Doxorubicin-induced Nephrotoxicity In Rats Research Articles

Comparative effects of incretin-based therapy on doxorubicin-induced nephrotoxicity in rats: the role of SIRT1/Nrf2/NF-κB/TNF-α signaling pathways.

Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20mg/kg, single I.P. on day 8), DOX + ALO (20mg/kg/day, P.O. for 10days), DOX + SEM (12μg/kg/day, S.C. for 10days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.

N-(2-hydroxy phenyl) acetamide ameliorate inflammation and doxorubicin-induced nephrotoxicity in rats

Doxorubicin (DOX) is an anthracyclin antibiotic used for the treatment of various cancers. Nephrotoxicity is among the serious side effects of DOX, therefore, DOX-induced nephrotoxic model has been widely used to study nephropathies. The objectives of this study is to investigate the possible anti-inflammatory and nephroprotective effects of salicylic acid derivative, N-(2-hydroxy phenyl) acetamide (NA-2), in a rat model of DOX-induced nephrotoxicity. The in vitro anti-inflammatory potential of NA-2 was manifested by whole blood oxidative burst and nitric oxide (NO) assays with no toxicity on normal human fibroblast (BJ) cells, human embryonic kidney (HEK-293) cells, and normal monkey kidney epithelial (Vero) cells. The in vivo study included five groups: Normal control, DOX (6 mg/kg DOX-i.v.via tail vein), NA-2 treated control-i.p., NA-2/DOX treated-i.p., and prednisolone/DOX treated. After 7 days of DOX administration, rats with urinary protein level of >50 mg/kg/day were selected. Treatment group rats received i.p. doses of NA-2 (10 mg/kg/day) for 3 weeks with weekly monitoring of urinary protein excretion and body weights. mRNA expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and kidney injury molecule (KIM)-1 was analyzed by quantitative polymerase chain reaction (qPCR). Protein expressions were analyzed by immunohistochemistry. NA-2 attenuated DOX-induced changes in serum and urine levels, and improved inflammatory profile of the renal tissue. Histopathological findings revealed protective effects of NA-2 showing lesser lesions. We conclude that NA-2 is able to protect against DOX-induced renal damage functionally, biochemically and histopathologically with corresponding improvement in the kidney inflammatory profile.

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis.

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM's antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.

The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats

Doxorubicin (DOX) is a well-known anti-neoplastic agent that is widely employed to treat several types of malignancies. The current study was designed to investigate the renoprotective potential of berberine (BEB) on the doxorubicin (DOX)-induced nephrotoxicity and renal fibrosis. Rats were allocated into four groups; Negative Control, DOX nephrotoxic-induced group received a single dose of DOX (20 mg/kg, i.p.), BEB-group received (50 mg/kg, p.o.) for 14 days, and co-treatment group BEB + DOX where rats were pre-treated with BEB for 10 successive days, then received a single dose of DOX on the 11th day, followed by 4 days of receiving BEB. DOX resulted in nephrotoxicity manifested by significant increments in urea, creatinine, and kidney injury molecule (KIM-1), these biochemical findings were supported with the histopathological lesions in renal tissues. Moreover, DOX provoked oxidative stress through enhancing renal malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents, and decreased renal catalase (CAT) activity. DOX triggered renal fibrosis represented by increased transforming growth factor beta-1 (TGF-β1) and elevated collagen deposition. DOX stimulated apoptosis and inflammation in renal tissues as confirmed by increased immunoexpression of caspase-3 and NF-κB, respectively. These effects were alleviated by BEB co-treatment. Co-treatment with BEB markedly prohibited DOX-induced oxidative damage, inflammation, apoptosis, and fibrosis in renal tissue. Histopathological and immunohistochemical investigations showed the nephroprotective potential of BEB on renal injury, which was consistent with the biochemical findings. Accordingly, it could be concluded that the nephroprotective potential of BEB against DOX-induced kidney injury and fibrosis might be mediated by the anti-oxidant, anti-inflammatory and anti-fibrosis activities.

The protective effect of metformin and exenatide on doxorubicin-induced nephrotoxicity in rats

Objective The aim was to study the protective effect of metformin and exenatide on doxorubicin (DOX)-induced nephrotoxicity in rats. Background DOX is an effective chemotherapeutic agent used for treatment of various solid as well as hematological neoplasms. Its use is limited owing to well-documented nephrotoxicity. Treatment with metformin and exenatide ameliorates nephrotoxicity in rats through antioxidant and antiapoptotic effects. Materials and methods In this experimental study, rats were divided as follows: group 1 was injected with saline intraperitoneal and orally, group 2 was injected with intraperitoneal DOX (15 mg/kg) and oral saline, group 3 was injected with intraperitoneal DOX and received metformin (250 mg/kg/day) orally, group 4 was injected with intraperitoneal DOX and received exenatide (10 μg/kg twice daily) Sc, and group 5 was injected with intraperitoneal DOX and metformin + exenatide. Basal body weight (Wt.), final body Wt., kidney Wt., kidney index, kidney malondialdehyde (MDA), reduced glutathione (GSH), serum tumor necrosis factor-α (TNF-α), serum albumin, serum urea and creatinine, urinary proteins, histopathological examination of hematoxylin and eosin, and caspase-3 immunostaining were evaluated. Results DOX group showed a significant decrease in body Wt, GSH levels, and serum albumin, with an increase in kidney Wt., kidney index, serum TNF-α, kidney MDA levels, urine proteins, serum urea and creatinine, and caspase-3 immunoexpression compared with the control group. In contrast, metformin-, exenatide-, and metformin + exenatide-treated groups showed significant increase in body Wt. and kidney GSH levels, with a decrease in kidney Wt., serum TNF-α, kidney MDA levels, and caspase-3 immunoexpression compared with DOX group. Conclusion Metformin and exenatide improved DOX nephrotoxicity in rats.

Antioxidant and Anti-Inflammatory Effects of Crocin Ameliorate Doxorubicin-Induced Nephrotoxicity in Rats.

Doxorubicin is a drug that belongs to the anthracycline antibiotics. Nephrotoxicity is one of the serious side effects of doxorubicin treatment. Crocin, which is one of the most bioactive components of saffron, has antioxidant, anti-inflammatory, and antitumor effects. The current study was aimed at investigating the possible protective effects of crocin against doxorubicin-induced nephrotoxicity to elucidate the underlying mechanism of this effect. The study included four groups, six rats in each group: normal control, crocin control, doxorubicin, and crocin/doxorubicin. Doxorubicin and crocin/doxorubicin groups received intraperitoneal injections of doxorubicin (3.5 mg/kg twice weekly for 3 weeks). Rats in the crocin control group and the crocin/doxorubicin group were treated with intraperitoneal injections of crocin (100 mg/kg body weight per day) for 3 weeks. Biomarkers of kidney function and oxidative stress as well as the abundance of mRNA for nuclear factor-κβ and inducible nitric oxide synthase were evaluated. In addition, the abundance of cyclooxygenase 2 and tumor necrosis factor α immunoreactivity was evaluated. Crocin treatment had renoprotective effects manifested by significant improvement in kidney function as well as a reduction in the abundance of biomarkers of oxidative stress markers and inflammatory mediators. In conclusion, crocin has a protective effect against doxorubicin-induced nephrotoxicity in rats by serving as an antioxidant and attenuating the expression of NF-κB, iNOS, COX2, and TNFα.

Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury.

Background and purpose:The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats.Experimental approach:Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks.Findings/Results:DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity via alleviation of all the above-mentioned parameters when compared to DXR-control rats.Conclusion and implications:The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.

Effect of Ethanolic extract of Boerhvia diffusa against doxorubicin induced Nephrotoxicity in Albino Rats

Anthracycline derivative i.e. doxorubicin (Dox) has proven efficacy in several malignancies such as breast cancer, Hodgkin and non-Hodgkin lymphoma, acute leukemia, lung, thyroid and ovarian cancer. The clinical usefulness is restricted due to its cardiotoxicity and nephrotoxicity. Boerhaavia diffusa belongs to family Nyctaginaceae and in Ayurveda, it is claimed for use in renal disorders. The main phytoconstituents of the plant are alkaloids, terpenoids, tannins, glycosides, flavonoids, phenolic compounds. To investigate the ameliorative role of ethanolic extract of petals of B. diffusa in doxorubicin-induced nephrotoxicity in rats. Nephrotoxicity was produced by administering doxorubicin (2.5 mg/kg b.w., i.p. alternate day) in six equal injections for two weeks to become cumulatively 15 mg/kg. Low (LEBD–100 mg/kg p.o.) and high (HEBD–200 mg/kg p.o.) dose of ethanolic extract of Boerhhvia diffusa was administered as a pretreatment before doxorubicin administration. The general parameters such as body weight, food, and water intake were measured throughout the study period. Serum markers such as blood urea nitrogen (BUN), serum creatinine and albumin were measured. Antioxidant enzymes such as glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were monitored after the last dose. Histopathological studies were also carried out to evaluate nephrotoxicity. The repeated administration of doxorubicin produces several morphological changes, decreased body weight, food, and water consumption. Serum markers such as BUN and serum creatinine were increased and albumin levels decreased. The GSH, SOD, and CAT were decreased, whereas the MDA level was increased, and deteriorating changes in the histological architecture of kidney tissue were observed. The HEBD pretreated groups dosedependently increased body weight and food and water intake (p is less than 0.01 and p is less than 0.05), whereas LEBD does not show any significant changes. The LEBD and HEBD pretreated groups decreased the BUN (p is less than 0.05 and p is less than 0.01) and serum creatinine (p is less than 0.05 and p is less than 0.05) and increased in the albumin (p is less than 0.05 and p is less than 0.05) levels, respectively. The pretreatment with LEBD and HEBD increased the level of the antioxidant enzyme i.e., GSH (p is less than 0.05 and p is less than 0.01), SOD (p is less than 0.05 and p is less than 0.01), CAT (p is less than 0.05 and p is less than 0.01) and decreased the MDA level (p is less than 0.05 and p is less than 0.01) respectively. Histopathological studies showed that the pretreatment with LEBD and HEBD groups minimized the tubular damage and reduced the inflammation as compared to doxorubicin-treated group. The biochemical and histopathological results data support the nephroprotective effect of ethanolic extract of B. diffusa, which might be credited to its antioxidant property.

Effect of meloxicam (cyclooygenase-2 inhibitor) versus vitamin D3 (cholecalciferol) as ameliorating agents of progressive doxorubicin-induced nephrotoxicity in rats.

Doxorubicin (DOX)-induced nephropathy hampered its antineoplastic efficiency. The objective of the current work is to assess the prospective ameliorating effects of meloxicam versus vitamin D3 (Vit D3, cholecalciferol) against progressive DOX-induced nephropathy in rats trying to ascertain the possible mechanism underlying such amelioration. Ninety Male Wistar rats were randomly distributed to five experimental groups for 3 weeks, with saline, meloxicam (daily), DOX (single dose), Vit D3+DOX, or both meloxicam and DOX. We measured levels of urinary protein, serum creatinine, malondialdehyde (MDA) and renal reduced glutathione (GSH). In addition, tumor necrosis factor-alpha (TNF-α) expression and renal histopathology were assessed. Meloxicam alone treated group revealed no significant difference in urinary protein and serum creatinine. It also presented non-significant reduction in the MDA content while an increase in the reduced GSH content in contrast to the control group, which is more evident after the first week. Renal sections of rats received meloxicam only showed no significant histological changes and negative immunoreactivity compared to the control group. DOX induced a significant increase in urinary protein, serum creatinine, decrease reduced GSH, increased renal MDA and disrupted renal morphometric parameters and histology with increased TNF-α expression. Combination groups of Vit D3+DOX and meloxicam+DOX showed improvement of all DOX disturbed parameters. Meloxicam showed better results most likely due to anti-inflammatory and antioxidant activities superimposing the immune-modulatory effect of Vit D3. So, it is recommended to use meloxicam in patients receiving DOX as a renoprotective agent in addition to its analgesic effects required by cancer patients.

Evaluation of the protective effect of edaravone on doxorubicin nephrotoxicity by [99mTc]DMSA renal scintigraphy and biochemical methods.

To evaluate the nephroprotective effect of edaravone on doxorubicin-induced nephrotoxicity. In this experimental study, twenty-eight Wistar male rats were used. The rats were separated into 4 groups (n = 7); group І (control), rats were treated with saline (4ml/kg) and group ІІ (doxorubicin), nephrotoxicity was induced by three doses of 18mg/kg/i.p. doxorubicin, at a 24-h interval on the 12th, 13th, and 14th days. Group ІІІ (edaravone), rats were treated with edaravone (30mg/kg/for 14days), and group ІV (edaravone + doxorubicin), rats were treated with edaravone (30mg/kg/for 14days) and doxorubicin were injected (18mg/kg/for 3days; at a 24-h interval on the 12th, 13th, and 14th days). On the 15th day of the experiment, technetium-99m-labeled dimercaptosuccinic acid ([99mTc]DMSA) uptake was obtained in both kidneys and biochemical parameters from serum and kidney tissue were measured. Doxorubicin led to nephrotoxicity through elevation of serum blood urea nitrogen (BUN), creatinine and tumor necrosis factor-α (TNF-α), nitric oxide (NO), and interleukin-6 (IL-6) in kidney tissue and decreased [99mTc]DMSA uptake level in the kidney when compared with control group (p < 0.01). Pretreatment edaravone significantly decreased BUN and creatinine, also kidney tissue TNF-α, IL-6, NO, and increased [99mTc]DMSA uptake level compared with the doxorubicin. Edaravone has a significant nephroprotective effect through the attenuation of oxidative stress and inflammatory markers during doxorubicin-induced nephrotoxicity in rats.

Effect of infliximab, a tumor necrosis factor-alpha inhibitor, on doxorubicin-induced nephrotoxicity in rats.

Treatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by nephrotoxicity. We investigated the possible protective effect of infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor on DOX-induced nephrotoxicity. Rats were treated with a single intraperitoneal (ip) injection of DOX (17.5mg/kg) in the absence or presence of infliximab (5mg/kg, i.p.). Plasma and urinary markers of kidney function, oxidative stress, and inflammation were measured. Kidney and heart tissue was evaluated histopathologically. DOX-induced nephrotoxicity was confirmed by increased plasma urea, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and clusterin concentrations. In addition, DOX increased urinary albumin/creatinine ratio, N-acetyl-β-D-glucosaminidase (NAG) activity, kidney injury molecule (KIM-1) concentrations, and reduced creatinine clearance. DOX significantly reduced renal antioxidants and increased plasma inflammatory markers and adiponectin concentrations. Concomitant treatment with infliximab did not significantly affect DOX-induced changes in plasma creatinine, cystatin C, or creatinine clearance. However, infliximab significantly reduced DOX-induced action on plasma urea, NGAL, clusterin, and adiponectin. Infliximab also significantly reduced urinary albumin/creatinine ratio, NAG activity, and KIM-1 concentrations, as well as the occurrence of fibrotic lesions in kidney tissue. Fibrosis detected in the heart was unchanged. In addition, infliximab reduced DOX-induced effects on plasma inflammatory markers, renal superoxide dismutase (SOD) and total antioxidant capacity. Our results show that infliximab is partially effective in mitigating DOX-induced nephrotoxicity in rats.

Nicorandil combats doxorubicin–induced nephrotoxicity via amendment of TLR4/P38 MAPK/NFκ-B signaling pathway

Nicorandil ameliorated doxorubicin-induced nephrotoxicity; this study aimed to show and explain the mechanism of this protection. A precise method was elucidated to study the effect of nicorandil on doxorubicin-induced nephrotoxicity in rats depending on the critical inflammation pathway TLR4/MAPK P38/NFκ-B. Adult male rats were subdivided into four groups. The 1st group was normal control, the 2nd group received nicorandil (3 mg/kg; p.o., for 4 weeks), the 3rd group received doxorubicin (2.6 mg/kg, i.p., twice per week for 4 weeks), and the fourth group was combination of doxorubicin and nicorandil for 4 weeks.Nephrotoxicity was assessed by biochemical tests through measuring Kidney function biomarkers such as [serum levels of urea, creatinine, albumin and total protein] besides renal kidney injury molecule-1 (KIM-1) and cystatin C], oxidative stress parameters such as [renal tissue malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase and nrf-2], mediators of inflammation such as [Toll like receptor 4 (TLR-4), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), p38 MAPK, Interleukin 1 beta (IL-1 β), and Tumor necrosis factor alpha (TNF-α)] and markers of apoptosis [BAX and Bcl-2 in renal tissue]. Finally, our data were supported by histopathology examination.Nicorandil pretreatment resulted in a significant decrease in nephrotoxicity biomarkers, oxidative stress markers, inflammatory mediators and prevented apoptosis through decreasing BAX and increasing Bcl-2 in renal tissues. Nicorandil prevented all the histological alterations caused by doxorubicin. Nicorandil is a promising antidote against doxorubicin-induced nephrotoxicity by neutralizing all toxicity mechanisms caused by doxorubicin through normalizing inflammatory cascade of TLR4/MAPK P38/NFκ-B.

Protective effect of irbesartan against doxorubicin-induced nephrotoxicity in rats: implication of AMPK, PI3K/Akt, and mTOR signaling pathways.

Nephrotoxicity is one of the serious undesirable effects related to doxorubicin (DOX). Herein, we have investigated the potential protective effect of irbesartan (IRB) against chronic nephrotoxicity induced by DOX, and the implication of different mechanistic pathways underlying these effects. Rats were treated with either DOX (2.5 mg/kg i.p., 3 times/week) for 2 weeks, and (or) IRB (40 mg/kg, daily) for 3 weeks. IRB prohibited nephrotoxicity induced by DOX, which was evident by the increase in blood urea nitrogen and creatinine levels and histopathological changes. IRB improved DOX-induced alterations in oxidative status by diminishing lipid peroxidation and upregulating the antioxidant enzymes. Also, upon DOX treatment, the renal expression of tumor necrosis factor-α, interleukin-6, and caspase-3 were significantly increased; IRB diminished DOX-induced alterations in these parameters. Moreover, DOX significantly decreased the expression level of AMP-activated protein kinase (AMPK). Meanwhile, DOX induced activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) and mammalian target of rapamycin (mTOR) pathways that cross talked with AMPK. On the contrary, IRB successfully counterbalanced all these effects. Collectively, these outcomes suggest that the modulation of AMPK, PI3K, Akt, and mTOR pathways plays a critical role in conferring the protective effects of IRB against DOX nephrotoxicity.

Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats

L-theanine is the unique amino acid found in tea plants, has antioxidant and antiinflammatory activities, and functions in mental concentration and sleep quality. In this study, it is aimed to investigate the effects of L-theanine on doxorubicin (DOX, a chemotherapeutic agent) induced nephrotoxicity in rats, especially via GSH related enzymes. 32 male Sprague Dawley rats weighing 300-400 g were randomly assigned into 4 groups (n = 8) and the substances were given intraperitoneally to them: Control group (saline for 5 days); Theanine group (200 mg/kg/day theanine for 5 days); DOX group (single dose of 20 mg/kg DOX); DOX + Theanine group (20 mg/kg DOX at first day and 200 mg/kg/day theanine for 5 days). Kidney tissues were evaluated by histopathological analysis. Serum levels of blood urea nitrogen (BUN) and creatinine by spectrophotometrically; percentage of apoptosis indexes (AI%) in the tissues by TUNEL method; caspase-3 levels, reduced and oxidized glutathione (GSH and GSSG), gamma-glutamyltransferase 1 (GGT1), glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione S-transferase (GST), nuclear factor kappa B p65 (NF-kB p65) by commercial kits; malondialdehyde (MDA) by spectrophotometrically were determined in plasma and kidney tissues. According to DOX group, the DOX + Theanine group has much lower tissue and plasma GSSG, GGT1, NF-κB p65 levels and tissue AI%, whereas significantly higher GSH levels and GPx, GR, GST activities (P < 0.05). It is suggested that L-theanine may have protective effects by enhancing effects on the antioxidant system of GSH and GSH-related enzymes against DOX-induced nephrotoxicity in rats. But this finding needs to be supported with further studies.

Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats

Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis.Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin.

Effect of Pravastatin on Levels of Filtration Slit Diaphragm Protein and Oxidative Stress in Doxorubicin- Induced Nephrotoxicity

Abstract: Introduction: Nephrotoxicity is one of the complications the use of doxorubicin (DXR) which may be caused by the formation of free radicals. The aim of this study was to investigate the effects of pravastatin (PS) on doxorubicin-induced nephrotoxocity. Methods: The rats were divided into control, doxorubicin (15 mg/kg, i.p.), PS (20 mg/kg orally, 5 days prior to DXR injection) + DXR and DXR + PS (5 days after DXR injection) groups. At the end of the 20th day, kidneys were removed for evaluation. Podocin mRNA and protein were determined by real–time PCR and Western blotting. Also, the level of tissue’s malondialdehyde (MDA), catalase (CAT), Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were determined. Results: Adminstration of pravastatin increased (P < 0.005) the mRNA and protein expression of podocin and the activities of CAT, SOD and GPx which were decreased in doxorubicin group. Pravastatin also, reduced (P < 0.005) the elevated MDA level in doxorubicin group. Conclusion: The present study showed that that pravastatin can improve doxorubicin-induced nephrotoxicity in rats which is associated with the increase in expression of podocin and antioxidant enzymes activities, and decrease in level of MDA. Key words: Pravastatin, Doxorubicin, Nephrotoxicity, Oxidative stress, Podocin.

Thymoquinone attenuates Doxorubicin-induced nephrotoxicity in rats: Role of Nrf2 and NOX4

Doxorubicin (DOX) is a chemotherapeutic drug widely used for the treatment of various neoplastic conditions. However, its application is limited because of its toxic effects in many organs. Nephrotoxicity is a serious effect of DOX. The aim of this study was to determine the protective effect of thymoquinone (TQ), a predominant bioactive constituent of Nigella sativa oil, with well documented potent anti-oxidative and anti-inflammatory effects. Male Sprague Dawley rats received DOX (3.5mg/kg twice weekly) with or without TQ (50mg/kg/day, oral supplementation) for 3weeks. Elevated levels of serum urea, creatinine and urinary albumin excretion were observed in DOX-treated animals, indicating DOX-induced nephrotoxicity. Moreover, enhanced lipid peroxidation (LPO), as equivalents of malondialdehyde (MDA), in the renal tissue was accompanied by a significant decrease in the activities of superoxide dismutase (SOD) and glutathione-S-transferase (GST) in DOX-treated group. In addition, DOX treatment induced significant increase in renal levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NADPH oxidase 4 (NOX-4), and marked decrease in interleukin-10 (IL-10) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA levels and nuclear binding activity. Histopathological analysis showed severe damage in the renal tissue of DOX treated animals. Animals treated with TQ were found to have markedly reduced renal damage with restoration of all mentioned markers toward normal values. In conclusion, DOX-induced renal damage involved a redox imbalance in renal tissue, which could be reversed by TQ, suggesting a possible potential role for TQ in DOX-induced nephrotoxicity.

Protective effect of captopril, olmesartan, melatonin and compound 21 on doxorubicin-induced nephrotoxicity in rats

Chronic kidney disease (CKD) represents a serious public health problem with increasing prevalence and novel approaches to renal protection are continuously under investigation. The aim of this study was to compare the effect of melatonin and angiotensin II type 2 receptor agonist compound 21 (C21) to angiotensin converting enzyme inhibitor captopril and angiotensin II type 1 receptor blocker olmesartan on animal model of doxorubicin nephrotoxicity. Six groups of 3-month-old male Wistar rats (12 per group) were treated for four weeks. The first group served as a control. The remaining groups were injected with a single dose of doxorubicin (5 mg/kg i.v.) at the same day as administration of either vehicle or captopril (100 mg/kg/day) or olmesartan (10 mg/kg/day) or melatonin (10 mg/kg/day) or C21 (0.3 mg/kg/day) was initiated. After four week treatment, the blood pressure and the level of oxidative stress were enhanced along with reduced glomerular density and increased glomerular size. Captopril, olmesartan and melatonin prevented the doxorubicin-induced increase in systolic blood pressure. All four substances significantly diminished the level of oxidative burden and prevented the reduction of glomerular density and modestly prevented the increase of glomerular size. We conclude that captopril, olmesartan, melatonin and C21 exerted a similar level of renoprotective effects in doxorubicin-induced nephrotoxicity.

Effect of coenzyme-q10 on Doxorubicin-induced nephrotoxicity in rats.

Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox) as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10) on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100 mg/kg) of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15 mg/kg) at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH) and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology). Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox-induced nephrotoxicity with a precaution to dosage adjustment.

The protective effect of aminoguanidine on doxorubicin‐induced nephropathy in rats

Reactive oxygen species and cytokines have been implicated in the nephrotoxicity induced by doxorubicin. The goal of the present study was to determine protective effect of aminoguanidine on doxorubicin-induced nephrotoxicity in rats. Different groups of male Wistar rats received doxorubicin (67.75 mg/kg/i.p./2 days), aminoguanidine alone and aminoguanidine (200 and 400 mg/kg/i.p./30 days) prior to doxorubicin, respectively. Doxorubicin significantly increased serum creatinine (505%), blood urea nitrogen (333%), nitric oxide (406%), and plasma tumor necrosis factor-alpha (706%) as well as urinary albumin (452%) and N-acetyl-β-D-glucosaminidase (415%) compared to control. Moreover, renal glutathione (334%), superoxide dismutase (283%), and catalase (513%) were significantly reduced accompanied with elevation in renal malondialdehyde compared to control. Pretreatment with aminoguanidine mitigated such changes in all mentioned parameters. Histopathological changes showed that doxorubicin-caused significant structural damages to kidneys that were reduced with aminoguanidine. Results indicate that reactive oxygen species and cytokines are involved in doxorubicin-induced nephrotoxicity, which can be reduced by aminoguanidine.