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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 6  |  Page : 1270-1281
Mixed hydroalcoholic extracts of Nigella sativa and Curcuma longa improves adriamycin-induced renal injury in rat


1 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences; Department of Physiology, Neurogenic Inflammation Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4 Department of Pathology, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
5 Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

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Date of Web Publication18-Dec-2017
 

   Abstract 


Extracts of both Curcuma longa (CL) and Nigella sativa extract (NS) are reported to have protective effects on renal damage. In this study, we investigated the protective effect of a combination of NS and CL on Adriamycin (ADR)-induced renal damage. Forty eight rats were divided into six groups as: Control (CO), ADR, Vitamin C + ADR, CL + ADR, NS +ADR, and CL + NS + ADR. ADR was injected intravenously on the 7th day of the study. 24-hour urine and orbital blood samples were collected on day 0, 48 hr after ADR injection and at the end of weeks 2, 3, 4, and on the 35th day. Glomerular filtration rate (GFR) was calculated on each sample, and on the 35th day, renal index and histological changes were also evaluated. In the ADR-treated rats, significant renal pathological changes were demonstrated compared to CO group. The renal index and urine protein excretion significantly increased, and serum albumin and GFR in the ADR-treated rats were significantly decreased compared to CO group. In NS + ADR group, the serum albumin significantly decreased compared to ADR group. In CL + NS + ADR group, the urine protein excretion was lower than ADR group, and serum albumin concentration was significantly higher than ADR group. In addition, in CL + ADR and NS + ADR groups also, the urine protein was significantly lower compared to ADR group. This study shows that the mixed extracts of N. sativa and CL have positive synergistic effects on renal damage in nephropathy induced by ADR in rats.

How to cite this article:
Mohebbati R, Shafei MN, Beheshti F, Soukhtanloo M, Roshan NM, Anaeigoudari A, Parhizgar S, Hosseinian S, Khazdeir MR, Rad AK. Mixed hydroalcoholic extracts of Nigella sativa and Curcuma longa improves adriamycin-induced renal injury in rat. Saudi J Kidney Dis Transpl 2017;28:1270-81

How to cite this URL:
Mohebbati R, Shafei MN, Beheshti F, Soukhtanloo M, Roshan NM, Anaeigoudari A, Parhizgar S, Hosseinian S, Khazdeir MR, Rad AK. Mixed hydroalcoholic extracts of Nigella sativa and Curcuma longa improves adriamycin-induced renal injury in rat. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Dec 8];28:1270-81. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1270/220880



   Introduction Top


Adriamycin (ADR) also known as doxorubicin is an anthracycline antibiotic that has been used for several years in the treatment of a wide variety of cancers. Several side effects, especially nephrotoxic effects, have been reported after treatment with ADR. Both acute and chronic effects of ADR on kidneys have been reported.[1] ADR also is a well-known inducer of renal injury in rodents. Adriamycin-induced nephropathy (AN) in rodents has been extensively studied and has enabled a greater understanding of the processes underlying the progression of renal injury.[2]

The Chinese traditional medicine Curcuma longa (CL) is a member of the ginger family, and it has recently attracted much attention because it exhibits a variety of biological activities, including nematocidal activity,[3] anticancer effects,[4] topoisomerase inhibition,[5] strong antioxidant activity,[6] and it also protects against alcohol-induced liver toxicity.[7] Curcumin is a major yellow pigment in the ground rhizome of CL, which is used widely as a spice and coloring agent in several foods as well as cosmetics and drugs.[8] Curcumin represents a class of anti-inflammatory and antioxidant agents, which has been reported to be a potent inhibitor of inflammation and also reactive oxygen species (ROS) formation.[9] Curcumin exhibited antioxidant activity in normal renal cell line[10] and ameliorated ferric nitrilotriacetic-induced renal oxidative stress in mice.[11] Indeed, administration of curcumin has been reported to prevent renal lesions in streptozocin-induced diabetic rats.[12] Another study indicates that curcumin as a natural antioxidant can be considered as a potent protective agent against renal oxidative damage mediated by gentamicin.[13]

Nigella sativa (NS), commonly known as black seed or black cumin, has been used as a natural remedy for a number of diseases including asthma,[14] cough, bronchitis, headache, eczema, fever, dizziness, and influenza.[15] NS contains more than 30 w/w of a fixed oil, and 0.40–0.45 w/w of a volatile oil. It has been shown that the volatile oil of NS contain 18.4%–24% thymoquinone (TQ) and 46% monoterpenes such as p-cymene and apinene.[1] Recently, clinical and experimental studies of NS extract have demonstrated many therapeutic effects including immunomodulative,[17] anti-inflammatory,[18] antitumor,[19] antidiabetic,[20] anticancer,[21] and antiulcergenic[22] effects. Furthermore, recent toxicological studies have demonstrated that crude extracts of the seeds and some of its active constituents (volatile oil and TQ) might have a protective effect against nephrotoxicity,[23] neurotoxicity,[24] and hepatotoxicity induced by either disease or chemicals.[15] The histopathological studies in the kidney of rats that treated by TQ showed that TQ markedly reduced the toxicity of cadmium (Cd) and preserved the normal histological architecture of the renal tissue.[25]

Recently, there are opinions that combination of extracts may be more beneficial. Since both N. sativa and CL have protective effects, it is possible that use of a combination of these two extracts may have synergistic and better effect. Therefore, we conducted this study to elucidate the effects of combined use of extracts of NS and CL on ADR-induced renal injury in rats.


   Materials and Methods Top


Experimental

Animals and groups

Forty-eight male Wistar rats (weighing 220–250 g) were kept in cages at 22°C ± 2°C in a room with a 12 h light/dark cycle (light on at 7:00 am). Animals were randomly divided into six groups of 8 each as:

  1. Control group (CO) which received normal saline through a tail vein on the 7th day of the study
  2. ADR group which received ADR (5 mg/kg BW)[26] through a tail vein on the 7th day of the study
  3. Vitamin C (Vit C) +ADR group which received Vit C (100 mg/kg BW)[27] in drinking water for 35 consecutive days and ADR on the 7th day of the study
  4. CL + ADR group which received CL extract (1000 mg/kg BW)[28] in drinking water for 35 consecutive days and ADR on the 7th day of the study
  5. NS + ADR group which received NS extract in drinking water for 35 consecutive days and ADR (5 mg/kg BW) on the 7th day of the study
  6. Mixed extract of CL and NS plus ADR group (CL + NS + ADR) which received ADR (5 mg/kg BW) through a tail vein on the 7th day of the study and mixed extract of NS (200 mg/kg BW) and CL (1000 mg/kg BW) in drinking water for 35 consecutive days.


After ADR injection, 24-hour urine and orbital blood samples were collected on day 0, day 10, 14, 21, 28, and 35th day. On the 35th day of experiment, under deep anesthesia by ether, the left kidneys were obtained for histopathological evaluation from the animals.

Extract preparation

CL rhizomes (100g) and N. Sativa seeds (100 g) were purchased from a local market in Mashhad, Iran. These were cleaned, dried, grounded, weighed, and homogenized in 95% ethanol at a ratio of 1:10 of plant to ethanol and then left to be soaked for three days at 37°C with occasional shaking and stirring. The mixture was then filtered, and the resulting liquid was concentrated under reduced pressure at 45°C in an EYELA rotary evaporator (7%, w/w). The concentrated extract was then kept in the incubator at 45°C for three days to evaporate the ethanol residue yielding the crude extract.[29] Extracts were then dissolved in 96% ethanol (0.5%, w/w) before being orally administrated (dissolved in drinking water) to animals.

Biochemical assessment

Blood samples were taken from all rats in before the ADR injection (day 0) and after the ADR injection (days 10, 14, 21, 28, and 35) to determine serum creatinine and albumin levels by using a albumin and creatinine kit (Pars Azmoon Company, Tehran, Iran). 24-h urine samples were taken from all rats before (day 0) and after ADR injection (days 10, 14, 21, 28 and 35) to determine the urine protein levels by using a TCA method and urine creatinine levels by using a creatinine kit (Pars Azmoon Company, Tehran, Iran). Glomerular filtration rate (GFR) was estimated using creatinine clearance.

Histopathological examination

The left kidneys of animals were halved through a coronal section after removal from the body. Then, the two halves were fixed by a 10% solution of formalin. After processing, they were embedded in paraffin and cut into 3–4 μm slices. The slices were mounted on glass slides and stained with hematoxylin and eosin (H and E) for light microscopic analysis in a blinded way. The pathologic changes of the kidneys were recorded using a grading scale of 0–4 which was adapted from Goering et al[30] as follows:

  • 0 = indistinguishable from controls
  • 1 = minimal, ≤25% cortex and medulla affected
  • 2 = mild, >25% and ≤50% cortex and medulla affected
  • 3 = moderate, >50% and ≤75% cortex and medulla affected
  • 4 = severe, >75% cortex and medulla affected.


High-performance liquid chromatography evaluation

The retention time of curcumin and TQ was determined by high-performance liquid chromatography (HPLC) method. After injection of 20 μL of standard solution of considered active ingredients were given and the area under the curve were calculated. Then, 20 μL of NS and CL extracts were injected. To be sure, 20 μL of extract solution containing the standard solution of considered active ingredients were given as separate injections. In HPLC method, retention time of curcumin and TQ was 13.300 and 13.217, respectively. The curves are shown in [Figure 1]. The standard values of curcumin and TQ in CL and NS extracts in this method evaluated about 746 μg/g of CL extract and 505 μg/g of NS extract, respectively.
Figure 1: RP-HPLC Chromatographic profiles of Nigella sativa extract and Curcuma longa monitored at 254 and 420nm. The peaks correspond to thymoquinone (a) and curcumin (b).

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   Statistical Analysis Top


All data were expressed as means ± standard error of the mean. Normality test (Kolmogorov–Smirnov) was done. Different groups were compared by one-way ANOVA followed by Tukey's post hoc comparison test. Differences were considered statistically significant when P <0.05. The data was analyzed by using Statistical Package for the Social Sciences version 11.5.


   Results Top


In the ADR group, the renal index significantly increased (P <0.05) and GFR significantly decreased (P <0.05) compared to CO group [Figure 2] and [Table 1]. GFR in treated rats with Vit C, CL, NS, and CL + NS along with ADR did not show significant change in comparison with ADR group [Table 1].
Figure 2: Comparison of the renal tissue damage in different groups of animals. Data are presented as Mean ± standard error of the mean.
**P <0.01 and ***P <0.001 compared with the CO group. ##P <0.01 and ###P <0.001 compared with the ADR group. CO: Control, ADR: Adriamycin, Vit C: Vitamin C, CL: Curcuma longa.


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Table 1: Glomerular filtration rate (mL/min) in all experimental groups of animal (n = 8 for each group).

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The percentage of the renal tissue damages through scoring method in various experimental groups of rats was observed. ADR-treated rats had a significant increase in the kidney tissue injury compared to the CO group (P <0.001). Although compared to the control group, all other experimental groups treated with a combination of ADR and extracts or Vit C demonstrated a significantly higher renal tissue damage (P <0.01 and P <0.001), the degree of the damage was much less [Figure 2]. These data indicate that all animals treated with a combination of ADR and extracts or Vit C significantly have lower renal tissue damage than the ADR-treated group (P<0.001). However, the renal index percentage that increased by ADR induction did not significantly change in other groups compared to ADR group [Figure 3].
Figure 3: Renal index percentage in all experimental groups of animal (n = 8 for each group). Values are the mean ± standard error of the mean. The data were analyzed using one-way ANOVA and post hoc Tukey. A significant difference between CO group with ADR group was considered at P <0.05#.
CO: Control, ADR: Adriamycin, Vit C: Vitamin C, CL: Curcuma longa.


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In histopathological examination of the CO group, we did not observe any notable pathological changes [Figure 4], whereas nephrotoxicity effects of ADR group (group 2) were found to be prominent with marked vacuolization of the cortical distal convoluted tubular epithelium, erosion, hyaline casts, and cystic dilatation of the Bowman capsule as compared to the control tissue [Figure 5]. Similar results with mild severity were seen in the rats of Vit C + ADR group (group 3), where vacuolization of the renal tubular epithelium, erosion, and hyaline cast were recorded [Figure 6]. The examined sections from the rats of groups 4, 5, and 6 showed considerably much less of the above-described damages with only a few fibroblasts and mononuclear cell infiltrations seen in the sections, as compared to the CO groups [Figure 7] [Figure 8] [Figure 9].
Figure 4: Microscopic cross sections stained with hematoxylin and eosin. Cortex area (A) corticomedulla (B) and medulla (C) of the CO group, magnification × 40. Healthy glomeruli (G), collecting ducts (CD) and proximal tubules (P) and distal tubules (D) are observed (Scale bar = 20 μm).

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Figure 5: Microscopic cross sections stained with hematoxylin and eosin. Cortex area (A) corticomedulla (B) and medulla (C) of the ADR group, magnification × 40. Vacuolization (V), vascular congestion and inflammation (I), hyaline casts (HC) and the tubular dilation (DT) are observed (Scale bar = 20 μm).

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Figure 6: Microscopic cross sections stained with hematoxylin and eosin. Cortex area (A) corticomedulla (B) and medulla (C) of the Vit C+ADR group, magnification × 40. Relatively lesser degree vacuolization (V), vascular congestion and inflammation (I), hyaline casts (HC), and the tubular dilation (DT) are observed (Scale bar = 20 μm).

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Figure 7: Microscopic cross sections stained with hematoxylin and eosin. Cortex area (A) corticomedulla (B) and medulla (C) of the CLE+ADR group. Relatively lesser degree in vacuolization (V) and vascular congestion are observed (Scale bar = 20 μm).

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Figure 8: Microscopic cross sections stained with hematoxylin and eosin. Cortex area (A) corticomedulla (B) and medulla (C) of the N.SE+ADR group, magnification × 40. Relatively lesser degree t in vacuolization (V) and vascular congestion are observed (Scale bar = 20 μm).

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Figure 9: Microscopic cross sections stained with hematoxylin and eosin. Cortex area (a) corticomedulla (b) and medulla (c) of the CL+NS+ADR group, magnification × 40. Relatively lesser degree of vascular congestion is observed (Scale bar = 20μm).

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Effect of ADR on serum albumin and proteinuria has been shown in [Figure 10] and [Figure 11], respectively. ADR significantly decreased serum albumin in comparison with the CO group in days 10, 14, 21, 28, and 35 (P <0.05, P <0.001) and significantly increased urine protein in comparison with the CO group in days 21, 28, and 35 (P <0.01, P <0.001). In NS + ADR group, the serum albumin was significantly decreased compared to ADR group in the 10th day of the study [Figure 10]. In NS + CL + ADR group compared to ADR group, on days 21 (P <0.05), 28, and 35 (P <0.01), serum albumin increased significantly.
Figure 10: Serum albumin concentration in six groups (n = 8 in each group). Values are the Mean ± standard error of the mean. The data were analyzed using One-Way ANOVA and post hoc tukey. ADR decreased the serum albumin concentration compared to CO group in days 10 (P <0.01), 14, 21 (P <0.05), 28 (P <0.01) and 35 (P <0.001). The serum albumin concentration enhanced in N.S+ADR group compared to ADR group in 10th day (P<0.001); also in NS+CL+ADR group compared to ADR group in days 21 (P <0.05), 28 and 35 (P<0.01) were significantly increased.
CO: Control, ADR: Adriamycin, Vit C: Vitamin C, CL: Curcuma longa.


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Figure 11: Urine protein concentration in six groups (n = 8 in each group). Values are the mean ± standard error of the mean. The data were analyzed using One-Way ANOVA and post hoc Tukey. ADR increased the urine protein concentration compared to CO group in days 21 (P <0.01), 28 (P <0.001) and 35 (P <0.001). The urine protein concentration decreased in N.S+C.L+ADR group compared to ADR group in 28th day (P <0.001). The urine protein concentration decreased in NS+CL+ADR, CL+ADR and NS+ADR groups compared to ADR group in 35th day (P <0.001).
CO: Control, ADR: Adriamycin, Vit C: Vitamin C, CL: Curcuma longa.


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In NS + CL + ADR group, the urine protein excretion significantly decreased on days 28 and 35 compared to ADR group (P <0.001; [Figure 10]). Furthermore, in CL + ADR and NS + ADR groups, the urine protein significantly decreased on the 35th day compared to ADR group (P <0.001; [Figure 11]).


   Discussion Top


ADR is an experimental model of human focal segmental glomerulosclerosis, which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. Novel findings suggest that dysfunction of the proliferator-activated receptor-γ coactivator (PGC)-lα-mitochondria axis is highly involved in ADR-induced podocyte injury.[31] Results of our study showed significant renal injury and proteinuria in ADR group. All experimental animals developed nephropathy characterized by proteinuria, hypoalbuminemia, elevated creatinine levels, and progressive renal injury. Overt proteinuria appeared shortly after an intravenous injection of ADR and remained significantly elevated throughout the experimental period, similar to the study by Wang et al.[32] Histological studies confirm renal damage in ADR group. Several histological studies showed inflammation, destruction and loss of epithelial cells, renal tubular dilation, and hyaline casts in the ADR group. Liang et al in 2014 showed that intravenous injection of ADR in the 6 mg/kg BW cause inflammation and glomerular membrane disruption.[33]

The current study in accordance with Wapstra et al showed that a single dose injection of ADR significantly decreased the serum albumin concentration and GFR and increased proteinuria associated with nephrotic syndrome characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, edema, and ascites formation in ADR-treated rats which affirmed the accuracy of this investigation in induction of nephropathy.[34]

Mohan et al in 2010 showed that oral administration of the Solanum torvum extract with doses 100 and 300 mg/kg BW to rats for 28 days improved tubular necrosis, inflammation, and bleeding in the cortex. Also, the glomerular damage and disruption caused by ADR in the cortex of all rats was improved.[35] Our study assessed the efficacy of treatment with extracts of plants CL and NS on the kidney damage caused by ADR.

The biochemical results of the present study demonstrated that CL and N. sativa extract significantly attenuated decreased serum albumin induced by ADR administration. However, effect of coadministration of extracts was better than either one separately.

Curcumin, the yellow curry pigment isolated from turmeric, has been reported to reduce ischemic renal injury.[36] More recently, curcumin was shown to protect from ADR-induced cardiotoxicity in rats.[37] Curcumin treatment was also accompanied by significant reduction in urinary excretion of glycosaminoglycan in ADR-treated rats and suggests that this treatment may influence the integrity of the glomerular basement membrane (GBM) against ADR-induced damage.[38] Curcumin might play a critical role in suppressing ROS-mediated destruction of basement membrane and proteinuria.[37] Other studies showed that the renal protective effect of curcumin is also evident by a remarkable improvement of renal function, as judged by the restoration of GFR in ADR group. It is also interesting to note that urinary fibronectin (FN) levels[39] are modulated in curcumin-treated ADR rats.

Other plant was NS. The active ingredients of NS have beneficial effects against many diseases, including cancers. For example, it is effective in diminishing the risk of atherosclerosis by decreasing the serum low-density lipoprotein cholesterol level and increasing the serum high-density lipoprotein cholesterol levels.[40]

In this study, pathology review of all groups by taking the percentage of renal damage in the view of the presence of droplets of protein, inflammation, tubular hyaline casts, bleed, cell swelling, loss of tubular and glomerular integrity, increased glomerular area, tubular atrophy of glomeruli, and dilation was performed. It showed that there was significantly higher percentage of kidney damage in each group of ADR, Vit C + ADR, ADR + CL extract, CL + NS + ADR compared to the CO group. However, in those who were administered CL extract, NS extract and CL + NS with ADR renal damage were significantly lower than the ADR group. A previous study also showed that NS and CL extracts improved ADR-induced oxidative stress.[41] Researchers showed that TQ is a high potential antioxidant and it has marked effect on the suppression of AN. The data also may suggest that TQ might be applicable as a protective agent for proteinuria and hyperlipidemia associated with nephrotic syndrome.[42] TQ has protective effects on diabetic nephropathy in experimental animals. Both mesenchymal and epithelial markers serve as excellent predictors of early kidney damage and indicators of TQ responsiveness in streptozotocin-induced diabetic nephropathy.[43]

In the present study, treatment with CL extract showed significant increase in serum albumin and GFR and decrease in proteinuria in comparison with ADR group. Other findings of this study showed that treatment with N. sativa and CL extract has synergistic effects on renal damage improvement when compared with ADR group.


   Conclusion Top


The current study suggests seventy percent hydroalcoholic extract of CL and NS, in doses of 1000 and 200 mg/kg respectively, as well as vitamin C 100 mg/kg, with ADR resulted in a significant protective effect on renal tissue damage. However, it requires more investigations to clarify the mechanisms involved in producing the positive effects of these herbs on ADR-induced renal damage in rats.


   Acknowledgment Top


The authors would like to thank Research Center of Herbal Plants and Vice President of Research of Mashhad University of Medical Sciences for the financial support.

Conflict of interest: None declared.



 
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Correspondence Address:
Abolfazl Khajavi Rad
Department of Physiology, Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences Mashhad
Iran
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DOI: 10.4103/1319-2442.220880

PMID: 29265038

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    Figures

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    Abstract
   Introduction
    Materials and Me...
   Statistical Analysis
   Results
   Discussion
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   Acknowledgment
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