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Harmaline improved oxidative stress and inflammation markers in nephrotoxicity induced by bisphenol-A in human renal tubular epithelial cells
*Corresponding author: Zahra Tafazzoli, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. khoseinynejad@yahoo.com
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Received: ,
Accepted: ,
How to cite this article: Hoseinynejad K, Radan M, Nejaddehbashi F, Dianat M, Tafazzoli Z. Harmaline improved oxidative stress and inflammation markers in nephrotoxicity induced by bisphenol-A in human renal tubular epithelial cells. Indian J Physiol Pharmacol. doi: 10.25259/IJPP_566_2023
Abstract
Objectives:
Bisphenol A (BPA) is a toxic agent which affects the kidney nephrons through inflammation and apoptosis in kidney cells. Harmaline has remarkable anti-inflammatory and anti-oxidative stress properties. Accordingly, the aim of the present study was to investigate the antioxidant effect of harmaline against nephrotoxicity caused by BPA in human kidney 2 (HK-2) cells.
Materials and Methods:
HK-2-cells were considered in the following groups: Control, bisphenol and harmaline with concentrations of 50, 100 and 200 mM. The cytotoxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis method. Reactive oxygen species generation was measured by the flow cytometry technique. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels were measured using a spectrophotometric method. Anti-inflammatory and pro-inflammatory cytokines were measured using the enzyme-linked immunosorbent assay method.
Results:
The present study showed that exposure of HK-2 cells to BPA causes nephrotoxicity by reducing cell viability and increases in free radicals, which were associated with an increase in the MDA level and a decrease in the TAC concentration compared to the control group. In harmaline co-treatment groups, production of free radicals and MDA levels significantly decreased, and TAC levels significantly increased compared to the bisphenol A (BSA) group. Interleukin (IL)-6 level showed a remarkable increase in cells exposed to BPA. Although the IL-10 concentration significantly decreased compared to the control. Harmaline in all concentrations significantly decreased the IL-6 and increased IL-10 compared to the BPA cells.
Conclusion:
The results of this study confirmed the protective effects of harmaline in preventing inflammation, oxidative damage and toxicity caused by BPA in renal epithelial cells.
Keywords
Bisphenol A
Harmaline
Human kidney 2 cell
Inflammation
Nephrotoxicity
Oxidative stress
INTRODUCTION
Bisphenol A (BPA) plays a crucial role in the production of polycarbonate plastics, epoxy and phenolic resins, polyacrylates and polyesters, which are extensively utilised in the creation of various medical and dental products. Research has indicated that exposure to BPA can induce oxidative stress in tissues, resulting in abnormal development of certain organs, particularly the reproductive system, during foetal and neonatal stages.[1-4] BPA is associated with various negative health effects, primarily due to its xenoestrogen-like properties. In addition to its estrogenic effects, research indicates that BPA can disrupt cytokine regulation and induce oxidative stress in vital organs such as the brain, liver and kidneys.[5,6] The primary mechanism underlying its nephrotoxic effects involves the generation of reactive oxygen species (ROS) within kidney cells, which may result in inflammation and the programmed cell death of mesangial cells in the kidneys.[7] Furthermore, exposure to BPA may lead to a reduction in the glomerular filtration rate. Due to the key role of antioxidants as the defence system against free radicals, the use of these compounds today has significant importance in the treatment of disorders caused by oxidative stress and inflammation.[7,8]
Phenolic agents are a vital component which have well-known antioxidant properties as well as several health benefits.[9] Numerous phenolic acid compounds have demonstrated significant antioxidant properties, with research highlighting the importance of both free and esterified forms, as well as glycosylated and non-glycosylated phenolics. Peganum harmala, a member of the Zygophyllaceae family, is utilised as a medicinal remedy in various countries, including Pakistan, China, Morocco, Algeria and Spain, for the treatment of several chronic ailments. The antiparasitic and antispasmodic effects of harmala are well established in the literature.[10-12] In addition, harmala has significant efficacy in treating asthma and kidney disorders, and in reducing fever in chronic malaria.[13] The scavenging ring effects of this substance have been reported in several in vivo and in vitro studies.[13,14] Considering the potential efficacy of BPA in initiating and the progression of oxidative stress conditions, the aim of this study was to assess the antioxidant and anti-inflammatory properties of harmaline against nephrotoxicity caused by BPA in human kidney 2 (HK-2) cells.
MATERIALS AND METHODS
Cell culture
Human proximal tubular epithelial cells (HK-2) were obtained from Pasteur Institute of Iran and cultured at a density of 5 × 106 cells in 100 mm containers containing Roswell Park Memorial Institute 1640 (RPMI-1640) + 10% foetal bovine serum medium and a final volume of 10 mL and incubated in an incubator (37°C and 5% carbon dioxide, the medium was changed every 2 days). When the confluency reached 80– 90%, passage was performed, and then the cells were placed in the following groups:
Control group: HK-2-cells without any treatment (duration: 24 h)
The group of HK-2-cells + BPA (1000 μM) (duration: 24 h)[15]
The group of HK-2-cells + BPA (1000 μM)+ harmaline (50 μM) (duration: 24 h)[16]
The group of HK-2-cells + BPA (1000 μM)+harmaline (100 mM) (duration: 24 h)[16]
The group of HK-2-cells + BPA (1000 μM)+harmaline (200 mM) (duration: 24 h)[16]
The group of HK-2-cells with the most effective dose of harmaline (200 mM) (duration: 24 h).
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis of HK-2 cytotoxicity
In this order, after the incubation time (24 h), the culture medium was removed. Then, 200 microliters of culture medium plus 100 mg/mL of MTT solution (Sigma-Aldrich, USA) were mixed and then added to each well and maintained in a carbon dioxide incubator for 2 h at 37°C. During the incubation time, MTT is revealed using the succinate dehydrogenase, as the main enzyme in the biocycle of mitochondrial respiration. The regeneration and decomposition of this ring causes the production of purple formazon crystals, which are easily recognised under the microscope. The amount of colour produced is directly related to the number of cells that are metabolically active (viable cells). Considering that formazon crystals are insoluble in water, they must be dissolved with a solvent such as dimethyl sulfoxide before colourimetry. Finally, the average absorption of treatment was divided by the absorption rate of the control and multiplied by 100. The resulting numbers show the percentage of viability.
Detection of ROS production in kidney cells
Reactive probe (2',7'-Dichlorofluoresceindiacetate, DCFHDA, [Merck, USA], 10 μM) was used to detect intracellular ROS in the cell medium. The cells were cultured in a 6-well plate with a density of 106 cells/well and stimulated with the medium for 48 h, and then incubated with DCFH-DA at 37°C for 30 min and washed again by phosphate-buffered saline. Finally, the number of free radicals was evaluated by the flow cytometry method.
Measurement of total antioxidant capacity (TAC) and malondialdehyde (MDA) in kidney cells
For this purpose, after 24 h, the cell supernatant was removed and stored at −80°C. Then, the supernatant solution was applied to measure the TAC (CAT NO# KTAC96), malondialdehyde (MDA) (CAT NO# KMDA96), superoxide dismutase (SOD) (CAT NO# KSOD96) and glutathione (GSH) concentration (CAT NO# KTHI96) levels using the assay kits (Kiazist, Iran) and spectrophotometric method.
Measurement of inflammatory markers in kidney cells
In this order, the cell supernatant from the medium of all cell groups were removed and applied to measure the level of a pro-inflammatory cytokine (interleukin [IL]-6) and an anti-inflammatory cytokine (IL-10: KPG-HIL10), using the special assay kits (Karmania Pars gene, Iran) and through the enzyme-linked immunosorbent assay method.
Statistical methods
The Statistical Package for the Social Sciences software (V26.0) was employed for the purpose of data analysis. The analysis of variance test and post hoc test were employed to compare groups. The data were analysed and resulted in mean ± standard error of the mean, with significance established at P < 0.05.
RESULTS
Figure 1 represents the statistical analysis of the cell viability using MTT in different cell groups which showed a significant decrease in the cell group exposed to BPA compared to the control group (P < 0.001). Furthermore, cell treatment using different concentrations of harmaline (50, 100 and 200 μM) led to a significant increase in cell survival rate compared to the BPA group. Statistical analysis demonstrated that the highest increase in survival rate was shown in the treatment group with 200 μM concentration (P < 0.01) [Figure 1].
- Comparison of cell viability in different groups: The group receiving bisphenol A (BPA) 1000 μM (BSA), the group receiving BPA with harmaline 50 (BSA + HR50), harmaline 100 (BSA + HR100), harmaline 200 (BSA + HR200) and harmaline 200 (HR200). ***P > 0.001 versus control group. ##P > 0.01, #P > 0.5 versus BPA group. The comparison of groups has been done by oneway analysis of variance, t-test and honestly significant difference. BSA: Bisphenol A, HR: Harmaline.
Figure 2 shows that a significant increase in ROS detection was recorded in the cell group exposed to BPA compared to the control group (P < 0.001). Although exposing the cells to different concentrations of harmaline (50, 100 and 200 μM) led to a significant decrease in ROS generation compared to the BPA cells. The highest reduction was shown in the treatment group with concentration 200 μM (P < 0.001). Figure 3 represents the concentration level of MDA, which was investigated as an indicator of oxidative stress in all cell groups. The results showed that the amount of MDA in cell groups exposed to BPA was significantly higher than the control group (P < 0.01). In all cell groups that were co-treated with different concentrations of harmaline, the level of MDA was significantly lower than the group exposed to BPA. Statistical analysis shows that the highest reduction was detected in the treatment group with concentration 200 μM (P < 0.001) [Figure 3].
- Comparison of reactive oxygen species production in different groups: The group receiving bisphenol A (BPA) 1000 μM (BSA), the group receiving BPA with harmaline 50 (BSA + HR50), harmaline 100 (BSA + HR100), harmaline 200 (BSA + HR200) and harmaline 200 (HR200). ***P > 0.001 versus control group. ##P > 0.01, ###P > 0.001 versus BPA group. The comparison of groups has been done by one-way analysis of variance, t-test and honestly significant difference. BSA: Bisphenol A, HR: Harmaline.
- Comparison of malondialdehyde level in different groups: The group receiving bisphenol A (BPA) 1000 μM (BSA), the group receiving BPA with harmaline 50 (BSA + HR50), harmaline 100 (BSA + HR100), harmaline 200 (BSA + HR200) and harmaline 200 (HR200). **P > 0.01 versus control group. #P > 0.5, ##P > 0.01, ###P > 0.001 versus BPA group. The comparison of groups has been done by one-way analysis of variance, t-test and honestly significant difference. BSA: Bisphenol A, HR: Harmaline,
Figure 4 represents in the group receiving BPA, the TAC, SOD and GSH levels were significantly lower than the control group (P < 0.01, P < 0.01 and P < 0.001, respectively). Co-treatment with harmaline showed a significant increase in antioxidant enzyme concentrations in all cell groups compared to the BPA alone. Statistical analysis shows that the highest elevation of TAC (P < 0.01), SOD (P < 0.01) and GSH (P < 0.001) were detected in the treatment group with concentration 200 μM (P < 0.001).
- Comparison of total antioxidant capacity (a), superoxide dismutase (b) and GHS (c) levels in different groups: The group receiving bisphenol A (BPA) 1000 μM (BSA), the group receiving BPA with harmaline 50 (BSA + HR50), harmaline 100 (BSA + HR100), harmaline 200 (BSA + HR200) and harmaline 200 (HR200). **P > 0.01 versus control group. #P > 0.5, ##P > 0.01, ###P > 0.001 versus BPA group. The comparison of groups has been done by one-way analysis of variance, t-test and honestly significant difference. GHS: Glutathione, BSA: Bisphenol A, HR: Harmaline, ***P>0.001
Figure 5 shows that in the BPA group, the concentration level of IL-6 was significantly increased and the IL-10 concentration significantly decreased compared to the control group. Co-treatment with harmaline showed a significant decrease in IL-6 and an increase in IL-10 in all treatment-cell groups compared to the BPA alone. Statistical analysis shows that the highest efficacy of anti-inflammation properties was detected in the treatment group with a concentration of 200 μM.
- Comparison of interleukin (IL)-6 (a) and IL-10 (b) levels in different groups: The group receiving bisphenol A (BPA) 1000 μM (BSA), the group receiving BPA with harmaline 50 (BSA + HR50), harmaline 100 (BSA + HR100), harmaline 200 (BSA + HR200) and harmaline 200 (HR200). *P > 0.05 versus control group. #P > 0.5, ##P > 0.01, ###P > 0.001 versus BPA group. The comparison of groups has been done by one-way analysis of variance, t-test and honestly significant difference. BSA: Bisphenol A, HR: Harmaline
DISCUSSION
The current in vitro study documented the protective efficacy of harmaline in the culture medium of kidney cells against BPA-induced toxicity. The results of this study show that the antioxidant properties of harmaline significantly reduce the toxicity caused by BPA.
Renal disorders as a health issue have a remarkably high economic cost in the world.[17] Acute kidney injury (AKI) progresses rapidly and is characterized by a loss of kidney function, leading to the accumulation of toxic nitrogenous waste products and creatinine in the plasma.[18] AKI patients are at increased risk of de novo chronic kidney disease (CKD) or exacerbation of underlying CKD, leading to end-stage renal disease, which is in urgent need of kidney transplantation.[19] Renal tubule cells are rich in mitochondria, which causes to makes kidney cells particularly vulnerable to oxidative stress and injuries.[20] Free radicals and pro-oxidants produced during the development of AKI and CKD can exacerbate the damage and contribute to the onset of severe complications in other organs, such as the cardiovascular system.
Research indicates that estrogenic substances like BPA can produce unforeseen consequences on adipocyte differentiation and postnatal growth when ingested during crucial developmental phases.[21-23] BPA is likely absorbed through the gastrointestinal tract after consuming products stored in plastic containers, where it is then conjugated with glucuronic acid in both the intestine and liver, ultimately being excreted as BPA glucuronide in urine.[24] Consequently, BPA-related nephrotoxicity manifests as reduced glomerular filtration and creatinine clearance, along with diminished renal function. The accumulation of harmful BPA metabolites, coupled with the kidneys’ inability to excrete them, results in nephrotoxicity.[25] This condition leads to a rapid and sustained decline in renal function, causing the retention of nitrogenous waste products, such as urea and creatinine, as well as non-nitrogenous substances in the bloodstream. This phenomenon is referred to as AKI; thus, elevated levels of serum and urine creatinine and urea, resulting from decreased renal perfusion, can serve as indicators of AKI.[26] Literature documented that BPA induces inflammatory podocytopathy accompanied by proteinuria through the inhibition of nephrin and podocin production, which are gap junction proteins essential for maintaining podocyte health and regulating proteinuria.[27] Proteinuria arises from two primary mechanisms: the abnormal passage of proteins beyond the glomerulus due to heightened permeability of the glomerular capillary wall, and the compromised reabsorption of proteins by the proximal tubular epithelial cells. Consequently, it is plausible that BPA may also lead to renal tubular injury, further exacerbating the onset of proteinuria.[28] The importance of harmaline in mitigating oxidative stress and inflammation suggests that this compound, derived from the plant, may alleviate the oxidative stress induced by BPA in renal tissue. Recently, several comprehensive studies regarding the physiological condition and pathophysiological changes in response to ROS and antioxidants in health and disease have been documented. Reactive oxygen and nitrogen species reactive species are involved in various cellular pathways controlling cell growth process and differentiation, mitogenic responses, extracellular matrix degradation, apoptosis, oxygen detection and inflammatory processes.[29] Antioxidant adaptation is responsible for signal formation and the transfer of suitable antioxidants to the site of excessive production of free radicals and prooxidants.
Direct measurement of free radicals in an in vivo system is difficult for many reasons, such as short lifetime and technical issues. However, an in vitro study provides more practical and simpler ways to evaluate the amount of free radical production. In this regard, the present study used the flow cytometry technique to measure the production of free radicals. The results of this part of the study showed that the exposure of kidney cells for 24 h to BPA caused the production and significant increase of ROS. Therefore, the obtained data documented the role of oxidative stress in the toxicity caused by BPA. In this regard, the study of Kobroob et al., in 2018, showed that BPA is able to directly affect kidney mitochondria and cause mitochondrial oxidative stress, dysfunction and subsequently lead to functional and tissue damage in the kidney.[30] Furthermore, a study by Eid et al. in 2015[31] showed that exposure to BPA in neonatal mice significantly increased oxidative/nitrosative stress, decreased activity of antioxidant enzymes, DNA damage and severe chronic inflammation in liver tissue. These data show that BPA causes long-term adverse oxidative effects on the liver, leading to deleterious effects in the liver of female mice.[31]
TAC is a trustworthy general marker of the antioxidant system to measure oxidative stress. Moreover, lipid peroxidation produces a wide range of products, such as MDA, that can be used as biomarkers of oxidative stress conditions.
In the present study, 24 h after exposure of kidney cells to BPA, the TAC and MDA levels were evaluated by the spectrophotometry method. The results showed that the antioxidant capacity in kidney cells significantly decreased in response to oxidative stress. Conversely, the MDA level showed a remarkable increase in the bisphenol A (BSA) group. Co-treatment with harmaline significantly improved the TAC and MDA in all concentrations.
A study by Yagoubi et al. in 2021,[32] on the antioxidant properties of harmaline in streptozotocin-induced diabetes in rats, showed that treatment with harmaline increased the level of insulin and HDL by elevating the level of superoxide dismutase and catalase. In this study, the amount of MDA significantly decreased in the harmaline-treated group.[32] Another study by Moghadam et al., in 2021, on the assessment of harmaline efficacy on critical liver enzymes in the non-alcoholic fatty liver model of male rats showed that the harmaline-treated group increases the activity of antioxidant enzymes such as catalase, GSH peroxidase and superoxide dismutase in the liver tissue which was in line with a remarkable diminish in the serum levels of alanine aminotransferase, aspartate transferase, alkaline phosphatase, cholesterol and low-density lipoprotein in the harmaline treated groups.[33]
In line with mentioned studies, in the present experiment, different concentrations of harmaline including 50, 100 and 200 μM showed the significant antioxidant properties, especially at a concentration of 200, with reduce the production of free radicals, lipid peroxidation level and increase the antioxidant capacity leads to increase survival rate of kidney cells in BSA group. These data indicate the protective role of harmaline in oxidative damage caused by exposure to BPA in kidney cells. The current research revealed that renal damage induced by BSA was associated with oxidative stress and inflammation, consistent with earlier findings.[34,35] In this study, harmaline was shown to mitigate the severe condition caused by BSA administration. Our results indicated that harmaline’s protective effects against BSA treatment were partially due to its ability to restore histopathological alterations, exert antioxidant properties and inhibit inflammatory markers. Other studies have also validated the anti-inflammatory properties of harmaline.[13,36] Considering harmaline’s significant role in alleviating oxidative stress and inflammation, it can be posited that this plant-derived compound may help diminish the oxidative stress generated by BSA in renal tissues.
CONCLUSION
The results of the present study documented that the use of harmaline prevents inflammation and oxidative damage induced by BPA in kidney cells, probably due to its anti-inflammatory and antioxidant properties. However, more cellular and molecular studies are needed to elucidate the exact mechanisms underlying the protective role of harmaline.
Acknowledgement:
This article is part of Zahra Tafazzoli thesis (MD Degree). The authors of current manuscript appreciate the financial support of the Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran [Grant No. CMRC-0104, Ethical code: IR.AJUMS.MEDICINE.REC.1401.007].
Ethical approval:
The research/study was approved by the Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran [Grant No. CMRC-0104, Ethical code: IR.AJUMS.MEDICINE. REC.1401.007].
Declaration of patient consent:
Patient’s consent was not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that they have used artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript or image creations. English language revision and grammar correction were supported by an AI-based language model (ChatGPT) to improve clarity and readability.
Financial support and sponsorship: Persian Gulf Physiology Research Centre, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences (Grant No: CMRC- 0104. APRC-code IR.AJUMS.MEDICINE.REC.1401.007).
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