|Year : 2019 | Volume
| Issue : 3 | Page : 268-275
Falcaria vulgaris extract attenuates ethanol-induced renal damage by reducing oxidative stress and lipid peroxidation in rats
Cyrus Jalili1, Shiva Roshankhah2, Mohammad Reza Salahshoor2
1 Department of Anatomical Sciences, Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Department of Anatomy, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
|Date of Web Publication||9-Jul-2019|
Dr. Mohammad Reza Salahshoor
Department of Anatomy, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Alcohol consumption is capable of producing free radicals and inducing disturbance in body antioxidant. Falcaria vulgaris (F. vulgaris) is a vegetable and it has beneficial antioxidant effects. Materials and Methods: Forty-eight Wistar rats were divided randomly into eight groups (n = 6): control normal (saline) and ethanol (5g EtOH/kg body weight/24h) control groups, F. vulgaris groups (50, 100, and 150mg/kg), and F. vulgaris + ethanol treated groups (50, 100, and 150mg/kg). Treatments were administered intraperitoneally and through gavage daily for 12 weeks. Parameters related to the function and the histology of the kidneys were evaluated and statistically analyzed from kidney and blood serum samples with respect to the groups. Results: Ethanol administration increased significantly Bowman’s space, qualitative histopathology indices, kidney malondialdehyde (MDA) level, blood urea nitrogen (BUN), creatinine, and nitrite oxide levels and decreased significantly total antioxidant capacity (TAC) level and diameter and number of renal corpuscles compared to that in the control normal group (P < 0.001). The F. vulgaris and F. vulgaris + ethanol treatments in a dose-dependent manner reduced significantly Bowman’s space, qualitative histopathology indices, kidney MDA level, BUN, creatinine, and nitrite oxide levels and increased significantly TAC level and diameter and number of renal corpuscles compared to that in the ethanol normal group (P < 0.001). Conclusion: It seems that F. vulgaris administration in a dose-dependent manner improved kidney injury induced by ethanol in rats.
Keywords: Ethanol, Falcaria vulgaris, lipid peroxidation, oxidative stress, renal damage
|How to cite this article:|
Jalili C, Roshankhah S, Salahshoor MR. Falcaria vulgaris extract attenuates ethanol-induced renal damage by reducing oxidative stress and lipid peroxidation in rats. J Pharm Bioall Sci 2019;11:268-75
|How to cite this URL:|
Jalili C, Roshankhah S, Salahshoor MR. Falcaria vulgaris extract attenuates ethanol-induced renal damage by reducing oxidative stress and lipid peroxidation in rats. J Pharm Bioall Sci [serial online] 2019 [cited 2019 Jul 15];11:268-75. Available from: http://www.jpbsonline.org/text.asp?2019/11/3/268/262189
| Introduction|| |
The increasing use of ethanol as a beverage in various societies has gradually revealed its harmful effects, reported by numerous studies conducted on its negative effects. Ethanol is removed from the body in different ways. Part of the ethanol is excreted from the body via exhalation and urine. The pathogenicity of ethanol in kidneys is directly associated with the elevation of free radicals and oxidative stress, which leads to structural and functional disorders in kidneys. Ethanol induces oxidative stress by causing an imbalance between prooxidant and antioxidant systems, which in turn activate the P53 factor pathway, a factor playing a key role in apoptosis and deoxyribonucleic acid (DNA) damage. One of the most important destructive effects of free radicals is the initiation of lipid peroxidation, which causes cell membrane damage. These free radicals can lead to the production of lipid peroxidase by alkylating protein groups and other cellular macromolecules and by attacking unsaturated fatty acids, which brings about cell damage, especially in kidneys. Further, ethanol metabolism by P450 cytochromes can result in the production of hydrogen peroxide, a precursor of hydroxyl radicals. Acetaldehyde, a highly toxic product of ethanol oxidation in kidneys, is able to directly cause renal damage, to induce oxidative stress by increasing reactive oxygen species (ROS), and to play a role in the destructive outcomes of chronic ethanol consumption. Currently, herbal drugs constitute about one-third of the drugs used in human societies. Ghazzyaghi, scientifically named Falcaria vulgaris, is a biennial herb that grows naturally in southwest Iran and belongs to the family Umbelliferae. This plant has a stem and an average height of 30cm. It is used as vegetable and salad in the west of Iran and has been used for the treatment of skin ulcers, kidney stone, liver diseases, and digestive disorders. The phytochemical studies of the plant have shown the presence of tannin and saponin agents in this plant. Moreover, this plant contains vitamin C, phytosterol, protein, starch, and many antibiotics that are used for the treatment of skin ulcers. The results of high-performance liquid chromatography analysis in the study by Rafiey et al. showed that the antioxidant and antimicrobial compounds of F. vulgaris contain the highest concentrations of carvacrol (119mg/kg) and fumaric acid (966mg/kg). The antioxidant activity of F. vulgaris was tested by 2, 2-Diphenyl-1- picrylhydrazyl-radical scavenging assay, and the main components of different parts of the plant indicated antioxidant and radical scavenging activity of this plant. Ethanol has toxic effects and F. vulgaris extract has numerous beneficial properties, especially antioxidant properties. Further, to the best of our knowledge, no study has ever investigated the effects of F. vulgaris on the ethanol-induced impairments in the kidney tissue. Hence, this study was carried out to explore the effects of F. vulgaris on ethanol-induced impairments in the kidney of male rats.
| Materials and Methods|| |
This experimental study was conducted from May 2018 to December 2018 on 48 male Wistar rats (weighing 220–250g) at Kermanshah University of Medical Sciences. All animals were treated in accordance with the guidelines of National Institute of Health for the Care and Use of Laboratory Animals approved by the Research Deputy at Kermanshah University of Medical Sciences (ethics number: IR.KUMS.REC.1397.518). The rats were maintained on a regular diet and water with a 12:12h light/dark cycle at 23°C ± 2°C in animal room of medical school by considering 1-week adaptation before the experiments.
The rats were randomly divided into eight groups (n = 6), including, first group, the normal control group, which received normal saline (intraperitoneally injection) equivalent to the amount of experimental groups. Second group, the control group of ethanol, in this group, the rats were given single dose of ethanol (5g EtOH/kg body weight/24h) per day through gavage. Third to fifth groups, the F. vulgaris administration groups, in these groups, each animal, respectively, received 50, 100, and 150mg/kg of F. vulgaris intraperitoneally for 12 weeks at 10 am. Sixth to eighth groups, F. vulgaris + ethanol administration groups, in this group, each animal received single dose (5g EtOH/kg body weight/24h) of ethanol via gavage to induce kidney parameters damage, then they, respectively, received 50, 100, and 150mg/kg of F. vulgaris intraperitoneally for 12 weeks at 10 am.,,
Dissection and sampling
At the end of the treatment period, all rats were deeply anesthetized by intraperitoneal injection of ketamine HCl (100mg/kg) and xylazine (10mg/kg). The sampling included blood from the hearts (at least 1mL per animal) for evaluating the urea, creatinine, total antioxidant capacity (TAC), and nitrite oxide level. The animals were then killed. The left kidney was removed for histological and morphometric examinations and the right ones for the malondialdehyde (MDA) level estimations with respect to the groups.
F. vulgaris plant was obtained from a local store (time to pick and buy this plant is during spring in the western Iran) and its impurities were removed. After endorsement by a botanist, the plant was cleaned. The leaves and stems were desiccated in the shadow for 5 days and ground using a grinder. Next, 100g of the powder was added to 70% ethanol. The acquired solution was reserved in a warm water bath (36°C) under dark condition. Thereafter, the solution was progressively poured on Buchner funnel filter paper and cleaned by a vacuum pump. It was then transferred to a rotary device to obtain the extra solvent. The isolation process continued until a concentrated extract was obtained. The extract was dissolved in distilled water and administered intraperitoneally per kilogram of animal’s weight. It was sterilized after double filtration through a 0.2-μm filter.
Tissue preparing and staining
The non-parenchymal tissues were removed. Left kidneys were dissected and prepared in paraffin-embedded blocks using automatic tissue processor. The steps of this process consequently included fixation with 10% formal saline, washing thoroughly under running water, dehydrating by raised doses of ethanol, clearing by xylene, and embedding in soft paraffin. At this stage, 5-µm coronal histological thin sections were cut from paraffin-embedded blocks, by a microtome instrument (Leica RM 2125, Leica Microsystems, Nussloch, Germany), and five sections per animal were chosen. The routine protocol for hematoxylin and eosin staining was implemented. At the end of tissue processing, the stained sections were assessed under microscope Olympus BX-51T-32E01 research microscope connected to a DP12 camera with 3.34-million pixel resolution and Olysia Bio software (Olympus Optical, Tokyo, Japan).
Five sections per animal and five random fields for each section (25 fields totally) were captured at 100× magnifications, respectively, by the connected camera to the microscope. The field’s selection was carried out by zigzag form of monitoring of the round or nearly rounded renal corpuscles by a blind observer using a specialized software package (AE-3; Motic, Barcelona, Spain), respectively. Briefly, the diameter of each renal corpuscle was estimated as the mean length of two drawing lines, vertical to each other, which connected the distance between opposed basement membranes of the outer cell layer. The Bowman’s space, the distance between the outer and the inner cell layers, was estimated by drawing at least four lines (in opposed directions) that connected these two layers, and the mean measured amount of these lines was considered as the space volume.
Evaluation of blood urea nitrogen and creatinine
Blood serum was collected by centrifuging the samples separately and was stored at −80°C until the analysis of blood serum urea nitrogen and urine creatinine levels as the two functional universal biomarkers of the kidney. The concentrations of BUN and creatinine were analyzed in triplicates with a commercially available assay kit (BioAssay Systems, Hayward, CA) in accordance with the instructions.
Measurement of renal malondialdehyde
MDA levels in right renal tissues were evaluated as an index of lipid peroxidation. In this regard, homogenizing of the samples was carried out by homogenization buffer and the specimens were centrifuged at 1,500g for 10min, respectively. Then, the homogenized samples were added to a reaction mixture. Following boiling the mixture for 1h at 95°C and centrifuging at 3000g for 10min, the absorbency of the supernatant was measured by spectrophotometry at 550nm light length.
Estimation of renal total antioxidant capacity
To measure the TAC level, an acquisition kit (Cat no.: TAC-96A; ZellBio, Ulm, Germany) was purchased, which was the basis for the oxidation of colorimetric resuscitation. In this assay, the TAC level was equivalent to some antioxidant in the sample that was compared with ascorbic acid as standard. Final absorbance was read at 490nm and unit conversion was performed.
Measurement of nitrite oxide levels
Griess technique uses zinc sulfate powder to eliminate the serum protein of the samples. Accordingly, zinc sulfate powder (6mg) was mixed with serum samples (400 μL), and vortexed for 1min. The samples were centrifuged at 4°C for 10min at 12,000rpm and the obtained supernatant was used to measure the nitrite oxide. Briefly, 50 μL of sample was added to 100 μL of Griess reagent (Sigma Chemical Co., St. Louis, USA) and the reaction mixture was incubated for about 30min at room temperature. According to the manufacturer’s protocol, the sample’s optical density was measured by ELISA reader (Hyperion Inc., Miami, FL, USA) at a wavelength of 450nm.
The Kruskal–Wallis test was used to examine data normality and the homogeneity of variance at a significance level of 0.05. The data were analyzed by the Statistical Package for the Social Sciences (SPSS, IBM, Chicago, USA) software for windows (version 20) using one-way analysis of variance postulation followed by Tukey’s post hoc test, and P < 0.05 was considered as significant. The variables were represented as mean ± standard error of mean.
| Results|| |
Qualitative histopathology changes in treated groups
Qualitative histopathology evaluation of renal tissue in the studied groups showed that in ethanol control group, a significant increase (with score 31) was observed in all histopathological evaluations compared to that in the normal control group (P < 0.001). A significant decrease of these indices was observed in all F. vulgaris and F. vulgaris + ethanol groups compared to that in the ethanol control group (P < 0.001). Furthermore, there was a dose-dependent significant difference between the F. vulgaris + ethanol groups (P < 0.001) [Table 1], [Figure 1].
|Table 1: Renal histological qualitative parameters affected by ethanol administration and Falcaria vulgaris extract treatment and both in male rats|
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|Figure 1: Histological changes in kidneys by hematoxylin and eosin (H–E) staining (100×): (A) Normal control group. (B and C) In these ethanol control group microscopic pictures, increased Bowman’s capsule space and glomerular shrinkage (black arrow), distribution of lymphocytes (green arrow), bleeding in the space between the tubules (blue arrow), and formation of adipose tissue (yellow arrow) can be seen. (D) Normal kidney in Falcaria vulgaris (150mg/kg) and (E) in ethanol + F. vulgaris (150mg/kg) group|
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Number and diameter of renal corpuscles
Evaluation of the number and diameter of renal corpuscles between the groups showed a significant decrease in the ethanol control group compared to that in the normal control group (P < 0.001), but no significant difference was observed in F. vulgaris groups compared to that in the normal control group. In the all F. vulgaris and F. vulgaris + ethanol groups, a significant increase in the number and diameter of renal corpuscles was observed in comparison to that in the ethanol control group (P < 0.001). Comparing the number and diameter of renal corpuscles between the F. vulgaris + ethanol groups, a dose-dependent increase was observed, but these changes were not significant (P > 0.05) [Graph 1].
|Graph 1: Renal corpuscles number (A), diameter (B) and urinary space (C) changes in kidneys. *P < 0.05 compared to the normal control group, **P < 0.05 compared to ethanol control group, ***P < 0.05 compared to the ethanol control group. Eth = ethanol, F. vul = F. vulgaris, Res = resveratrol|
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Urinary (Bowman’s) space diameter
The results of the urinary space diameter showed a significant increase in ethanol control group compared to that in the normal control group (P < 0.001). Further, a significant decrease was observed in F. vulgaris and F. vulgaris + ethanol group than that in the ethanol control group (P < 0.001), whereas no significant effect on the urinary space diameter in all F. vulgaris groups was observed compared to that in the normal control group (P > 0.05) [Graph 1].
Measurement serum levels of blood urea nitrogen and creatinine
Evaluation of serum levels of BUN and creatinine showed a significant increase in the ethanol control group compared to that in the normal control group (P < 0.001). A significant decrease in BUN and creatinine levels was seen in all F. vulgaris and F. vulgaris + ethanol groups compared to that in the ethanol control group (P < 0.001), whereas no significant effect on the levels of BUN and creatinine was observed in all F. vulgaris groups compared to that in the normal control group (P > 0.05) [Graph 2].
|Graph 2: Effect of ethanol, Falcaria vulgaris, and ethanol + F. vulgaris on the mean kidney biochemical factors. (A) Blood urea nitrogen. (B) Creatinine. *P < 0.05 compared to the normal control group, **P < 0.05 compared to the ethanol control group, ***P < 0.05 compared to the ethanol control group. BUN = blood urea nitrogen, Eth = ethanol, F. vul = F. vulgaris, Res = resveratrol|
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Serum levels of MDA showed a significant increase in the ethanol control group compared to that in the normal control group (P < 0.001). Also, a significant decrease in MDA levels was observed in all F. vulgaris and F. vulgaris + ethanol groups compared to that in the ethanol control group (P < 0.001), whereas no significant effect was seen on the levels of MDA in all F. vulgaris groups compared to that in the normal control group (P > 0.05) [Graph 3].
|Graph 3: Comparison of ethanol, saline, and Falcaria vulgaris groups of kidney malondialdehyde (MDA) (A) and nitrite oxide (B) levels. *P < 0.05 compared to the normal control group, **P < 0.05 compared to the ethanol control group, ***P < 0.05 compared to the ethanol control group. Eth = ethanol, F. vul = F. vulgaris, Res = resveratrol|
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Nitrite oxide levels
The mean nitrite oxide level in the blood serum increased significantly in the ethanol control group compared to that in the normal control group (P < 0.001). It did not change significantly in all F. vulgaris groups compared to that in the normal control group (P > 0.05). The mean nitrite oxide level in the blood serum decreased significantly in all F. vulgaris and F. vulgaris + ethanol groups compared to that in the ethanol control group (P < 0.001) [Graph 3].
Total antioxidant capacity levels
The results of measured TAC levels in the study groups showed a significant decrease in the ethanol control group compared to that in the normal control group (P < 0.001). Also, a significant increase in TAC levels was seen in all F. vulgaris and F. vulgaris + ethanol groups compared to that in the ethanol control group (P < 0.001), whereas no significant effect was observed on the levels of TAC in all F. vulgaris groups compared to that in the normal control group (P > 0.05) [Graph 4].
|Graph 4: Total antioxidant capacity (TAC) level change in the kidney. *P < 0.05 compared to the normal control group, **P < 0.05 compared to ethanol control group, ***P < 0.05 compared to the ethanol control group. Eth = ethanol, F. vul = F. vulgaris|
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| Discussion|| |
The findings of this research suggested that ethanol administration had adverse effects on both histopathology and functional parameters of the kidney, oxidant–antioxidant imbalance, and increase in nitrite oxide level. On the other hand, F. vulgaris as a vegetables decrease the diverse effects of ethanol administration on kidney. This study results also showed that F. vulgaris is able to reduce lipid peroxidation (decreased MDA level) and to increase antioxidant capacity (increased TAC level) of kidney tissue, thus it reduces oxidative stress. Consistent with these findings, a large body of studies has shown antioxidant properties of F. vulgaris.,, Thus, it appears that F. vulgaris with its antioxidant properties could reduce MDA and increase TAC levels in the treatment groups. The histopathology changes following ethanol administration on renal tissue have been approved by some authors and our results in this regard are parallel with them, showing enlargement of Bowman’s space, injury in tubules of cortex, and occurrence of dramatic change in whole tissue qualitative indices., This study also indicated the recovery effect of F. vulgaris on renal tissue and on the function of this organ by decreasing the amounts of biochemical markers of renal function. In this study, the serum nitrite oxide level was significantly higher in the ethanol control group than that in the normal control group. In all groups receiving ethanol + F. vulgaris, a significant decrease was observed in serum nitrite oxide compared to that in the ethanol control group. Nitrite oxide is a free radical that is produced in the mammalian cells and it interferes with the regulation of biologic processes. Administration of ethanol can elevate nitrotyrosine and nitrite oxide biomarkers in the body. Nitrotyrosine is known as an inflammatory marker involved in the production of nitrite oxide and is an appropriate marker for the induction of damage by nitrite oxide–derived ROS. Chan et al. showed that administration of ethanol significantly enhanced serum nitrite oxide and lipid peroxidation levels in rats, confirming the results of this study. Animal studies have shown that antioxidants are able to eliminate free radicals. Antioxidants such as F. vulgaris can destroy the nitrite oxide system. The results of this study showed histological damage was followed by a significant decrease in the number and size of glomeruli and a significant increase in glomerular spaces in the ethanol control group than that in the normal control group. In all ethanol + F. vulgaris groups, tissue damage repair showed a significant increase in the number and size of glomeruli and a significant decline in the glomerular spaces compared to that in the ethanol control group. As glomerular filtration is dependent on the number, mean diameter, and structural consistency of these components, reduced number and mean diameter of glomeruli and increased glomerular space can be followed by functional renal disorders. Therefore, it can be concluded that administration of ethanol significantly changes the morphology of renal glomeruli. The membrane of renal cells contains a large amount of unsaturated fatty acids, which can induce lipid peroxidation through the invasion of oxidants. Seemingly, ethanol induces the production of lipid peroxidation in renal cells, thereby causing histological impairment via DNA breakdown. The frequent ethanol-induced histological damages reported in the recent studies can be due to production of oxidative stress. The results of Shirai et al. confirmed the findings of this study in that ethanol-induced kidney damage, and cell necrosis. Ethanol may exert its biologic effect through an electrophilic attack on the cells in tissues and stimulation of ROS production. The protective effects of F. vulgaris on the kidney in this study might have been applied via suppression of expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Kβ) pathway signals. The findings of Cyrus et al. revealed that F. vulgaris administration reduced the production of ROS and nitrite oxide in proximal tubular cells exposed to high glucose, which is in line with the results of this study.F. vulgaris appears to exert its anti-inflammatory activities through different ways such as inhibiting the expression of COX1 and COX2 and downregulation of NF-Kβ and I-kappa-B (I-Kb) activities. The increased BUN and creatinine levels due to ethanol administration in this research is indicative of glomerular damage and can be due to reduced renal excretion of this material. Administration of F. vulgaris in this study increased the antioxidant level and decreased the BUN and creatinine levels. The findings of Latchoumycandane et al. were in agreement with the results of this study in that ethanol administration significantly elevated creatinine, urea, and hepatic enzyme levels in male albino mice. The elevated BUN level shows renal damage and can cause oxidative stress. On the other hand, induced oxidative stress and elevated production of free radicals can induce glomerular necrosis and affect the renal filtration capacity. The effects of F. vulgaris in the recent studies seem to be due to the presence of polyphenol hydroxyl groups in F. vulgaris, which inhibits the free radicals. The findings of Rafiey et al. showed that F. vulgaris caused decreased plasma glucose, creatinine, and oxidative stress levels, confirming the results of this research. This study showed that ethanol-induced renal damage in rats could be reduced by plant antioxidants such as F. vulgaris. Therefore, according to the foregoing, F. vulgaris can improve the renal dysfunction, which has been caused by ethanol-induced toxicity considering its antioxidant properties.
| Conclusion|| |
The results of this study showed that ethanol administration might negative effects on kidney parameters. The study approves that eliminated renal oxidant–antioxidant balance as molecular advocator due to the administration of ethanol, would supervise cellular chain reaction, observable either with light microscopy. F. vulgaris, improves oxidant system in contrast to Ethanol administration. Finally, the antioxidant properties of F. vulgaris may be a main reason for its positive effect on kidney parameters; however, additional studies are required to define its exact mechanism of action.
We gratefully acknowledge the Research Council of Kermanshah University of Medical Sciences (no.: 97518) for the financial support.
Financial support and sponsorship
Research Council of Kermanshah University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Graph 1], [Graph 2], [Graph 3], [Graph 4]