arsenite on kidney tissue, lipid peroxidation index and antioxidant capacity of serum.
0.3 0.2 0.1 0 Control
Sodium arsenite Curcumin + sodium arsenite
Curcumin
Fig. 3. Total antioxidant capacity of serumin mice treated with sodium arsenite and curcumin. Mean SD, n = 6 per group. Means with the same superscripts do not differ significantly. ANOVA, Tukey's test,p<0.05.
Conflict of interest None.
Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
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Acknowledgments This research was supported by a grant from the Research and Technology department of Arak University. There is no conflict of interest in this article. References Ahmad SA, Sayed MH, Barua S, Khan MH, Faruquee MH, Jalil A, et al. Arsenic in drinking water and pregnancy outcomes. Environ. Health Perspect. 2001;109:629–31. Akter KF, Owens G, Davey DE, Naidu R. Arsenic speciation and toxicity in biological systems. Rev. Environ. Contam. Toxicol. 2005;184:97–149. Ayotte JD, Montgomery DL, Flanagan SM, Robinson KW. Arsenic in groundwater in eastern New England: occurrence, controls, and human health implications. Environ. Sci. Technol. 2003;37:2075–83. Bengmark S. Curcumin an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN. J. Parenter. Enteral Nutr. 2006;30:45–51. Blanca M, Nunez AB, Aceves N, Teres L, Gimeno R, Quintanar T, et al. An unusual case of acute arsenic poisoning in which the patient made good progress. Emergencias 2007;19:225–8. Chattopadhyay S, Ghosh S, Debnath J, Ghosh D. Protection of sodium arseniteinduced ovarian toxicity by coadministration of L-ascorbate (vitamin C) in mature wistar strain rat. Arch. Environ. Contam. Toxicol. 2001;41:83–9. Chinoy NJ, Tewari K, Jhala DD. Fluoride and/or arsenic toxicity in mice testis with formation of giant cells and subsequent recovery by some antidotes. Fluoride 2004;37:172–84. Dabidi Roshan V, Rahimi M, Shirinbayan V, Mahjoub S, Hosseinzadeh M. Protective effect of the combination of exercise and curcumin supplementation on cardiac system in rats exposed to lead. Int. J. Nutr. Metab. 2012;4:114–20. Das J, Ghosh J, Manna P, Sinha M, Sil PC. Taurine protects rat testes against NaAsO (2)-induced oxidative stress and apoptosis via mitochondrial dependent and independent pathways. Toxicol. Lett. 2009;187:201–10. El-Demerdash FM, Yousef MI, Radwan FM. Ameliorating effect of curcumin on sodium arsenite-induced oxidative damage and lipid peroxidation in different rat organs. Food Chem. Toxicol. 2009;47:249–54. El-Wakf AM, Elhabiby EM, El-kholy WM, El-Ghany EA. Use of tumeric and curcumin to alleviate adverse reproductive outcomes of water nitrate pollution in male rats. Nat. Sci. 2011;7:229–39. Emin S, Yordanova K, Dimov D, Ilieva V, Koychev A, Prakova G, et al. Total antioxidant capacity of plasma determined as ferrous reducing ability of plasma in patients with copd. Trakia J. Sci. 2010;8:205–13. Ferzand R, Gadahi JA, Saleha S, Ali Q. Histological and haematological disturbance caused by arsenic toxicity in mice model. Pak J. Biol. Sci. 2008;11:1405–13.
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Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
Experimental and Toxicologic Pathology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Experimental and Toxicologic Pathology journal homepage: www.elsevier.de/etp
Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice Hamid Reza Momeni, Ph.D., Associated Professor* , Najmeh Eskandari, M.Sc. Biology Department, Faculty of Science, Arak University, Arak 38156-8-8349, Iran
A R T I C L E I N F O
Article history: Received 26 July 2016 Accepted 22 August 2016 Keywords: Adult mouse Antioxidant capacity Curcumin Kidney Malondialdehyde Sodium arsenite
A B S T R A C T
Sodium arsenite is an environmental pollutant with the ability to generate free radicals and curcumin acts as a potent antioxidant. This study investigates the effect of curcumin on kidney histopathology, lipid peroxidation and antioxidant capacity of serum in the mice treated with sodium arsenite. Adult male mice were divided into four groups: control, sodium arsenite, curcumin and curcumin + sodium arsenite. The treatments were delivered for 5 weeks. After the treatment period, blood samples were collected and the concentrations of malondialdehyde (MDA) and total antioxidant capacity of serum were determined. Left kidney was dissected, weighed and used for histopathological and histomorphometrical studies. Sodium arsenite-treated mice showed a significant decrease in the diameter of glomerulus and proximal tubule, glomerular area, total antioxidant capacity of serum as well as a significant increase in serum concentration of MDA compared to the control group. However, no significant difference was found in kidney weight, area and diameter of Bowman's capsule as well as the diameter of distal tubule in mice treated with sodium arsenite compared to the control. In curcumin + sodium arsenite group, curcumin significantly reversed the adverse effects of sodium arsenite on the diameter of glomerulus and proximal tubule, glomerular area, total antioxidant capacity of serum and serum concentration of MDA compared to the sodium arsenite group. The application of curcumin alone significantly increased the total antioxidant capacity of serum compared to the control. Curcumin compensated the adverse effects of sodium arsenite on kidney tissue, lipid peroxidation and total antioxidant capacity of serum. ã 2016 Elsevier GmbH. All rights reserved.
1. Introduction Environmental pollution is one of the greatest threats to human health. Human activity releases toxic heavy metals such as arsenic. Arsenic mobilization in the environment is enhanced by microorganisms but human intervention also affects the natural equilibrium of the ecosystems (Akter et al., 2005). Arsenic compounds are used to make special glass types, wood preservatives, herbicides, insecticides (Kannan and Flora, 2004) as well as medicines for the treatment of blood cancer (Hu et al., 2005). The main source of arsenic exposure is via the use of arsenic-contaminated foods and water that endangers health (Ayotte et al., 2003; Karagas et al., 2002). Arsenic poisoning has adverse effects on human health (Ahmad et al., 2001; Rossman,
* Corresponding author. E-mail addresses: [email protected] (H.R. Momeni), [email protected] (N. Eskandari).
2003) and damages all the target organs including kidney (Blanca et al., 2007). Decrease in tubular volume (Rubatto Birri et al., 2010) and lumen (Ferzand et al., 2008), the shrinkage of the glomerulus (Roy and Bhattacharya, 2006), increase in the Bowman's space, acute tubular and glomerular degeneration (Ferzand et al., 2008) and increase in blood creatinine and urea (Rizwan et al., 2014) are some kidney complications associated with arsenic exposure. Several lines of evidence have shown that arsenic exerts its toxicity through reactive oxygen species (ROS) and generation of free radicals (Gurr et al., 2003; Shi et al., 2004). Arsenic is able to induce lipid peroxidation in the membranes (Gupta and Flora, 2005), leading to apoptosis in a wide variety of cells (Das et al., 2009). Therefore, the application of antioxidants, particularly the antioxidants which are derived from medical plants, can be a possible strategy for protecting cellular damages against arsenic toxicity. Antioxidants are known as free radical scavenger and reduce the impact of the free radicals created by oxidative stress (Bengmark, 2006).
http://dx.doi.org/10.1016/j.etp.2016.08.006 0940-2993/ã 2016 Elsevier GmbH. All rights reserved.
Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
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Curcumin is a polyphenol compound derived from the tumeric with powerful anti inflammatory and antioxidant properties (ElWakf et al., 2011). In addition, the presence of methoxy groups on the phenyl ring increases curcumin activity (Priyadarsini, 2013). Curcumin is shown to inhibit ROS formation and scavenge free radicals in pathological conditions, resulting in the protection of vital cellular components such as lipids, proteins and DNA (ElWakf et al., 2011). Previous studies have shown the adverse effects of sodium arsenite on kidney. To our knowledge, however, no study has examined the effect of curcumin on sodium arsenite mediated toxicity in kidney histopathological changes and serum antioxidant capacity of adult mice. The present study was therefore conducted to investigate the effect of curcumin on kidney histopathology and histomorphometry, lipid peroxidation index and total antioxidant capacity of serum in adult mice treated by sodium arsenite. 2. Material and methods 2.1. Animals and treatments In this experimental study adult male NMRI mice (32 5 gr) were purchased from Pasture's Institute, Tehran, Iran. The animals were housed in plastic cages at 12-h light/dark cycle, 24 2 C with water and food available ad libitum. The mice were divided into four groups (n = 6 for each group): control, sodium arsenite (5 mg/kg, Sigma, USA), curcumin (100 mg/kg, Sigma, USA) and curcumin + sodium arsenite. The treatments were delivered by intraperitoneal injection for five weeks (Chinoy et al., 2004). The experiments were approved by the local ethical committee at Arak University. Sodium arsenite and curcumin were dissolved in distilled water and dimethyl sulfoxide (DMSO) respectively. Based on the solvants, two control groups were selected; distilled water and DMSO. Since no significant difference was found between the results of the controls, distilled water data was considered as control group. At the end of the treatments, the animals were weighed and anesthetized. Blood samples were collected from the heart and centrifuged, and serum samples were stored at 80 C for biochemical analysis. Left kidney was dissected, decapsulated, weighed and fixed for the histopathological and histomorphometrical studies. 2.2. Tissue preparation for histopathological and histomorphometrical evaluation
Table 1 Kidney weight in mice treated with sodium arsenite and curcumin. Weight (g)
Control
Kidney
0.232 0.02 0.245 0.01 0.215 0.01 0.231 0.02
Curcumin
Sodium arsenite
Curcumin + Sodiumarsenite
Mean SD, n = 6 per group. ANOVA, Tukey’s test, p < 0.05.
concentration was calculated by its molar extinction coefficient 1.56 105M 1 cm 1and expressed as nmol/ml. 2.4. Assessment of total antioxidant capacity of serum The ferric reducing antioxidant power assay (FRAP) is a routine method for estimating total antioxidant capacity. The principle of this method is based on the reduction of Fe3+ to Fe2+due to the action of antioxidants. Interaction of Fe2+with 2,4,6-tri(2-pyridyl)1,3,5-triazine (TPTZ) provides a maximum absorption at 593 nm (Emin et al., 2010). Briefly, 900 ml of freshly prepared and pretempered (37 C) FRAP reagent (300 mM acetate buffer, pH 3.6 with 10 mM TPTZ solution in 40 mM HCl and 20 mM FeCl3 solution in ratio10:1:1 respectively) was added to 100 ml of serum (previously diluted 1:1 with distilled water) which was then incubated for 4 min at 37 C. The absorbance was determined at 593 nm by a spectrophotometer. Different concentrations of FeSO47H2O were used for the preparation of standard curve preparation. The total antioxidant capacity of the samples was then calculated using regression equation obtained from the standard curve and expressed in mmol/l. 2.5. Statistical analysis Results were expressed as mean standard deviation (SD) for six animals per group. One-way analysis of variance (ANOVA) followed by Tukey's test was used to assess the statistical significance of data. p < 0.05 was considered significant. 3. Results 3.1. Kidney weight No significant difference was found in kidney weight among the four groups (p > 0.05) (Table 1). 3.2. Kidney histopathology
The kidneys were fixed in Bouin's fixative for 36 h. They were subsequently dehydrated, embedded in paraffin, sectioned at 5 mm and stained via Heidenhain’s Azan method (Mehranjani et al., 2009). The sections were then examined and photographed under an optical microscope. Motic Image 2000 Software was used to measure the area and the diameter of glomerulus, Bowman's capsule as well as distal and proximal tubules. 2.3. Assessment of serum malondialdehyde Malondialdehyde (MDA) is an end-product of lipid peroxidation during oxidative stress and is frequently used as an indicator of lipid peroxidation. The amount of serum MDA was measured using the thiobarbituric acid (TBA) assay according to the method described by Turki and Moayad Naji (Turki and Moayad Naji, 2011). In brief, 1000 ml of trichloroacetic acid, thiobarbituric acid and hydrochloric acidreagent (TCA15% w/v, TBA 0.375% w/v and HCl0.25 N) was added to 500 ml of serum sample and heated for 15 min in boiling water bath. The samples were then cooled and centrifuged at 1000g for 10 min. The absorbance of the supernatant was determined using a spectrophotometer at 535 nm. The MDA
The control and curcumin groups (Fig. 1a–d respectively) displayed an expected structure of renal tubules, glomeruli and Bowman's capsule. Shrinkage of glomerulus, increase in the Bowman's space, vacuolation of tubular epithelium and acute tubular and glomerular degeneration were observed in the sodium arsenite group (Fig. 1b). In addition, degenerated epithelial cells were extruded into tubular lumen in this group. Curcumin compensated for the adverse effect of sodium arsenite in the curcumin + sodium arsenite group compared to the sodium arsenite group (Fig. 1c). 3.3. Kidney histomorphometry The histomorphometrical analysis of the kidney (Table 2) showed a significant decrease in the diameter of glomerulus and proximal tubule (p < 0.001) as well as glomerular area (p < 0.01) in the sodium arsenite group compared to the control. Curcumin significantly reversed the adverse effect of sodium arsenite on the diameter of glomerulus and proximal tubule (p < 0.001) as well as glomerular area (p < 0.05) in the curcumin + sodium arsenite group
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Fig. 1. Kidney tissue in mice treated with sodium arsenite and curcumin. a, c, d: Glomerulus and Bowman's capsule with regular arrangement of renal tubules in control, sodium arsenite + curcumin and curcumin (100 mg/kg) groups respectively; b: glomerular atrophy (1), extrusion of degenerated epithelial cells into tubular lumen (2), the vacuolation of tubular epithelium (3) and increase in Bowman's space (* 4) in sodium arsenite group (5 mg/kg). Heidenhain’s Azan staining. Scale bar: 50 mm.
as compared with the sodium arsenite group. However, sodium arsenite had no significant effect on the area and the diameter of Bowman's capsule and the diameter of distal tubule compared to the control (p > 0.05). Animals treated with curcumin showed no significant difference in the histomorphometrical parameters compared to the control. 3.4. Serum malondialdehyde Fig. 2 shows that sodium arsenite induced a significant (p < 0.001) increase in serum MDA compared to the control. In the sodium arsenite + curcumin group, curcumin significantly (p < 0.001) reversed serum MDA compared to the sodium arsenite
group. No significant difference was found in serum MDA among the curcumin and the control groups (Fig. 2). 3.5. Total antioxidant capacity of serum Total antioxidant capacity of serum was significantly (p < 0.001) decreased in the sodium arsenite group compared to the control. The administration of curcumin significantly (p < 0.001) ameliorated the total antioxidant capacity of serum in the curcumin + sodium arsenite group when compared to the sodium arsenite group. In addition, the application of curcumin alone significantly (p < 0.001) increased the total antioxidant capacity of serum compared to the control (Fig. 3).
Table 2 Kidney histomorphometrical parameters in mice treated with sodium arsenite and curcumin. Histomorphometrical parameters
Control
Curcumin
Sodium arsenite
Curcumin + Sodium arsenite
Glomerular diameter (mm) Glomerular area (mm2) Bowman's capsule diameter (mm) Bowman's capsule area (mm2) Proximal tubule diameter (mm) Distal tubule diameter (mm)
54.27 5.95 b 2364.62 165.77b 64.11 10.04 a 3922.01 764.26 a 35.97 1.09 b 22.68 1.36 a
53.28 7.09 b 2413.27 244.30b 64.42 2.08 a 3775.66 463.34 a 34.84 1.49 b 23.79 2.93 a
40.83 2.87 a 1962.13 168.60a 55.10 6.53 a 3370.74 477.23a 30.72 0.64a 23.64 0.85a
55.12 3.16 b 2325.03 286.31 63.06 7.51 a 3784.70 596.59 35.45 2.76 b 24.09 1.03 a
b
a
Mean SD, n = 6 per group. Means with the same superscripts do not differ significantly. ANOVA, Tukey’s test,p < 0.05.
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b
4.5 Serum MDA (nmol/ml)
4 3.5 3
a
a
2.5
a
2 1.5 1 0.5 0
Control
Sodium arsenite Curcumin + sodium arsenite
Curcumin
Fig. 2. Evaluation of serum malondialdehyde (MDA) in mice treated with sodium arsenite and curcumin. Mean SD, n = 6 per group. Means with the same superscripts do not differ significantly. ANOVA, Tukey's test, p < 0.05.
4. Discussion The present study showed the toxic effects of sodium arsenite on histopathologic and histomorphometric changes of kidney tissue and the ameliorating effect of curcumin on sodium arsenite toxicity in adult mice. No significant difference was found in kidney weight in sodium arsenite-treated mice. Our results were consistent with previous studies (El-Demerdash et al., 2009; Yu and Beynen, 2001). This might be due to the fact that toxic effect of sodium arsenite depends on dose and/or treatment period (Chattopadhyay et al., 2001).In agreement with previous findings (Ferzand et al., 2008; Roy and Bhattacharya, 2006), sodium arsenite led to the shrinkage (atrophy) of the glomerulus, a reduction in glomerular area and diameter as well as an increase in the Bowman's space (but not the area and diameter of Bowman's capsule) compared to the control group. Increase in the Bowman's space may occur as a consequence of glomerular atrophy. The structural integrity of the glomerulus is associated with the integrity of membrane in this organ. Collagen is the most abundant protein component of glomerular basement membrane and is required to maintain glomerular integrity (Miner, 2012). Arsenic affects cell antioxidant defense system to induce lipid peroxidation and the disruption of cell membrane polyunsaturated fatty acid (Shi et al., 2004). On the other hand, arsenic inhibits protein synthesis (Liao et al., 2004). This pollutant with its electrophilic nature readily interferes with the cellular
Total anoxidant capacity of serum (μmol/l)
0.9
a
0.8 0.7
c
a b
0.6
metabolism through interaction with thiol and sulfhydryl groups in proteins to inhibit their enzymatic activity (Das et al., 2009). Arsenic also triggers the dysfunction of proteins by binding to the protein carbonyl groups (Manna et al., 2008) and the inhibition of protein synthesis by the prevention of transcription factor activity (Liao et al., 2004). Animals exposed to sodium arsenite showed a reduction in the diameter of proximal tubule of the nephrons. In addition, vacuolation and acute degeneration of these tubules were abundant. However, no significant change was observed in the diameter of distal tubule in this group. Arsenic accumulation in the kidney caused histopathological changes including tubular disruption (Tsukamoto et al., 1983). The epithelial cells of proximal tubule are more susceptible than distal tubule due to their high mitochondrial content and are the primary targets of renal injury due to arsenic toxicity (Hall et al., 2009). One possibility for sodium arsenite-induced nephrotoxicity is shown to be related to metabolic changes in proximal tubule cells (Rizwan et al., 2014). Furthermore, sodium arsenite can cause mitochondrial membrane depolarization (Peraza et al., 2003) and affect cell viability which may itself lead to proximal tubule injury. Cytoplasmic vacuolation might be due to the degradation of cytoplasmic material especially the denaturation of proteins components which produce vacuoles in the cytoplasm (Ferzand et al., 2008). Kidney is rich in phospholipids and very susceptible to oxidative damage. ROS produced by arsenic (Shi et al., 2004) and/or reduction in cell antioxidant defense system (Das et al., 2009) attacks unsaturated fatty acids in the cell membrane of this organ which in turn causes lipid peroxidation. We hypothesized that kidney histopathological and histomorphometrical changes induced by sodium arsenite might be due to the ability of this toxicant in the induction of oxidative stress. To test this hypothesis, we assessed the concentration of MDA and total antioxidant capacity in serum. Sodium arsenite-treated mice showed a significant increase in the serum concentration of MDA and a significant decrease in the total antioxidant capacity of serum compared to the control. Such oxidative stress markers could be strong evidence for the induction of oxidative stress by sodium arsenite in the kidney. We also used a potent antioxidant, curcumin, in combination with sodium arsenite to provide further evidence for this hypothesis. In curcumin + sodium arsenite group, curcumin reversed the adverse effects of sodium arsenite on renal histopathological and histomorphometrical changes. Furthermore, this antioxidant increased the concentration of serum MDA and decreased the total antioxidant capacity of serum. Curcumin as a polyphenolic compound with methoxyl group is a powerful free radical scavenger that suppresses lipid peroxidation (Priyadarsini, 2013). Interestingly, the use of curcumin alone significantly increased the total antioxidant capacity of serum compared to the control. In addition to its direct antioxidant activity, curcumin may function indirectly as an antioxidant by enhancing the synthesis of glutathione (Dabidi Roshan et al., 2012) and improve antioxidant defense system. 5. Conclusion
0.5 0.4
Since kidney is a main target of arsenic toxicity, the present study was conducted to evaluate the protective effect of curcumin on sodium arsenite nephrotoxicity. Curcumin as an antioxidant compensated for adverse effects of sodium arsenite on kidney tissue, lipid peroxidation index and antioxidant capacity of serum.
0.3 0.2 0.1 0 Control
Sodium arsenite Curcumin + sodium arsenite
Curcumin
Fig. 3. Total antioxidant capacity of serumin mice treated with sodium arsenite and curcumin. Mean SD, n = 6 per group. Means with the same superscripts do not differ significantly. ANOVA, Tukey's test,p<0.05.
Conflict of interest None.
Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006
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Please cite this article in press as: H.R. Momeni, N. Eskandari, Effect of curcumin on kidney histopathological changes, lipid peroxidation and total antioxidant capacity of serum in sodium arsenite-treated mice, Exp Toxicol Pathol (2016), http://dx.doi.org/10.1016/j.etp.2016.08.006