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ORIGINAL ARTICLE |
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Year : 2020 | Volume
: 7
| Issue : 2 | Page : 34-40 |
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Isoniazid/rifampicin-induced nephrotoxicity in rats: Protective Potential of selenium
Elias Adikwu, Nelson Clemente Ebinyo, Possible Jumbo
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria
Date of Submission | 29-Oct-2020 |
Date of Decision | 04-Jan-2021 |
Date of Acceptance | 13-Jan-2021 |
Date of Web Publication | 25-Aug-2021 |
Correspondence Address: Dr. Elias Adikwu Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State Nigeria
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jina.jina_11_19
Background and Objectives: Nephrotoxicity has characterized the use of isoniazid–rifampicin (INH-RIF). Selenium (Se) has potential to protect tissues from damage. This study evaluated the protective activity of Se against INH-RIF-induced nephrotoxicity in rats. Methods: Forty-five adult male albino rats (200-230 g) randomized into nine groups of n = 5 were used. Group A (placebo control) and Group B (solvent control) were treated with normal saline (0.2 mL/day/per oral [p.o]) and corn oil (0.2 mL/day/p.o) for 21 days, respectively. Groups C–E were treated with Se (0.1, 0.2, and 0.4 mg/kg/day/p.o, respectively) for 21 days. Group F was treated with INH-RIF (50/100 mg/kg/day/p.o) for 21 days. Groups G–I were supplemented with Se (0.1, 0.2, and 0.4 mg/kg/day/p.o, respectively) before treatment with INH/RIF (50/100 mg/kg/day/p.o) for 21 days. After treatment, the rats were anesthetized. Blood samples were collected and evaluated for serum renal function markers (creatinine, urea, uric acid, total protein, and albumin). Kidneys were assessed for histology, malondialdehyde (MDA), and antioxidants (superoxide dismutase, glutathione, catalase, and glutathione peroxidase). Results: Body weight was decreased whereas kidney weight was increased significantly (P < 0.01) in INH-RIF-treated rats when compared to control. INH-RIF caused significant (P < 0.001) increases in serum renal function markers and kidney MDA level when compared to control. INH-RIF caused significant (P < 0.001) decreases in kidney antioxidants when compared to control. Kidneys of INH-RIF-treated rats showed tubular necroses and widened Bowman's space. INH-RIF-induced nephrotoxicity was significantly reduced in a dose-dependent fashion in rats supplemented with Se (0.1, 0.2, and 0.4 mg/kg) at P < 0.05, P < 0.01, and P < 0.001, respectively, when compared to INH-RIF. Se may clinically protect against INH-RIF-induced nephrotoxicity. Conclusion: This study showed that Se may clinically prevent INH-RIF-related nephrotoxicity.
Keywords: Isoniazid, kidney, rat, rifampicin, selenium, toxicity
How to cite this article: Adikwu E, Ebinyo NC, Jumbo P. Isoniazid/rifampicin-induced nephrotoxicity in rats: Protective Potential of selenium. J Integr Nephrol Androl 2020;7:34-40 |
How to cite this URL: Adikwu E, Ebinyo NC, Jumbo P. Isoniazid/rifampicin-induced nephrotoxicity in rats: Protective Potential of selenium. J Integr Nephrol Androl [serial online] 2020 [cited 2023 Dec 1];7:34-40. Available from: http://www.journal-ina.com/text.asp?2020/7/2/34/324506 |
Introduction | |  |
Tuberculosis (TB) is an infection that is highly prevalent in tropical regions of the world. It is one of the leading infections with the highest mortality and morbidity, worldwide. Anti-TB medications have reduced TB-associated mortality and morbidity, but their adverse effects can decrease adherence with consequent effects on therapeutic outcomes in some situations.[1] Isoniazid–rifampicin (INH-RIF) is an essential combination, which has reduced TB infection and related death, especially in the tropics. However, it has been associated with nephrotoxicity.[1] Its nephrotoxicity is said to be due to the formations of immune complexes by anti-rifampicin antibodies that are deposited in blood vessels or interstitium causing glomerular endotheliosis.[2] Notable features of its nephrotoxicity include elevations in serum urea and creatinine and kidney structural changes, which may be characterized by atrophy of glomerular tuft, inflammatory cells infiltration, and dysplastic renal tubules.[3] Also, oxidative stress characterized by lipid peroxidation (LPO), inflammation and cell apoptosis were observed in animal models of INH-RIF-induced nephrotoxicity.[3],[4]
Selenium (Se) is an important micronutrient that has multiple and complex biological activities on human health. Se as a vital component of selenoproteins is imperative for human well-being. Selenoproteins have redox status and thus regulate the cells of the immune system.[5] Low Se level has been associated with increased risk of cognitive decline, mortality, and poor immune function. It is essential for successful female and male reproductive function and decreases the risk of developing autoimmune thyroid disease. Higher Se levels could decrease the risk of lung, prostate, bladder, and colorectal cancers.[6] Selenoproteins are essential components of antioxidants such as glutathione peroxidase (GPx), which play essential functions in a variety of biological processes including the modulation of redox-sensitive enzyme cascades and reduction of excess reactive oxygen species (ROS) activity.[7] The regulatory effect of Se on ROS could prevent structural and functional impairments of biomolecules, such as proteins, lipids, and DNA.[8] Se supplementation has prevented tissue damage in animal models of drug-induced nephrotoxicity,[9],[10],[11] but with no study on its protective effect against INH-RIF-induced nephrotoxicity in animal models.
Materials and Methods | |  |
Drugs/chemicals and animals
Se (sodium selenite) used was manufactured by Bactolac Pharmaceutical Inc 7 Oser Avenue Hauppauge, NY 11788, USA. INH-RIF was manufactured by Oxalis Labs, Village-Kheda, Dist. Solan, Baddi - 174 101, Himachal Pradesh, India. Forty-five healthy adult male albino rats (220–230 g) obtained from the Animal Breeding Unit of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria, were used. The rats were housed in polypropylene cages and maintained under standard conditions (12-h light and dark cycles and 27°C ± 5°C). Standard pelletized feed and tap water were provided ad libitum. The rats were allowed to acclimatize for 14 days before the experiment commenced. Ethical approval for this study (NDU/PHARM/PCO/AEC/064A) was provided by the Research Ethics Committee of the Department of Pharmacology/Toxicology, Faculty of Pharmacy, Niger Delta University on 4 August 2020.
- Group A (placebo control) (n = 5): Rats were treated with saline (0.2 mL/day/per oral [p.o]) for 21 days
- Group B (solvent control) (n = 5): Rats were treated with corn oil (0.2 mL/day/p.o) for 21 days
- Groups C–E (n = 5): Rats were treated with Se (0.1, 0.2 and 0.4 mg/kg/day/p.o, respectively)[12] in corn oil for 21 days
- Group F (n = 5): Rats were treated with INH-RIF (50/100 mg/kg/day/p.o)[13] in normal saline for 21 days
- Groups G–I (n = 5): Rats were supplemented with Se (0.1, 0.2, and 0.4 mg/kg/day/p.o, respectively) before treatment with INH-RIF (50/100 mg/kg/day/p.o) for 21 days.
Animal sacrifice
After overnight fast, the rats were anesthetized using diethyl ether. Blood samples for biochemical analyses were collected from the heart. Kidneys were surgically excised and separated into two parts for histological examination and biochemical evaluation.
Evaluation of biochemical parameters
Blood samples were centrifuged at 2500 rpm for 15 min, and clear serum samples were separated and evaluated for creatinine, urea, uric acid, total protein, and albumin using commercial laboratory test kits (Randox Laboratories, UK). Serum chloride concentration was determined according to Schales and Schales, 1941,[14] whereas serum bicarbonate concentration was determined as described by Van Slyke and Neil, 1924.[15] The method described by Magoshes and Vallee, 1956[16] was used to evaluate potassium and sodium concentrations. Kidney samples were minced and homogenized in 0.1 M Tris-HCl buffer (pH 7.4). The homogenates were centrifuged at 2000 g for 15 min, and the supernatants were decanted for catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA), and GPx assay. CAT was estimated according to Aebi (1984).[17] SOD was assayed as described by Sun and Zigman, 1978.[18] GSH was estimated as explained by Sedlak and Lindsay.[19] MDA was measured as described by Buege and Aust.[20] GPx was measured as explained by Rotruck et al., 1973.[21]
Histological examination of the kidney
Kidneys were excised from the control and treated groups and fixed in 10% neutral-buffered formalin. Kidney samples were rinsed in serial concentrations of alcohol. Kidney samples were embedded in paraffin blocks and sectioned (5 μm thick) with the aid of a microtome. The sectioned kidney tissues were stained with hematoxylin and eosin and examined for histological changes using a light microscope.
Statistical analysis
Data expressed as mean ± standard error of mean. Comparison among groups was performed using one-way analysis of variance (ANOVA) followed by Tukey's post hoc test with the aid of GraphPad Prism version 5.01, San Diego, CA, USA. P < 0.05, P < 0.01, and P < 0.001 were considered to be statistically significant.
Results | |  |
Effects of selenium on body and kidney weights and renal function markers of isoniazid–rifampicin-administered rats
Body and kidney weights were normal (P > 0.05) in Se-administered rats when compared to control (Placebo). However, body weight was decreased whereas kidney weight was increased significantly (P < 0.01) in INH-RIF-treated rats when compared to control. Body and Kidney weights were restored in rats supplemented with Se (0. 2 mg/kg and 0.4 mg/kg) with significance observed at P < 0.05 and P < 0.01, respectively, when compared to INH-RIF [Table 1]. Serum creatinine, urea, uric acid, total protein, and albumin levels were normal (P > 0.05) in Se-treated rats when compared to control. In contrast, INH-RIF-treated rats showed significant (P < 0.001) increases in serum creatinine, urea, and uric acid levels with significant (P < 0.001) decreases in total protein and albumin levels when compared to control [Figure 1], [Figure 2], [Figure 3], [Figure 4],[Figure 5]. However, serum creatinine, urea, and uric acid levels were significantly decreased, whereas total protein and albumin levels were significantly increased in a dose-dependent fashion in rats supplemented with Se (0.1, 0.2, and 0.4 mg/kg) at P < 0.05, P < 0.01, and P < 0.001, respectively, when compared to INH-RIF [Figure 1], [Figure 2], [Figure 3], [Figure 4],[Figure 5]. Serum sodium, potassium, chloride, and bicarbonate levels were normal (P > 0.05) in Se-treated rats when compared to control. However, serum levels of the aforementioned electrolytes were decreased significantly (P < 0.001) in INH-RIF-treated rats when compared to control. Interestingly, serum sodium, potassium, chloride, and bicarbonate levels were significantly increased in a dose-dependent fashion in rats supplemented with 0.1 mg/kg (P < 0.05), 0.2 mg/kg (P < 0.01), and 0.4 mg/kg (P < 0.001) of Se when compared to INH-RIF [Table 2]. | Table 1: Effects of selenium on body and kidney weights of isoniazid–rifampicin-administered rats
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 | Table 2: Effect of selenium on serum electrolytes of isoniazid-administered rats
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 | Figure 1: Effect of selenium on serum urea of isoniazid–rifampicin-administered rats. Data expressed as mean ± SEM, n = 5. Se: Selenium, INH-RIF: Isoniazid–rifampicin. πP < 0.001 when compared to control, #P < 0.05 when compared to INH-RIF, *P < 0.01 when compared to INH-RIF, **P < 0.001 when compared to INH-RIF, SEM: Standard error of mean
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 | Figure 2: Effect of selenium on serum creatinine of isoniazid–rifampicin-administered rats. Data expressed as mean ± SEM, n = 5. Se: Selenium, INH-RIF: Isoniazid–rifampicin. πP < 0.001 when compared to control, #P < 0.05 when compared to INH-RIF, *P < 0.01 when compared to INH-RIF, **P < 0.001 when compared to INH-RIF, SEM: Standard error of mean
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 | Figure 3: Effect of selenium on serum uric acid of isoniazid–rifampicin-administered rats. Data expressed as mean ± SEM, n = 5. Se: Selenium, INH-RIF: Isoniazid–rifampicin. πP < 0.001 when compared to control, #P < 0.05 when compared to INH-RIF, *P < 0.01 when compared to INH-RIF, **P < 0.001 when compared to INH-RIF. SEM: Standard error of mean
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 | Figure 4: Effect of selenium on serum total protein of isoniazid–rifampicin-administered rats. Data expressed as mean ± SEM, n = 5. Se: Selenium, INH-RIF: Isoniazid–rifampicin. πP < 0.001 when compared to control, #P < 0.05 when compared to INH-RIF, *P < 0.01 when compared to INH-RIF, **P < 0.001 when compared to INH-RIF. SEM: Standard error of mean
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 | Figure 5: Effect of selenium on serum albumin of isoniazid–rifampicin-administered rats. Data expressed as mean ± SEM, n = 5. Se: Selenium, INH-RIF: Isoniazid–rifampicin. πP < 0.001 when compared to control, #P < 0.05 when compared to INH-RIF, *P < 0.01 when compared to INH-RIF, **P < 0.001 when compared to INH-RIF. SEM: Standard error of mean
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Effects of selenium on kidney oxidative stress markers and histology of isoniazid–rifampicin-administered rats
Kidney GSH, CAT, GPx, SOD, and MDA levels were normal (P > 0.05) in Se-treated rats when compared to control (Placebo). In contrast, INH-RIF-treated rats showed significant decreases in kidney GSH, CAT, GPx, and SOD levels with significant (P < 0.001) increases in MDA levels when compared to control [Table 3]. On the other hand, significant increases in kidney GSH, CAT, GPx, and SOD levels with significant decreases in kidney MDA levels in a dose-dependent fashion occurred in rats supplemented with Se (0.1, 0.2, and 0.4 mg/kg) at P < 0.05, P < 0.01, and P < 0.001, respectively, when compared to INH-RIF [Table 3]. The kidney of control rat showed normal histology [Figure 6]a, whereas the kidney of INH-RIF-treated rat showed severe tubular necrosis and widened Bowman's space [Figure 6]b. The kidneys of rats supplemented with Se (0.1 and 0.2 mg/kg) showed mild tubular necroses and widened Bowman's space [Figure 6]c and [Figure 6]d. The kidney of rat supplemented with Se (0.4 mg/kg) showed mild tubular necrosis and normal glomerulus [Figure 6]e. | Table 3: Effect of selenium on kidney oxidative stress markers of isoniazid–rifampicin-administered rats
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 | Figure 6: The kidney of control rat showed normal glomerulus (F) and tubules (G) (a). Kidney of INH-RIF-administered rat showed severe tubular necrosis (H) and widened Bowman's space (I) (b). The kidney of rat supplemented with Se (0.1 mg/kg) showed mild tubular necrosis (K) and widened Bowman's space (J) (c). The kidney of rat supplemented with Se (0.2 mg/kg) showed mild tubular necrosis (l) and widened Bowman's space (M) (d). The kidney of rat supplemented with Se (0.4 mg/kg) and INH-RIF showed mild tubular necrosis (N) and normal glomerulus (P) (e) (×400). Se: Selenium, INH-RIF: Isoniazid–rifampicinxs
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Discussion | |  |
Drugs are common cause of nephrotoxicity, which may be reversible when detected early. Its clinical signs may not be apparent in its early phase until it reaches an advanced stage when acute deterioration of renal function or chronic renal insufficiency manifests.[22] The nephrotoxic effect of INH-RIF has negatively impacted its use as an anti-TB drug.[23],[24] Se is an essential trace element with potential to prevent tissues from damage.[25] This stimulated the evaluation of the protective effect of Se against INH-RIF-induced nephrotoxicity in rats. Se had no effect on body and kidney weights, but increase in body weight and decrease in kidney weight occurred in INH-RIF-treated rats. However, Se supplementation restored body and kidney weights in INH-RIF-treated rats. Renal diseases are often characterized by profound alterations in serum creatinine, urea, and uric acid due to the impaired ability of the kidney to regulate the aforementioned parameters. Serum urea concentration is often considered a more reliable renal function indicator than serum creatinine. Also, alterations in serum total protein and albumin concentrations are key indices for renal disease assessments.[26] In this study, treatment with Se had no effect on serum creatinine urea, uric acid, total protein, and albumin levels. However, treatment with INH-RIF produced remarkable increases in serum creatinine urea and uric acid concentrations with decreases in total protein and albumin concentrations. The observation in INH-RIF-treated rats is a sign of kidney perturbation, which is consistent with earlier report.[27] However, Se supplementation prevented INH-RIF-induced renal perturbation. This was characterized by decreased serum creatinine, urea, and uric acid levels and increased total protein and albumin levels in a dose-dependent fashion. Studies in animal models of kidney injuries reported the possibility of ROS generation at the site of injury prompting oxidative stress and antioxidant depletion.[28] Normal levels of kidney antioxidants (CAT, SOD, GPx, and GSH) were observed in Se-treated rats. The administration of INH-RIF caused remarkable depletions in kidney antioxidants. The observation in INH-RIF-treated rats is a vivid mark of oxidative stress, which is in resonance with previous reports.[29] However, Se supplementation increased kidney antioxidants in dose-dependent fashion in INH-RIF-treated rats. ROS-induced LPO plays an important role in the pathogenesis of kidney dysfunction. LPO can be established by measuring conjugated dienes, MDA, 4-hydroxynonenal, and other by-products. This study validates the occurrence of LPO by measuring MDA concentration.[30] MDA levels were normal in Se-treated rats. On the other hand, MDA level was remarkably increased in INH-RIF-treated rats. The observation in INH-RIF-treated rats showed LPO earlier reported by some scholars.[31] Interestingly, Se supplementation decreased kidney LPO, which was marked by decreased MDA levels in a dose-dependent fashion. Interstitial nephritis and tubular necrosis are some histological features of nephrotoxicity caused by INH-RIF.[32] The present study observed tubular necrosis and widen Bowman's space in INH-RIF-treated rats, which were attenuated in Se-supplemented rats.
The mechanisms by which INH-RIF causes nephrotoxicity have been speculated to involve immune complex formation,[2] inflammation, and oxidative stress.[3],[4] The current study showed that oxidative stress is a key index by which INH-RIF causes nephrotoxicity due to observed decrease in kidney antioxidants and increased in MDA. This observation may be a consequence of the induction of excess ROS in the renal tissues by INH-RIF. Renal tissues have abundant lipids of polyunsaturated fatty acids' origin, which are substrates for ROS attack.[33] The induction of ROS by INH-RIF might have caused LPO, and biomolecular damage in the kidneys of rats.[34],[35] Se supplementation might have prevented INH-RIF-induced nephrotoxicity through its antioxidant activity. Se-dependent enzymes such as GPx can reduce hydrogen peroxide, lipid, and phospholipid hydroperoxides, thereby dampening the propagation of ROS. It can also reduce hydroperoxide intermediates in cyclooxygenase and lipoxygenase pathways, thus reducing inflammation. Se can modulate respiratory burst, by removing hydrogen peroxide and superoxide anion.[36] Se can also increase the gene expressions of CAT, GPx, and SOD, thereby facilitating their syntheses and activities.[37] This helps to maintain membrane integrity and reduces the likelihood of further propagation of oxidative damage to biomolecules, such as lipids, lipoproteins, and DNA.[38],[39]
Conclusion | |  |
This study showed that Se may clinically prevent INH-RIF-related nephrotoxicity.
Acknowledgments
The authors are grateful to Mr. Obi Cosmso of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria, for animal handling.
Financial support and sponsorship
Nil.
Conflicts of interest
The authors declare no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]
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