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Environmental Science and Pollution Research

, Volume 26, Issue 1, pp 179–187 | Cite as

Curcumin attenuates nephrotoxicity induced by zinc oxide nanoparticles in rats

  • Abbas Heidai-Moghadam
  • Layasadat KhorsandiEmail author
  • Zahra Jozi
Research Article

Abstract

Curcumin (Cur) effects on renal injury induced by zinc oxide nanoparticles (NZnO) in rats were investigated. NZnO at a dose of 50 mg/kg for 14 days was administered to rats as intoxicated group. In protection group, Cur at a dose of 200 mg/kg was administered for 7 days prior to NZnO treatment and followed by concomitant administration of NZnO for 14 days. Plasma concentrations of uric acid, creatinine (Cr), and blood urea nitrogen (BUN) were detected to evaluate renal injury. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels were determined for evaluation oxidative stress. TUNEL staining and histological changes were also performed. Administration of NZnO caused a significant elevation in the uric acid, Cr, and BUN levels. Oxidative stress was increased in the kidney by NZnO through enhancing MDA contents and reducing activities of SOD and GPx enzymes. According to histological examinations, treatment with NZnO caused proximal tubule damages, which was accompanied by the accumulation of red blood cells, infiltration of inflammatory cells, and reducing glomerular diameters. Significant increase was observed in the apoptotic index of the renal tubules in NZnO-treated rats. In present work, pretreatment of Cur reduced the histological changes, decreased biomarker levels, attenuated apoptotic index, and ameliorated oxidative stress by decreasing the MDA contents and increasing the activities of SOD and GPx enzymes. These findings indicate that Cur effectively protects against NZnO-induced nephrotoxicity in the rats.

Keywords

Zinc oxide nanoparticles Curcumin Nephrotoxicity Oxidative stress Antioxidants Rats 

Introduction

Previous studies have shown that nanoparticles (NPs) accumulate in various tissues such as liver, spleen, brain, testis, and kidneys (Borm and Kreyling 2004; Bisht et al. 2005; Moridian et al. 2015). Zinc oxide nanoparticle (NZnO) is one of the most used metal NPs (Nohynek et al. 2007). Multiple products benefited from the NZnO, including sunscreens, food additives, pigments, rubber manufacture, and electronic devices (Wiking et al. 2008). It can be applied in the structure of food packaging or drugs due to its digestible nature (John et al. 2010; Tankhiwale and Bajpai 2012). It has been revealed that NZnO has toxic impacts on various tissues such as kidney (Yan et al. 2012; Xiao et al. 2016), liver (Almansour et al. 2017), and testis (Mozaffari et al. 2015; Moridian et al. 2015). NZnO disturbs energy metabolism and induces cell membrane defect in the renal tissue of rats (Yan et al. 2012). In the study of Guan et al. (2012), NZnO induced oxidative stress in embryonic kidney cells.

Curcumin (Cur) has been shown to be an active ingredient of the turmeric pigment in Curcuma longa (Farombi et al. 2008). Cur has many beneficial effects including anti-inflammatory (Edwards et al. 2017), antioxidant (Ak and Gülçin 2008), anticancer (Khazaei Koohpar et al. 2015), antimicrobial (De et al. 2009), and anti-hyperlipidemic (Pari and Murugan 2007). Yousef et al. (2010) showed that Cur restored the elevation of BUN and Cr induced by sodium arsenic in rats. Ameliorating effects of Cur against nephrotoxicity induced by cadmium (Kim et al. 2018), cisplatin (Ueki et al. 2013), and methotrexate (Morsy et al. 2013) have also been reported. The present study was performed to explore the efficacy of Cur in NZnO-induced nephrotoxicity.

Material and methods

Presentation of study animals

The present study was conducted on 32 healthy male Wistar rats aged 8 to 10 weeks and weighted 180 to 200 g that were prepared from the Ahvaz Jundishapur University of Medical Sciences, Experimental Research Center, Iran. Ethics committee of Jundishapur University approved this study (code of ethics: IR.AJUMS.REC.1395.405). The rats were housed in clean cages with a 12:12-h dark-light cycle and a relative humidity of 50 ± 5% at 22 ± 3 °C and were free to access commercial pellet food and tap water.

Study design

The animals were randomly categorized into four groups of eight as follows:

Control: administered by 0.2 ml of normal saline for 21 days.

Cur: received 200 mg/kg Cur (Wu et al. 2017; Topcu-Tarladacalisir et al. 2016) for 21 days.

NZnO: initially received 0.2 ml saline for 7 days followed by concomitant administration of 50 mg/kg NZnO for 14 days (Yan et al. 2012).

Cur + NZnO: initially received 200 mg/kg of Cur for 7 days and was followed by concomitant administration of 50 mg/kg NZnO for 14 days.

The duration time of NZnO was based on previous studies (Yan et al. 2012; Chien et al. 2017). Therefore, we treated the animals with Cur for 7 days prior to administration of NZnO, in order to evaluate its protective effects.

No information is available on the daily exposure level of NZnO in the human being, but there is a health risk for people exposed to high level of NZnO. Thus, we used the toxic dose of NZnO to examine whether Cur could prevent renotoxicity effects of this NP.

No mortality or morbidity was observed in control and experimental groups. However, NZnO-intoxicated animals were less active and lethargic.

The NZnO was purchased from Sigma-Aldrich Company, and diluted in milli-Q water. Morphology and size of the NZnO were evaluated using an atomic force microscope (AFM). In addition, the average particle size distribution, polydispersity index (PDI), and zeta potential of the NZnO were assessed using a dynamic light scattering method by Zetasizer-Nano-ZSP (Malvern, UK). The most NPs had a spherical morphology as revealed by AFM. The NPs were discrete and had a homogeneous particle size distribution and a mean size between 50 and 90 nm (Fig. 1). The average particle size given by AFM was in line with that found using DLS (69.8 ± 6.3), and most of the particles were observed to be distributed less than 90 nm. The zeta potential value of NZnO was about + 23.5 mV, which was high enough to make the NPs repel each other, thus avoiding particle aggregation. The polydispersity index of NZnO was about 0.17, which indicated a good homogeneous size distribution of the NZnO.
Fig. 1

AFM image of NZnO nanoparticles. Round morphology and particle size homogeneous distribution are observed

After the last administration and blood sample taking, the rats were killed after anesthesia with ketamine/xylazine, and kidneys from each animal were removed immediately. Right kidneys were stored in − 80 °C for the MDA, SOD, and GPx assays. Left kidneys were fixed in 10% formalin for histological assessments and TUNEL staining.

Biochemical experiments

The collected blood samples were poured in heparinized tube and then centrifuged to measure the plasma concentrations of uric acid, creatinine (Cr), and blood urea nitrogen (BUN) by using available kits (Sigma).

Lipid peroxidation assay

The dissected renal tissues were centrifuged, and then, 500 μL of the obtained supernatant was poured into 1.5 mL of 10% trichloroacetic acid (TBA) and recentrifuged at 7500×g for 15 min. Next, 1.5 mL of the resulting supernatant was added to 2 mL of 0.67% TBA, and the mixture was heated for 0.5 h to boil. After cooling down, 2 mL of n-butanol was poured to each sample and centrifuged at 7500×g for 15 min. The optical density (OD) of the supernatants was read by a spectrophotometer at a wavelength of 535 nm.

Superoxide dismutase assay

The SOD activity was determined using Ransod kit (Randox Labs, Crumlin, UK). This method produces a water-soluble formazan dye upon reduction with the superoxide anion. The rate of the reduction is linearly related to the activity of xanthine oxidase, which is inhibited by SOD. The inhibition activity of SOD was measured by a spectrophotometer at 505 nm.

Glutathione peroxidase assay

GPx enzyme activity was measured using a commercial available kit (Randox Labs., Crumlin, UK). GPx can oxidize glutathione by cumene hydroperoxide. In the presence of NADPH and glutathione reductase, the oxidized glutathione converts to reduce form, and NADPH changes to NADP+. The decrease in absorbance can spectrophotometerically measure at 340 nm.

Zn content analysis

Approximately 0.5 mg of the renal tissue was maintained in nitric acid overnight. Then, a mixture of perchloric acid and nitric acid (1:6) was added and heated until the solutions were cleared. Blood samples were collected and centrifuged at 5000 rpm for 10 min to obtain the plasma. The Zn contents of plasma and renal tissues were analyzed with the aid of an atomic absorption spectrophotometer [ZEEnit 700 P, Analytikjena, Germany] (Sharma et al. 2012).

Histopathology analyses

In this study, six sections per rat were stained with hematoxylin and eosin (H&E) and evaluated for the following histological criteria: accumulation of inflammatory cells, proximal cell swelling, brush border loss, and red blood cell (RBC) accumulation. The histological criteria were graded into four categories and the averages were considered. The categories were normal (0), weak (1), moderate (2), and intense (3). Two coworkers unaware of the control and intervention groups explored separately the slides and measured glomerular diameter with the aid of the Motic Images Plus 2.0 software (Alidadi et al. 2018).

TUNEL assay

TUNEL staining was performed by In Situ Cell Death Detection kit (POD, Invitrogen). The prepared tissue cross-sections were deparaffinized and incubated with proteinase K for 30 min at 26 °C. The sections were exposed to a TUNEL reaction mixture in a humidity chamber at 37 °C for 1 h. The incubation of the sections was done in the presence of anti-fluorescein-AP at the temperature of 37 °C for 30 min. Then, they were washed with deionized water and subjected to DAB for 5 min. Cells with homogeneous dark brown nucleus were considered as TUNEL-positive cells (Khorsandi et al. 2008).

Statistical analysis

The analysis of collected data was carried out using one-way ANOVA and post hoc LSD test. The data were reported as mean and standard deviation. The significance level was considered to be P < 0.05.

Results

Weight changes

Body weights in control and Cur groups were similar, and there were no significant difference between them. Body and renal weights in NZnO-intoxicated rats were significantly decreased (P < 0.01). Pretreatment of Cur caused a significant increase in body and kidney weights in comparison with NZnO-intoxicated animals (P < 0.05). These results are shown in Table 1.
Table 1

Kidney and body weight for control and experimental groups

Groups

Body weights

Kidney weights

Control

226.8 ± 18.9

1.23 ± 0.23

Cur

233.4 ± 16.7

1.24 ± 0.27

NZnO

188.3 ± 12.3*

0.66 ± 0.14**

Cur + NZnO

210.6 ± 11.8*

0.91 ± 0.23*#

Values expressed as mean ± SD for eight rats. *P < 0.05, **P < 0.01, #P < 0.05; * and # symbols, respectively, indicate comparison to control and NZnO-intoxicated groups

Renal concentration of Zn

In Cur-treated rats, Zn concentration of plasma and renal tissue was similar to that of the control group. Concentration of Zn in both plasma and renal tissue was significantly increased in the NZnO group (P < 0.001). In the NZnO + Cur group, the concentration of Zn in kidney and plasma was not significantly altered in comparison with NZnO-intoxicated rats (Fig. 2).
Fig. 2

Plasma and kidney concentrations of Zn in control and experimental groups. Values are expressed as mean ± SD for eight rats. *P < 0.05

Biochemical tests

In the Cur-treated rats, BUN, Cr, and uric acid were slightly decreased compared to the control group. Plasma levels of BUN, Cr, and uric acid were significantly increased in the NZnO group (P < 0.001). According to Fig. 3, a significant decrease in the level of biochemical parameters was found in rats treated with Cur + NZnO in comparison with those treated with NZnO alone (P < 0.01).
Fig. 3

Biochemical tests of control and experimental groups. Values expressed as mean ± SD for eight rats. *P < 0.05, **P < 0.001, #P < 0.01; * and # symbols indicate comparison to control and NZnO-intoxicated groups, respectively

Activity of SOD and GPx enzymes and MDA level

NZnO significantly increased MDA content in the renal tissue compared to control animals. This elevation was attenuated by Cur (P < 0.01). The GPx and SOD activities of the renal tissue were significantly reduced with the NZnO in comparison to the control group (P < 0.01). The activity level of the SOD and GPx enzymes was significantly enhanced after pretreatment of Cur, compared to the NZnO group (P < 0.05). These results are shown in Fig. 4.
Fig. 4

MDA level, SOD and GPx activities of control and experimental groups. Values are expressed as mean ± SD for eight rats. *P < 0.05, **P < 0.01, #P < 0.01; * and # symbols indicate comparison to control and NZnO-intoxicated groups, respectively

Histological changes

In the control and Cur groups, the kidney tissue showed normal appearance. Administration of NZnO markedly increased histological criteria including infiltration of inflammatory cells, accumulation of RBCs, and proximal cell damage, while the glomerular diameter was significantly reduced (P < 0.01). Administration of the Cur plus NZnO improved the histological changes (P < 0.01), compared with NZnO-intoxicated animals (Fig. 5 and Table 2).
Fig. 5

Light microscopy of cross sections of H&E-stained testis from control and experimental groups. a Control group; b Cur group; c NZnO-intoxicated group; d Cur + NZnO group. C: congestion of RBCs; I: infiltration of inflammatory cells; P: proximal cell swelling; magnifications: × 250

Table 2

Histology assessments in control and experimental groups

Histological criteria

Control

Cur

NZnO

Cur + NZnO

Normal (%)

98.6 ± 1.33

98.8 ± 1.1

72.4 + 5.6*

91.3 + 4.9

Proximal cell swelling (%)

0.79 + 0.17

0.75 + 0.16

19.1 ± 2.5***

6.4 + 1.3***”

Brush border loss (%)

0.61 ± 0.13

0.45 ± 0.11

8.5 + 1.5***

2.3 ± 0.21*”

Infiltration of leukocytes

0.13 ± 0.03

0.12 ± 0.02

2.2 + 0.31***

0.64 + 0.18**#

Congestion of RBCs

0.17 ± 0.03

0.13 ± 0.02

2.4 ± 0.22***

0.71 ± 0.13**#

Glomerular diameters (iu, m)

229 + 17.6

234.7 + 21.2

154.7 + 8.6**

189.6 ± 7.9′4

Values expressed as mean ± SD for eight rats. *P < 0.05, **P < 0.01, ***P < 0.001, #P < 0.05, ##P < 0.01; * and # symbols, respectively, indicate comparison to control and NZnO-intoxicated groups

TUNEL assay

As shown in Fig. 6, some normal renal tubules of the control group had TUNEL-positive cells. In Cur group, apoptotic index of renal tubules was slightly less than the control group. In the NZnO group, apoptotic index was significantly elevated in comparison with the control group (P < 0.001). In the Cur plus NZnO group, apoptotic index was significantly reduced, compared to the NZnO-treated animals (P < 0.001).
Fig. 6

TUNEL staining in the kidney sections (magnifications: × 250) and apoptotic index. a Control group; b Cur group; c NZnO-intoxicated group; d Cur + NZnO group. Arrows indicate TUNEL-positive cells. Values expressed as mean ± SD for eight rats. *P < 0.01, **P < 0.001, #P < 0.001; * and # symbols indicate comparison to control and NZnO-intoxicated groups, respectively

Discussion

This study demonstrated that Cur effectively improved renal injury induced by NZnO in rats. Biochemical tests and histological examinations indicated renotoxic impacts of NZnO. Nephrotoxic effects of NZnO have also been reported by Yan et al. (2012), Noori et al. (2014), and Lin et al. (2016). The NZnO caused a significant decrease in the body, and renal weights of the rats revealed the toxic effects of this NP. Body and organ weights are the main indicators for assessment of toxic impacts of various drugs or chemicals on animals (Wang et al. 2016). According to our results, Zn concentration in the plasma and kidney tissue was markedly increased in NZnO-treated rats. The NZnO can reach to different tissues through circulation and induce cell death in targeted organs. Inducing cell death in various tissues can lead to body weight loss. It has been revealed that NZnO after oral administration can accumulate in different tissues such as spleen, liver, kidney, digestive glands, and brain. (Borm and Kreyling 2004; Bisht et al. 2005; Marisa et al. 2016). In the study of Cho et al. (2013), Zn concentration in the kidney was markedly increased after oral administration of NZnO.

Cur could not decrease Zn contents in the plasma and kidney tissue of the rats. This indicated that Cur was unable to alter the clearance of NZnO. However, the increased kidney and body weights by Cur in NZnO-intoxicated animals indicated protective effects of Cur on the renal tissue and other organs. In a previous study, Cur improved renal weight loss induced by Gentamicin (El-Zawahry and Abu El Kheir 2007).

The plasma BUN, Cr, and uric acid levels were markedly increased by NZnO treatment in this study. In the kidney damage, these biomarkers release into the bloodstream from proximal cells. Thus, the elevation concentration of these biomarkers indicates proximal cell destruction (Zhu and Cao 2012). The reversal of the biochemical markers by Cur indicates beneficial effects of this flavonoid on proximal cells. Kim et al. (2018) found that Cur significantly reduced the acute elevation of BUN, Cr, and uric acid in cadmium-induced nephrotoxicity of rats. El-Maddawy and El-Sayed (2018) have also shown that Cur significantly attenuates the elevation serum levels of BUN and Cr induced by paracetamol in rats.

The significant increase in biochemical parameters induced by NZnO was accompanied by histological changes in the renal tissue such as proximal cell injury and reducing glomerular diameter. In addition, histological criteria such as proximal cell swelling, accumulation of RBCs, and infiltration of leukocytes revealed necrotic effects of NZnO on the renal tissue. Yan et al. (2012) reported that NZnO administration caused a tubular epithelial cell necrosis. In the study of Chien et al. (2017), inflammatory cells were infiltrated in renal tissue after oral administration of NZnO in rats.

In this study, Cur could suppress infiltration of inflammatory cells and necrosis induced by NZnO in the renal tissue. In the study of Ueki et al. (2013), cisplatin-induced renal dysfunction, inflammation, and renal tubular necrosis were ameliorated by Cur. Kuhad et al. (2007) have reported that Cur inhibits inflammation of cisplatin-induced nephrotoxicity in rats. Liu et al. (2016) showed the protective impact of Cur on renal ischemia reperfusion injury by suppressing the inflammatory and apoptotic mediators.

The kidney tissue of animals treated with NZnO showed apoptosis in addition to necrosis. Furthermore, the reduced glomerular diameters induced by NZnO may be a result of enhancing cell death which leads to kidney weight loss. In the study of Park et al. (2007), among six different NPs, NZnO had the most apoptotic effects on lung cancer cells. NZnO can damage mouse testicular tissue and induce germ cell apoptosis (Han et al. 2016). In the study of Lin et al. (2016), NZnO enhanced apoptosis in the mouse renal tissue.

In present work, Cur effectively reduced the apoptosis induced by NZnO in the proximal tubules. Jones et al. (2000) have demonstrated that treatment with Cur inhibits the expression of the apoptosis-related genes. Khan et al. (2012) have shown that Cur has a protective effect against arsenic-induced apoptosis in murine splenocytes in vitro. Topcu-Tarladacalisir et al. (2016) have also reported that Cur ameliorates cisplatin-induced nephrotoxicity by suppressing renal tubular cell apoptosis. The enhanced body and renal tissue weights by Cur may result from apoptosis disruption in renal tissue and other organs. Furthermore, the increased glomerular diameter by Cur may relate to inhibition of apoptosis in the kidney tissue.

As mentioned in the results, NZnO induced oxidative stress in the renal tissue by decreasing SOD and GPx enzymes activity, and increasing MDA contents. In the study of Guan et al. (2012), DNA damage and cytotoxicity occurred in the kidney cells due to oxidative stress induced by NZnO. It is well known that oxidative stress can stimulate apoptotic or necrotic cell death pathways (Chang et al. 2007).

Our results showed that Cur effectively reduced oxidative stress induced by the NZnO. In agreement with our results, Cur improved apoptosis, stress oxidative, and inflammatory signals in nephropathy induced by contrast agents in rats (Buyuklu et al. 2014). Wu et al. (2017) reported that Cur reduced oxidative stress and apoptotic index of renal tubules in an acute kidney injury induced by glycerol. He et al. (2015) showed that Cur attenuated renal tubular damage, biochemical parameters, oxidative stress, and apoptosis in nephrotoxicity induced by gentamicin.

Cur could inhibit adriamycin-induced renal injury by suppressing of oxidative stress, elevating kidney levels of GSH, and increasing glutathione peroxidase activity (Venkatesan et al. 2000).

The mechanism of Cur protection effects on nephrototoxicity induced by NZnO is not understood from this study. Cur administration could not reduce renal Zn contents. Thus, Cur could improve renal toxicity without affecting the clearance of NZnO. Anti-oxidative impacts of Cur may play an important role in its renoprotective effects. The oxidative stress can obviously trigger different types of cell death such as apoptosis and necrosis. Hence, Cur by suppressing oxidative stress can reduce apoptosis or necrosis in the renal tissue.

In addition, anti-inflammatory properties of Cur may suppress necrosis induced by NZnO. During the inflammatory process, the stimulated macrophages and neutrophils generate large amounts of ROS, superoxide, H2O2, nitric oxide, peroxynitrite, etc. These reactive species can induce localized oxidative stress and tissue injury (Fialkow et al. 2007). It is suggested that increased oxidative stress and inflammatory cytokines may increase the apoptosis levels in diabetic nephropathy (Sha et al. 2016). Mahgoub et al. (2017) have demonstrated that genipin ameliorates cisplatin-induced renal toxicity by inhibition oxidative stress, suppression of inflammation, and preventing renal cell death.

In summary, our results demonstrated that Cur effectively protected against NZnO-induced nephrotoxicity. The Cur is likely able to decrease the renal injury induced by NZnO through reducing the oxidative stress, apoptosis, and inflammation. Further researches are required to investigate crosstalk between various cell death pathways mediated by Cur and NZnO in the renal tissue.

Notes

Funding

This paper was supported by a grant (94s105) from the student research committee council of the Ahvaz Jundishapur University of Medical Sciences.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Student Research committeeAhvaz Jundishapur University of Medical SciencesAhvazIran
  2. 2.Cellular and Molecular Research Center, Faculty of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran

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