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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 4  |  Page : 775-786
The Effect of Nigella Sativa on Renal Oxidative Injury in Diabetic Rats


1 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Physiology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
3 Addiction and Behavioral Sciences Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
4 Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

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Date of Submission11-Jan-2019
Date of Decision11-Mar-2019
Date of Acceptance12-Mar-2019
Date of Web Publication15-Aug-2020
 

   Abstract 


Oxidative stress plays a key role in the evolution of diabetes complications. The current study looked into the potential effects of the hydroalcoholic extract of Nigella sativa on the oxidative injury of the rat kidneys in diabetic animals. The animals were placed into five study groups in a random manner as follows: (1) control, (2) diabetic, (3 and 4) treatment with two doses of N. sativa extract (200 and 400 mg/kg), and (5) treatment with metformin (300 mg/kg). The time course of administration was six weeks. The malondialdehyde (MD A) and total thiol groups, as well as the superoxide dismutase and catalase activities, were also assessed in the renal tissue and lipid profile in serum. In the diabetic groups, the level of MDA significantly increased (P < 0.01) and antioxidant levels decreased compared to the control (P < 0.05). In treated rats with N. sativa, the antioxidant status of renal tissue was improved (P < 0.05 to P < 0.001). The lipid profile also improved in the rats treated with the extract (P < 0.001). Our findings suggest that long-term administration of N. sativa in diabetic rats induced by streptozotocin can improve the status of the oxidative stress in kidney tissue.

How to cite this article:
Mohebbati R, Abbasnezhad A, Havakhah S, Mousavi M. The Effect of Nigella Sativa on Renal Oxidative Injury in Diabetic Rats. Saudi J Kidney Dis Transpl 2020;31:775-86

How to cite this URL:
Mohebbati R, Abbasnezhad A, Havakhah S, Mousavi M. The Effect of Nigella Sativa on Renal Oxidative Injury in Diabetic Rats. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Oct 21];31:775-86. Available from: https://www.sjkdt.org/text.asp?2020/31/4/775/292311



   Introduction Top


Diabetes mellitus as a metabolic issue remains a major medical issue. It is portrayed by absolute or relative lack of insulin secretion as well as insulin resistance that result in hyperglycemia and impeded carbohydrate, lipid, and protein metabolism. Diabetes mellitus has been known as an oxidative damage disorder caused by imbalance between free radical generation and the ability of the body’s natural antioxidant systems such as enzymatic and nonenzymatic.[1]

Diabetic nephropathy emerges from the mix of hyperglycemia and hypertension causing glomerular damage. The conceivable pathological changes include thickening of basement membrane, interstitial fibrosis, atrophy, and arteriosclerosis. Initially, this causes glomerular hyperfiltration and subsequently dynamic loss of renal function. Diabetic nephropathy occurs in 30%–40% of patients within 25 years. Boosted glomerular filtration pressures result in albuminuria, a driver for progressing renal damage.[2]

Reactive oxygen species (ROS) including superoxide anion radical, hydroxyl radical, and proxyl radical are commonly present in the biological structures, and their levels are controlled through biological antioxidants and different enzymatic activities such as peroxi- dase, superoxide dismutase (SOD), catalase (CAT), Vitamin C, α-tocopherol, and gluta- thione. Following a decrease in the antioxidant capacity or an improved ROS generation, an imbalance known as impaired redox homeo- stasis will occur.[3] ROS generation and disturbed capacity of the antioxidant defense in diabetic cases have been reported.[4] Mitigated redox homeostasis and glycative stress are believed to play a crucial role in the etiology of diabetes mellitus as well as its subsequent complications.[5] Earlier studies have suggested that hyperglycemia promotes the generation of advanced glycation end products (AGEs).[6] Hyperglycemia can induce oxidative injury by boosting AGEs, as well as protein kinase C activation and boosted flux through polyol/ aldose and hexosamine pathways.[7],[8] Oxidative stress is induced by diabetes through a significant reduction in CAT activity as well as in total thiol levels.[9]

Nigella sativa, also known as the black seed, is a green plant from the Ranunculaceae family.[10] The seeds contain 0.4%–2.5% essential oil, 36–38% settled oils, flavonoids, alkaloids, polyphenols, and saponins. The fixed oil is normally made of fatty acids including oleic, stearic, palmitic, and linoleic acids.[1] Pharmacologically, the main ingredient found in N. sativa, which amounts to almost 30–48%, is thymoquinone (TQ) along with its derivatives including thymol, thymohydroquinone, and dithymoquione.[11]

Some scientific researchers have demonstrated that N. sativa has cardiovascular, anti- diabetic, and protective effects, including anti- hypertensive[12],[13] and antihyperlipidemic,[14] and also attenuates endothelial dysfunction.[10],[15],[16] Former studies indicated that systemic oxi- dative stress promotes hypertension and endo- thelial dysfunction.[12],[17] Furthermore, the antioxidant property of N. sativa has been well documented. TQ is believed to serve as a free radical scavenger and enhances the redox homeostasis.[15],[18],[19],[20],[21] The hydroalcoholic extract of N. sativa decreases the doxorubicin-induced functional renal damage in rats and helps improve the glomerular filtration rate and reduces the glucosuria.[22]

Regardless of all these, sufficient information on how N. sativa affects the renal tissue is not available. Hence, the present study was designed to look into the effects of N. sativa hydroalcoholic extract on improving the redox homeostasis in the kidney tissue in rats, which were made diabetic using streptozotocin (STZ).


   Material and Methods Top


Plant material and preparation of the extract

Following the preparation in the local herbal shop in Mashhad, the N. sativa seed was approved by Eng. Joharchi in the Ferdowsi University of Mashhad herbarium (293-03031). About 100 g of seed was powdered, grounded, and shacked in 2 l of hydroalcoholic solution (50% ethanol and 50% water) for two days at a standard temperature. The extract solution was eventually filtered and underwent evaporation under vacuum at 40°C until the solvent fully vaporized. The doses 200 and 400 mg/kg were obtained from the dried extract.[23]

Chemicals and drugs

Metformin and STZ were purchased from Sigma Company (Germany). The assessment of serum glucose, cholesterol, and triglyceride concentrations was made using the Pars Azmoon kits (Tehran, Iran). The very-low- density protein (vLDL) level was obtained using the following formula: vLDL-c = TG/5.[24]

Animals and induction of diabetes

Male Wistar rats, weighing 240 ± 20 g, were kept in standard laboratory conditions with free access to food and drinking water.

Diabetes was induced by the injection of STZ (60 mg/kg, ip). Three days after STZ was injecting, the blood glucose level was evaluated using a glucometer and the development of diabetes was confirmed. Subjects with blood glucose levels of ≤ 250 mg/dL following 12 h of fasting were considered as diabetic rats.[25]

Experimental design

Forty male Wistar rats were placed into five groups in a simple random manner:

  1. Control (C): Rats receiving saline for six weeks orally.
  2. Diabetic (D): Rats receiving STZ intraperitoneally.
  3. Diabetic metformin (DM): Rats receiving STZ intraperitoneally and then treated with metformin for six weeks orally.
  4. Diabetic extract (DE200): Rats receiving STZ intraperitoneally and then treated with Nigella sativa (200 mg/kg) for six weeks orally.
  5. Diabetic extract (DE400): Rats receiving STZ intraperitoneally and then treated with Nigella sativa (400 mg/kg) for six weeks orally.


Metformin (300 mg/kg) and N. sativa extract (200 and 400 mg/kg) were administrated orally on a daily basis for a period of six weeks.[26]

Preparation and analysis of the samples

Using ether, the animals were anesthetized at days 0, 24, and 45. Following this, the blood samples were collected from the orbital sinus of the rats and finally centrifuged at 3000 g for evaluation of the plasma glucose, triglyceride, and cholesterol concentrations.

At the end of the experimental period (day 45), animals were weighed and sacrificed under deep anesthesia with urethane. Renal tissues were removed and immediately homogenized for the determination of renal redox parameters [malondialdehyde (MDA)], total thiol, SOD, and CAT].[8]

Determination of malondialdehyde

MDA, reacts with thiobarbituric acid and produces thiobarbituric acid reactive substance, generating a reddish complex. Finally, after the biochemical experiment, the absorbance rate was read at 535 nm. The MDA concentration was calculated based on the following equation. An extinction coefficient of 1.56*105/M per cm was used.[27]

Determination of total thiol

Determination of the total thiol groups was performed using DTNB -5,5’-dithiobis-(2- nitrobenzoic acid)- that reacts with the SH group and produces a yellow complex, which has a peak absorbance at 412 nm. In brief, after the biochemical process, the absorbance was read twice. The thiol concentration was determined using a spectrophotometric method based on the Ellman’s indicator. An extinction coefficient of 14,150 M-1 cm-1 was used.[28]

Assay of superoxide dismutase activity

The activity of SOD was assessed using the procedure introduced by Maedesh and Balasubramanian. In short, the concentration of enzyme causing 50% inhibition in the MTT reduction rate was defined as the unit of SOD activity.[29]

Assay of catalase activity

Using the method of Aebi, with hydrogen peroxide as the substrate, the CAT activity was assessed.[30]

Data analysis

The results of this study are expressed as mean ± standard error of the mean. Statistical analyses were performed using the one-way ANOVA, followed by the Tukey’s test and repeated measures ANOVA. P < 0.05 was defined as statistical significance.


   Results Top


Plasma glucose, cholesterol, VLDL, and triglyceride concentrations

The level of serum blood glucose in the diabetic rats was significantly higher than the controls (P < 0.001). In rats receiving N. sativa, the serum glucose level was significantly lower than that of the diabetic rats (P < 0.05-P < 0.01) [Figure 1]. Furthermore, serum blood glucose in rats treated with N. sativa (200 mg/kg) significantly decreased compared to the DM group (P < 0.05).
Figure 1: Effect of Nigella sativa seed extract on average serum glucose levels (mg/dL) in STZ-induced diabetic rats.
Repeated measures ANOVA test performed. Values are means ± standard error of the mean.
***P < 0.001 compared to the control group. #P < 0.05, and ##P < 0.01 compared to the diabetic group. +P <0.05 compared to the DM group.
C: Control, D: diabetes, DM: Diabetic + metformin, DE200: Diabetic + N. sativa extract of 200 mg/kg, DE400: Diabetic + N. sativa extract of 400 mg/kg.


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The serum cholesterol levels were observed to be higher in the diabetic rats in comparison with those in control animals (P < 0.001). The cholesterol levels were also decreased in all treated rats with N. sativa compared to the diabetic group (P < 0.001) [Figure 2].
Figure 2: Effect of Nigella sativa seed extract on average serum levels of cholesterol (mg/dL) in STZinduced diabetic rats.
Repeated measures ANOVA test performed. Values are means ± standard error of the mean. ***P < 0.001 compared to the control group. ###P < 0.001 compared to the diabetic group.
C: Control, D: Diabetes, DM: Diabetic + metformin, DE200: Diabetic + N. sativa extract of 200 mg/kg, DE400: Diabetic + N. sativa extract of 400 mg/kg.


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The serum triglyceride levels were shown to increase significantly in the diabetic groups compared to the controls (P < 0.001). In the treatment groups with N. sativa, the trigly- ceride levels were shown to decrease compared to the diabetic group (P < 0.01-P < 0.001) [Figure 3]. Furthermore, serum triglyceride in treated rats with two doses of N. sativa significantly decreased compared to the DM group (P<0.05 and P < 0.001).
Figure 3: Effect of Nigella sativa seed extract on average serum levels of triglyceride (mg/dL) in STZinduced diabetic rats.
Repeated measures ANOVA test performed. Values are means ± SEM.
***P < 0.001 compared to the control group. ##P < 0.01, and ###P < 0.001 compared to the diabetic group. +P < 0.05, and +++P < 0.001 compared to the DM group.
C: Control, D: Diabetes, DM: Diabetic + metformin, DE200: Diabetic + N. sativa extract of 200 mg/kg, DE400: Diabetic + N. sativa extract of 400 mg/kg.


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Serum VLDL levels were remarkably higher in the untreated diabetic group (P < 0.001). A significant decrease was observed in the VLDL levels in the DE200 group compared to the diabetic group (P < 0.05) [Figure 4].
Figure 4: Effect of Nigella sativa seed extract on average serum levels of vLDL in STZ-induced diabetic rats.
Repeated measures ANOVA test performed. Values are means ± standard error of the mean.
***P < 0.001 compared to the control group. #P < 0.05 compared to the diabetic group.
C: Control, D: Diabetes, DM: Diabetic + metformin, DE200: diabetic + N. sativa extract of 200 mg/kg, DE400: Diabetic + N. sativa extract of 400 mg/kg.


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Antioxidant status of the kidney tissue

The renal MDA content significantly increased and thiol content and SOD activity significantly decreased in diabetic rats compared to the controls (P < 0.05 and P < 0.01). In rats treated with N. sativa, the MDA content as well as SOD activity improved compared to the diabetic rats (P < 0.05 to P < 0.001) [Figure 5], [Figure 6], [Figure 7], [Figure 8].
Figure 5: The malondialdehyde levels of kidney tissue in control (C), diabetic (D), N. sativa seed extract (DE200 and DE400), and metformin (DM)-treated groups.
Values are means ± standard error of the mean (n=8). **P < 0.01 compared to the control group and +P < 0.05, +++P < 0.001 compared to the diabetic group.


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Figure 6: The thiol levels of kidney tissue in control (C), diabetic (D), N. sativa seed extract (DE200 and DE400), and metformin (DM)-treated groups.
Values are means ± standard error of the mean (n = 8). **P < 0.01 compared to the control group.


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Figure 7: The superoxide dismutase activity (U/100 mg tissue) of kidney tissue in control (C), diabetic (D), N. sativa seed extract (DE200 and DE400), and metformin (DM)-treated groups.
Values are means ± standard error of the mean (n = 8). *P < 0.05 compared to the control group and +P < 0.05, ++P < 0.01 compared to the diabetic group.


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Figure 8: The catalase activity (U/100 mg tissue) of kidney tissue in control (C), diabetic (D), N. sativa seed extract (DE200 and DE400), and metformin (DM)-treated groups.
Values are means ± standard error of the mean (n = 8). +P < 0.05 compared to the DM group.


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Furthermore, CAT activity in rats treated with N. sativa (200 mg/kg) significantly increased compared to the DM group (P < 0.05).

The weight difference

The weight difference in the diabetic groups significantly decreased compared to the control group [Figure 9]. Furthermore, weight difference in rats treated with N. sativa (400 mg/kg) significantly decreased compared to that of the DM group.
Figure 9: The weight difference in control (C), diabetic (D), N. sativa seed extract (DE200 and DE400), and metformin (DM)-treated groups.
Values are means ± standard error of the mean (n = 8). ***P < 0.001 compared to the control group. ++P < 0.01 compared to the DM group.


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   Discussion Top


The results of the current study suggest that long-term administration of N. sativa seed extract in STZ-induced diabetic rats has a hypoglycemic effect.[26] Therefore, the reduced plasma glucose concentration in the diabetic rats improves the diabetes-related cardiovascular complications.[31]N. sativa inhibits intestinal glucose reabsorption[32] and promotes glucose-induced insulin secretion from rat- isolated Langerhans islets.[33] It also causes AMP-activated protein kinase (AMPK) pathway activation and upregulation of muscle GLUT4 receptor density.[34] The boosted glucose concentrations increase the ROS formation with a drastic fall in the body antioxidant defense.[35]

Our findings show that administration of N. sativa seed extract for a period of six weeks in the STZ-induced diabetic rats has hypolipidemic effects. Previous studies have also reported that administration of N. sativa seed extract in STZ-induced diabetic rats improved the lipid profile such as TG and cholesterol.[26] Numerous studies have shown that N. sativa seed extract and TQ lead to a significant reduction in the plasma cholesterol and further decrease in the VLDL and TG after four weeks of treatment with the extract.[36],[37]

The results of the present study clearly show that oxidative stress increased in the kidney of diabetic rats. Long-term administration of N. sativa seed extract in the STZ-induced diabetic rats improves the redox balance of the renal tissue. To the best of our knowledge, this study is the first to report the antioxidant activity of N. sativa in the kidney of diabetic rats. Further studies have indicated the protective effects of N. sativa on the cardiovascular system against the destructive effects of the ROS, protecting the heart from toxicity and also reducing the adverse effects resulting from the ROS involved in high blood pressure.[12]

MDA, a marker of lipid peroxidation, and total thiol contents, the primary endogenous antioxidant, were evaluated in the renal tissue of the diabetic rats. The results showed that MDA levels were higher and total thiol levels were lower in the kidney of diabetic rats in comparison with the control group. As can be observed in the results of MDA in the N. sativa-treated groups, the prevention of oxidative injuries by the administration of the N. sativa seed extract is one of the most important findings of the present study. Furthermore, in this regard, some studies have shown increased levels of MDA in the endothelium and kidney of the diabetic rats.[12],[38],[39],[40] These high levels were improved by both TQ and N. sativa oil administration.[5],[41] Total thiol contents were boosted in the renal tissue in the N. sativa-treated groups compared to the diabetic rats. Reduced levels of thiols have been noted in various medical conditions including chronic renal failure and other diseases related to kidneys, cardiovascular disorders, alcoholic cirrhosis, diabetes mellitus, and other problems.[42]N sativa significantly boosted lipid peroxidation by increasing MDA level in diabetic rats.[26]

Furthermore, our results revealed that the SOD activity in the kidney of the diabetic rats was significantly reduced in comparison with the control group. We also observed a significant increase of this parameter in the treatment groups compared to the diabetic rats. The CAT activity of kidney tissue in diabetic rats was lower than in the control group, but these differences were not significant. In the treatment groups, CAT activity was not significantly increased in comparison with that of the diabetic rats. The decreased activities of SOD and CAT in the kidney and during diabetes may be due to the formation of ROS. Treatment with N. sativa seed extract increased the activity of these enzymes, and thus, it may help counteract the injury caused by the free radicals generated during diabetes.[26]

The reports about the activity of SOD and CAT are controversial. Many researchers have shown that the activities of SOD and CAT decrease in the kidney tissue e of diabetic rats,[43],[44],[45] while others reported the opposite.[46],[47] Some researchers have shown either increased or no significant different activity of SOD, whereas CAT decreased in kidney tissue of diabetic rats.[48],[49],[50] In the present study, the activity of SOD and CAT in the kidney tissue of groups treated with N. sativa extract was higher than that of the diabetic rats. It has been reported that administration of N. sativa oil and TQ significantly boosted activities of SOD and CAT in STZ diabetic rats.[19] In the previous studies, TQ reduced pyrogallol- induced endothelial dysfunction in the isolated aorta in rabbit. It has been suggested that this effect was mediated through increasing nitric oxide generation and its bioavailability.[15] In our study, metformin reduced blood glucose levels in the diabetic rats but that was not significant. Similar data were obtained in previous studies.[51] Metformin significantly decreased cholesterol levels in the diabetic rats that are in line with previous studies.[52] Metformin affects through AMPK signaling pathway. After activation of AMPK pathway, glucose production by the liver was inhibited and improved insulin sensitivity and glucose uptake by the striated muscles and induced fatty acid oxidation. AMPK pathway is a main cellular ameliorator of glucose and lipid metabolism.[53],[54] Metformin may be effective in the prevention of the diabetic problems through not only lowering the plasma glucose but also directly inhibition of AGEs generation.[55] Moreover, administration of metformin results in decreased MDA levels in the renal tissue as well as increased total thiol content. Treatment with metformin normalized CAT and SOD, thus confirming its efficacy in attenuating dexamethasone-induced type 2 diabetes mellitus in mice.[56] Metformin has been suggested to have antioxidant effects[57] by decreasing mitochondrial respiratory chain and NAD(P)H oxidase-induced activities in cells stimulated by glucose, finally decreasing intracellular ROS.[58]

Despite ingestion of large quantities of food in diabetic rats, the rapid weight loss and asthenia (lack of energy) occurred,[20] but in the treated groups, the extract could not improve this weight loss. It is possible that the doses of extract or experiment period have not been enough.


   Conclusion Top


The hydroalcoholic extract of N. sativa, especially at a dose of 200 mg/kg, improves the renal oxidative injury induced by STZ in diabetic rats. Furthermore, N. sativa ameliorates the glucose and lipid profile in diabetic rats. These results support the traditional belief about the beneficial effects of N. sativa seed extract on the diabetes and kidney tissue.

Conflict of interest: None declared.



 
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Correspondence Address:
Abbasali Abbasnezhad
Department of Physiology, School of Medicine, Gonabad University of Medical Sciences, Gonabad
Iran
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DOI: 10.4103/1319-2442.292311

PMID: 32801238

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