Methotrexate induces cell swelling and necrosis in renal tubular cells

Grönroos, M; Chen, Ming; Jahnukainen, Timo; Capitanio, Arrigo; Айзман, Р. И.; Celsi, Gianni

doi:10.1002/pbc.20471

Cited by 33 publications

(23 citation statements)

References 40 publications

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“…The results showed that MTX caused oxidative renal tissue damage, as evidenced by renal histopathological findings in the form of tubular distension, interstitial inflammation, perirenal inflammation, glomerular congestion, glomerular degeneration, parenchymal hemorrhage, and perirenal eosinophil infiltration, which is in agreement with the findings of previous studies [35][36][37]. Pretreatment with HLX before the administration of MTX ameliorated the MTX-induced damage of the kidneys.…”

Section: Discussionsupporting

confidence: 82%

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Methotrexate-Induced Nephrotoxicity in Rats: Protective Effect of Mistletoe (Viscum album L.) Extract

et al. 2017

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Background: The protective effect of mistletoe extract (Helixor®, HLX) against methotrexate (MTX)-induced acute oxidative stress and nephrotoxicity in rats was evaluated by histological and biochemical methods as well as the comet assay. Material and Methods: 32 female Wistar albino rats were divided into 4 groups: control group, HLX group (5 mg/kg body weight (bw), days 1-10, intraperitoneally (i.p.)), MTX group (10 mg/kg bw, days 7, 8, and 9, i.p.), and MTX + HLX group (10 mg/kg bw, days 7, 8, and 9, i.p. + 5 mg/kg bw, days 1-10, i.p.). At the end of the experiment, the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), nitric oxide (NO), and myeloperoxidase (MPO) levels were measured, and a histopathological analysis and comet assay were carried out. Results: MTX induced renal oxidative stress and nephrotoxicity in the rats. Pretreatment with HLX significantly improved the renal GSH-Px and SOD activities in the MTX + HLX group compared to the MTX group. The decrease in the NO and MPO levels in the rat groups pretreated with HLX was not significant. The histochemical evaluation revealed that HLX provided significant improvement in the MTX-induced renal degenerative changes, including tubule distension, interstitial inflammation, perirenal inflammation, glomerular congestion, glomerular degeneration, and parenchymal hemorrhage, in the MTX + HLX group compared to the MTX-administered group. According to the comet assay, pretreatment with HLX lowered the MTX-induced DNA damage in endogenous lymphocytes, although not significantly. Conclusion: This study demonstrated that HLX administration markedly reduced the MTX-induced acute oxidative stress and nephrotoxicity in rats through its antioxidant and anti-inflammatory properties.

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Section: Discussionsupporting

confidence: 82%

“…Each criterion was scored (1 score per rat) using a semiquantitative scale as follows: 0 = none, 1 = mild, 2 = moderate, 3 = severe [35][36][37].…”

Section: Histological Evaluationmentioning

confidence: 99%

Methotrexate-Induced Nephrotoxicity in Rats: Protective Effect of Mistletoe (Viscum album L.) Extract

et al. 2017

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“…Elevation in plasma MTX levels can lead to enhancement of MTX's other toxicities [1,3] . Routine monitoring of serum creatinine and MTX is being done for management of MTX-induced renal dysfunction [18] . The pathogenesis of MTX-induced renal dysfunction is not clear, although it is believed to be mediated via the precipitation of MTX and its metabolites in the renal tubules [19,20] or by a direct toxic effect of MTX on the renal tubules [21] .…”

Section: Introductionmentioning

confidence: 99%

Neutrophil Infiltration and Oxidative Stress May Play a Critical Role in Methotrexate-Induced Renal Damage

Kolli¹,

Abraham²,

Isaac

et al. 2009

Chemotherapy

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Background: Nephrotoxicity is one of the adverse side effects of methotrexate (MTX) chemotherapy. The mechanism of renotoxicity of MTX is not fully understood. It is essential to understand the mechanism of nephrotoxicity of MTX in order to diminish the side effects and hence maximize the benefits of chemotherapy. Objectives: The aim of the study was to verify whether oxidative stress and neutrophil infiltration play a role in MTX-induced renal damage using a rat model. Methods: Adult male rats were administered MTX at the dose of 7 mg/kg body weight intraperitoneally for 3 consecutive days and sacrificed 12 or 24 h after the last dose. Vehicle-treated rats served as controls. The kidneys were removed and used for light microscopic and biochemical studies. Myeloperoxidase activity, a marker of neutrophil infiltration was measured in kidney homogenates along with the markers of oxidative damage including protein carbonyl content, protein thiol and malondialdehyde. The activities of the antioxidant enzymes, namely glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase, were also assayed. Results: MTX treatment induced damage to the glomeruli and tubules. Plasma creatinine levels in the MTX-treated rats were significantly elevated compared with controls. A significant increase in myeloperoxidase activity (p < 0.05) was observed in the kidneys of MTX-treated rats. Protein carbonyl content and malondialdehyde, sensitive and reliable markers of oxidative damage to proteins and lipids, respectively, were significantly elevated (p < 0.01) in the kidneys of MTX-treated rats compared with controls. The activities of the antioxidant enzymes, namely, superoxide dismutase and glutathione peroxidase, were significantly elevated (p < 0.01 and p < 0.05, respectively) in kidneys of rats following MTX treatment. Conclusion: The results of the present study provide evidence for the role of neutrophil infiltration and oxidative stress in MTX-induced renal damage. Administration of inhibitors of myeloperoxidase or scavenging hypochlorous acid, the product of myeloperoxidase, by supplementation with antioxidants as an adjuvant therapy may be promising in alleviating the renal side effect of MTX.

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“…The software used was created by one of the authors (A.e.) and it is part of the software currently used at the image analysis core facility of the Department of Pathology, Karolinska University Hospital/Karolinska Institutet, Stockholm (14). Results were analysed using the STATISTICA software.…”

Section: Mathematical Determination Of Positivity In Immunohistochemimentioning

confidence: 99%

“…In the case of ERdj5, there was very high expression compared to internal control specifically located to the cytosol of the tumor cells of all patient cases. To measure and compare the different degrees of positivity of the expression patterns of the thioredoxin family proteins, we developed a system based on the evaluation of the saturation of the IHC staining of the tumor tissue compared to the non-tumor tissue of the same section (14). Comparisons within the same sections are the ideal internal control as both were treated exactly the same throughout the entire process from fixation to staining.…”

Section: Immunohistochemistry Ofhuman Hepatocellular Carcinoma Sectionsmentioning

confidence: 99%

Increased Expression of Specific Thioredoxin Family Proteins; A Pilot Immunohistochemical Study on Human Hepatocellular Carcinoma

Cunnea

Fernandes

Capitanio

et al. 2007

Int J Immunopathol Pharmacol

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Hepatocellular Carcinoma (HCC) is one of the most frequent cancers worldwide, however, prognosis remains poor following its discovery. We investigate the Thioredoxin superfamily of proteins as diagnostic markers for HCC. Furthermore, we delineate possible roles of the endoplasmic reticulum member of the superfamily, ERdj5, in carcinogenesis. Using antibodies against Thioredoxin 1, Thioredoxin Reductase 1 and ERdj5, we performed immunohistochemistry on paraffin embedded liver biopsy sections from HCC patients. All three redox proteins exhibited elevated expression levels in tumor tissue compared to internal control, with ERdj5 showing a remarkable 3-fold increase. In vitro cell viability experiments using Hepatocellular Carcinoma HuH7 cells treated with ERdj5 small interfering RNA showed that ERdj5 knockdown cells exhibited less resistance to Doxorubicin (chemotherapy drug), but more resistance to Tunicamycin (Endoplasmic Stress inducer), compared to control cells. In conclusion, we introduce members of the Thioredoxin superfamily as possible immunohistochemical markers in the diagnostics of hepatocellular carcinoma and indicate a potential defensive role for ERdj5 in chemotherapeutic drug resistance.

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Methotrexate induces cell swelling and necrosis in renal tubular cells

Cited by 33 publications

References 40 publications

Methotrexate-Induced Nephrotoxicity in Rats: Protective Effect of Mistletoe (<b><i>Viscum album</i></b> L.) Extract

Methotrexate-Induced Nephrotoxicity in Rats: Protective Effect of Mistletoe (<b><i>Viscum album</i></b> L.) Extract

Neutrophil Infiltration and Oxidative Stress May Play a Critical Role in Methotrexate-Induced Renal Damage

Increased Expression of Specific Thioredoxin Family Proteins; A Pilot Immunohistochemical Study on Human Hepatocellular Carcinoma

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