Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ Ligands against methotrexate-induced nephrotoxicity

Mohamed A. Ibrahim, Azza A K El-Sheikh, Hanaa M. Khalaf, Aly M. Abdelrahman

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Context: The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity. Objective: To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats. Methods: Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists. Results: MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression. Discussion: Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis. Conclusion: At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.

Original languageEnglish
Pages (from-to)130-137
Number of pages8
JournalImmunopharmacology and Immunotoxicology
Volume36
Issue number2
DOIs
Publication statusPublished - Apr 2014

Fingerprint

pioglitazone
Peroxisome Proliferators
Fenofibrate
Methotrexate
Ligands
Kidney
Tumor Necrosis Factor-alpha
Rats
Oxidative stress
Caspase 3
Toxicity
Oxidative Stress
Malondialdehyde
Catalase
Urea
Creatinine
Nitric Oxide

Keywords

  • Fnofibrate
  • Nitric oxide
  • Oxidative stress
  • Pioglitazone
  • TNF-α

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pharmacology
  • Toxicology

Cite this

Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ Ligands against methotrexate-induced nephrotoxicity. / Ibrahim, Mohamed A.; El-Sheikh, Azza A K; Khalaf, Hanaa M.; Abdelrahman, Aly M.

In: Immunopharmacology and Immunotoxicology, Vol. 36, No. 2, 04.2014, p. 130-137.

Research output: Contribution to journalArticle

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AU - Khalaf, Hanaa M.

AU - Abdelrahman, Aly M.

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N2 - Context: The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity. Objective: To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats. Methods: Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists. Results: MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression. Discussion: Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis. Conclusion: At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.

AB - Context: The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity. Objective: To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats. Methods: Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists. Results: MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression. Discussion: Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis. Conclusion: At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.

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KW - Pioglitazone

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