|Year : 2022 | Volume
| Issue : 2 | Page : 157-162
Selenium protects against tenofovir/lamivudine/efavirenz-induced nephrotoxicity in rats
Elias Adikwu1, Chidi Emmanuel Ezerioha2, Innocent Biradee3
1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria
2 Department of Pharmacology, Faculty of Basic Medical Sciences, University of Port Harcourt, Port Harcourt, Rivers State, Nigeria
3 Department of Biomedical Technology, School of Science Laboratory Technology, University of Port Harcourt, Port Harcourt, Rivers State, Nigeria
|Date of Submission||02-Dec-2020|
|Date of Decision||03-Apr-2021|
|Date of Acceptance||13-Jan-2022|
|Date of Web Publication||28-Apr-2022|
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State
Source of Support: None, Conflict of Interest: None
Context: Tenofovir/lamivudine/efavirenz (TLE) used for the treatment of human immunodeficiency virus may cause acute or chronic nephrotoxicity. Aim: This study assessed the ability of selenium (Se) to prevent TLE-induced nephrotoxicity in albino rats. Materials and Methods: Forty healthy male albino rats (200–250) randomized into four groups (n = 10) were used. Group 1 (Control) was orally treated with normal saline (0.2 mL) daily for 90 days. Group 2 was orally treated with Se (0.1 mg/kg) daily for 90 days. Group 3 was orally treated with TLE (8.6/8.6/17.1 mg/kg) daily for 90 days. Group 4 was orally co-treated with Se (0.1 mg/kg) and TLE (8.6/8.6/17.1 mg/kg) daily for 90 days. After treatment, the rats were anesthetized and blood samples were collected and evaluated for serum renal function markers. Kidneys were examined for histology and oxidative stress indices. Results: Kidney oxidative damage in TLE-treated rats were marked by significant (P < 0.001) decreases in glutathione (GSH), GSH peroxidase, superoxide dismutase, and catalase levels with significant (P < 0.001) increases in kidney malondialdehyde levels when compared to control. Altered serum renal biochemical markers in TLE-treated rats were characterized by significant (P < 0.001) increases in creatinine, uric acid, and urea levels with significant (P < 0.001) decreases in total protein, albumin, bicarbonate, sodium, chloride, and potassium levels when compared to control. Tubular necrosis, lipid accumulation, and mesangial proliferation were observed in the kidneys of TLE-treated rats. TLE-induced nephrotoxicity was significantly (P < 0.01) reversed in Se supplemented rats when compared to TLE. Conclusion: Se may be clinically used for TLE-associated nephrotoxicity.
Keywords: Antiretroviral, kidney, rat, selenium, toxicity
|How to cite this article:|
Adikwu E, Ezerioha CE, Biradee I. Selenium protects against tenofovir/lamivudine/efavirenz-induced nephrotoxicity in rats. J Nat Sci Med 2022;5:157-62
|How to cite this URL:|
Adikwu E, Ezerioha CE, Biradee I. Selenium protects against tenofovir/lamivudine/efavirenz-induced nephrotoxicity in rats. J Nat Sci Med [serial online] 2022 [cited 2022 May 21];5:157-62. Available from: https://www.jnsmonline.org/text.asp?2022/5/2/157/344203
| Introduction|| |
A variety of drugs belonging to different therapeutic classes are known to cause nephrotoxicity. Drug-induced nephrotoxicity is increasingly known as a primary contributor to kidney diseases such as acute and chronic kidney injuries. In kidney injuries, nephrotoxicity accounts for 40%–70% morbidity and mortality and 66% of cases of renal failure in elderly people. Epidemiology also showed an incidence of 16% in pediatrics and 14%–26% in adults. Drug-induced nephrotoxicity has a wide spectrum, based on damage to different segments of the nephron. Both glomerulus and tubule are established targets for drug-induced nephrotoxicity, which may lead to acute or chronic functional changes. Risk factors associated with nephrotoxicity are many and depend on the drug regimen used and patient factors.
Tenofovir/lamivudine/efavirenz (TLE) is one of the commonly used highly active antiretroviral therapies (HAART) for the treatment of human immunodeficiency virus (HIV) infection. Its use has been remarkable, but may cause acute or chronic nephrotoxicity, which is primarily attributed to its tenofovir (TDF) component, and can be compounded by partner drugs. TLE-related chronic renal dysfunction may be characterized by decreased glomerular filtration rate and kidney necrotic changes. Fanconi syndrome is also a notable feature of TLE-related chronic renal dysfunction marked by alterations in serum electrolytes and acid-base balance.,,, The speculated mechanism by which TLE causes nephrotoxicity is via kidney mitochondria damage-causing reactive oxygen species (ROS) production leading to oxidative stress. Oxidative stress is inseparably linked to mitochondrial damage, as mitochondria are generators of ROS and targets for ROS. The induction of kidney oxidative stress by TLE has been associated with the incapacitation of kidney antioxidants characterized by depleted glutathione (GSH), catalase, superoxide dismutase (SOD), and GSH peroxidase (GPx). The induction of kidney lipid peroxidation (LPO) marked by elevated malondialdehyde (MDA) is also a pointer to the induction of oxidative stress by TLE.,,
Selenium (Se) is an important trace element present in dairy products, seafoods, vegetables, whole grains, and organ meats. It is an essential component of selenoproteins, which perform redox activity and transport functions. GPx and GSH reductase (GR) are part of selenoproteins, which inhibit oxidative stress, and protect cellular components from the destructive impact of oxidative stress. Experimentally, Se has shown immunomodulatory effect by increasing the proliferation of T-cells, and Natural-killer-cell activity. Its inflammatory action includes the inhibition of nuclear factor-kappa B cascade, which can prevent the production of inflammatory mediators. Se has received research attention due to potential therapeutic effects on diseases such as cancer, diabetes, and hypertension. It has also shown protective effects on gentamicin, adriamycin, and acrylamide. induced nephrotoxicity in animal models. There is a significant lack of information on the protective impact of Se on antiretroviral drug-induced nephrotoxicity. This study explored the protective impact of Se supplementation on TLE-induced nephrotoxicity in a rat model. Rat model was used due to some biological similarities with humans.
| Materials and Methods|| |
Animals, drugs and chemicals
Adult male albino rats (200–250 g) were purchased from the animal unit of the Department of Pharmacology/Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were kept in cages and fed with chow and water ad libitum. The rats were housed under 12 h light and 12 dark cycles and acclimated for 2 weeks. TLE tablets (Hetero Labs Limited, Hyderabad, India) and Se capsules (Sodium selenite) (Bactolac Pharmaceuticals Inc 7 Oser Avenue Hauppauge, NY 11788, USA) were used. TLE (8.6/8.6/17.1 mg/kg) which is twice the clinical dose and Se (0.1 mg/kg) were used. The study was approved on 4th Aug, 2020 by the Research Ethics Committee (NDU/PHARM/AEC/047) of the Department of Pharmacology/Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The directive of the European Parliament and of the Council (2010/63/EU) was used for animal handling. Animal treatment to sacrifice lasted for 110 days.
Animal treatment and sacrifice
Forty healthy adult male albino rats were randomized into four groups (n = 10). Group A (Control) was orally administered daily with 0.9% normal saline (0.2 mL) for 90 days. Group B was orally administered daily with Se (0.1 mg/kg) in 0.9% normal saline (0.2 mL) for 90 days. Group C was orally administered daily with TLE (8.6/8.6/17.1 mg/kg) in 0.9% normal saline for 90 days. Group D was orally administered daily with Se (0.1 mg/kg) and TLE (8.6/8.6/17.1 mg/kg) for 90 days. After treatment, the rats in the control and experimental groups were anesthetized (Diethyl ether). Blood samples were obtained through cardiac puncture and evaluated for biochemical parameters. The rats were sectioned; kidney samples were harvested and rinsed in physiological saline. The kidney samples were homogenized in buffered (pH 7.4) 0.1 M Tris-HCl. The homogenates were centrifuged (MY-B064, Huangpu, China) (1500 rmp for 20 min), the supernatants were decanted and evaluated for oxidative stress indices.
Evaluation of serum renal function markers
Serum creatinine, urea, uric acid, total protein, albumin, bicarbonate, potassium, chloride, and sodium concentrations were evaluated with an auto analyzer (Konelab™ PRIME 60i, Thermo Scientific, Vantaa, Finland).
Determination of kidney oxidative stress markers
The method described by Sun and Zigman was used to assay SOD whereas the method described by Aebi was used to assay catalase (CAT). MDA was assayed as described by Buege and Aust. GSH was determined as reported by Sedlak and Lindsay. GPx was assessed according to Rotruck et al.
Histological evaluation of the kidney
Kidney samples were taken from rats in the control and treated groups and were fixed in 10% neutral buffered formalin. Kidney samples were rinsed in serial dilutions of alcohol, processed, and embedded in paraffin. Paraffin blocks were sectioned (3 μm thick) using a sledge microtome and stained with hematoxylin and eosin (Bio Lab Diagnostics Limited, India). The stained sections were examined for histological changes using a light microscope.
GraphPad Prism 5.0 software was used for data analysis (GraphPad Software Inc., La Jolla, CA, USA). Data were expressed as mean ± standard error of the mean (SEM). The means of the control and treated groups were compared using one-way analysis of variance (ANOVA) followed by Tukey's post-hoc tests. P < 0.05; 0.01; and 0.001 were considered statistically significant.
| Results|| |
Effect of selenium on serum renal function markers of tenofovir/lamivudine/efavirenz–treated rats
[Table 1] shows the result of serum creatinine, urea, uric acid, albumin, and total protein. In the Se-treated group, the aforementioned parameters were not significantly (P > 0.05) different when compared to the control group. On the other hand, serum creatinine, urea, and uric acid levels were elevated (P<0.001), whereas serum albumin and total protein levels were decreased (P<0.001) in the TLE-treated group in relation to the control group. However, the Se + TLE treated group showed decreases in serum creatinine, urea, and uric acid levels with increases in serum albumin and total protein levels at P < 0.01 in relation to the TLE-treated group.
|Table 1: Effect of selenium on serum renal function markers of tenofovir/lamivudine/efavirenz-treated rats|
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Effect of selenium on serum electrolytes of tenofovir/lamivudine/efavirenz-treated rats
[Table 2] shows the summary of the result of serum electrolytes. Serum electrolytes were normal (P > 0.05) in the Se-treated group when compared to control. In contrast, serum electrolytes were significantly (P < 0.001) decreased in the TLE-treated group in relation to control. However, serum electrolytes were significantly (P < 0.01) increased in the Se + TLE treated group in relation to the TLE-treated group.
|Table 2: Effect of selenium on serum electrolytes of tenofovir/lamivudine/efavirenz.treated rats|
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Effect of selenium on kidney oxidative stress indices and histology of tenofovir/lamivudine/efavirenz-treated rats
[Table 3] shows the summary of the result of kidney oxidative stress markers. Kidney MDA and antioxidants (SOD, CAT, GSH, and GPx) were normal (P > 0.05) in the Se-treated group when compared to control. Kidney MDA was significantly (P < 0.001) increased, whereas kidney antioxidants were significantly (P < 0.001) decreased in the TLE-treated group when compared to the control group. On the other hand, kidney MDA was significantly (P < 0.001) decreased whereas kidney antioxidants were significantly (P < 0.001) increased in the Se + TLE treated group in relation to the TLE-treated group. The kidney of rats in the control and Se-treated groups showed normal glomeruli and renal tubules [Figure 1] and [Figure 2]. The kidney of rats in the TLE-treated group showed lipid accumulation, tubular necrosis, and mesangial proliferation [Figure 3]. However, the kidney of rat in the SE + TLE-treated group showed normal glumerulus and renal tubule [Figure 4].
|Table 3: Effect of selenium on kidney oxidative stress indices of tenofovir/lamivudine/efavirenz-treated rats|
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|Figure 1: The kidney of rat in the control group showed normal glomerulus (A) and renal tubule (B)|
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|Figure 2: The kidney of rat in the Se-treated group showed normal glomerulus (C) and renal tubule (D)|
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|Figure 3: The kidney of rat in the tenofovir/lamivudine/efaviren-treated group showed mesangial proliferation (E), lipid accumulation (F) and tubular necrosis (G)|
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|Figure 4: The kidney of rat in Selenium + tenofovir/lamivudine/efaviren-treated group showed normal glomerulus (H) and renal tubule (I) (H and E) ×400|
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| Discussion|| |
The introduction of HAART in the treatment of HIV infection has led to a reliable regulation of HIV progression and has tremendously improved survival. However, the use of HAART may cause acute or chronic kidney injuries in people living with HIV. There is a significant paucity of therapeutic measures to treat or curtail kidney injury caused by HAART. A number of experimental studies envisage promising therapeutic activities of antioxidants in renal injuries. This study assessed the protective activity of Se on TLE-induced nephrotoxicity in rats. Serum creatinine is an essential diagnostic parameter in the first phase of renal disease, whereas uric acid and urea levels are imperatively used for the detection of the late phase of renal disease. The estimation of serum total protein, albumin, and electrolytes can predict the well-being of the renal system. Treatment with Se had no deleterious effects on all evaluated parameters. Nephrotoxicity was evident in rats treated with TLE due to increased serum creatinine, uric acid, and urea levels with decreased serum total protein, albumin, and electrolytes. Similarly, Manosuthi et al. established renal dysfunction marked by altered concentrations of the aforementioned indices caused by TLE. The observation in this study is also consistent with findings reported by Mathew and Knaus. Renal proximal tubules have mitochondria, which are essential for the energy-consuming process required for water and solutes reabsorption. Kidney mitochondria damage can produce ROS which can lead to oxidative stress-induced kidney dysfunction. Studies have correlated oxidative stress with sustained kidney antioxidants incapacitation, biomolecular dysfunction, and cellular apoptosis. The present study observed oxidative stress in TLE-treated rats, which was established by conspicuous depletion of kidney antioxidants. This observation supports report by Akang et al., (2020) on depleted kidney antioxidants in rats exposed to TDF-containing regimen for 56 days. Similarly, Abraham et al. 2013 documented decreased kidney antioxidants in rats exposed to TDF.
One of the consequences of oxidative stress is LPO. Experimentally, studies have correlated LPO with renal pathology. LPO of kidney cell membrane impairs the integrity and capacity for cell transport and energy generation especially in the proximal tubular segment. LPO also stimulates vasoactive peptides (prostaglandins and thromboxanes), which can decrease glomerular blood flow and filtration. MDA has been used as an important yardstick for LPO., In this study, TLE caused remarkable increase in kidney MDA concentration, which is an evidence of LPO. Similarly, Akang et al., (2010) reported elevated kidney MDA concentration in rats exposed to TDF containing regimen for 56 days. Abraham et al. also reported increase in kidney MDA concentration in TDF-treated rats. In this study, TLE caused morphological changes in kidney histology characterized by tubular necrosis, mesangial proliferation, and lipid accumulation. This finding is similar to studies that observed glomerulus and tubular dysfunctions in TLE-treated rats. Jang et al. also reported renal tubular damage caused by graded doses of TDF in rats. The mechanisms by which TLE causes nephrotoxicity are not clear. However, the observations in this study showed that oxidative stress may be a factor due to the incapacitation of kidney antioxidant defense and the induction of LPO by TLE, which might have caused perturbations in renal biochemical markers and kidney histology.
In the present study, TLE-induced nephrotoxicity was reversed by Se supplementation. The observed renal protection offered by Se was marked by restored serum levels of renal biochemical markers, and kidney morphology. It was also characterized by increased kidney antioxidants and decreased MDA levels. Similar to the current findings, Naziroglu et al. reported the renal protective effect of Se on cisplatin exposed rats. Sengul et al. also reported the protective impact of Se on a rat model of acrylamide-induced renal dysfunction. The renal protective activity of Se may be attributed to its antioxidant effect. Se might have downregulated oxidative stress by scavenging ROS generated by TLE in renal tissues. Se is an essential component of selenoproteins that is encoded by 25 genes, which include genes that encode GPx and GR. GPx and GR formed the GSH redox cycle, which is essential for antioxidants function., GSH is a substrate for GPx, which prevents the degradation of cell structures, and reduces free radicals and phospholipid hydroperoxides to harmless products. GR can maintain the concentration of GSH in cells used by GPx for the elimination of peroxides and the detoxification of ROS.,
| Conclusion|| |
Se reversed TLE-induced nephrotoxicity. It may have clinical use for TLE-associated nephrotoxicity.
The authors appreciate Mr. Cosmos Obi of the Department of Pharmacology, and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]