L-carnitine reverses methotrexate-induced nephrotoxicity in experimental rat model: Insight on SIRT1/PGC-1α/Nrf2/HO-1 axis

L-carnitine reverses methotrexate-induced nephrotoxicity in experimental rat model: Insight on SIRT1/PGC-1α/Nrf2/HO-1 axis

Methotrexate (MTX) is a chemotherapeutic agent used for treating several types of cancer as well as psoriasis and rheumatoid arthritis, but its use is limited due to its nephrotoxicity. The purpose of this research work was to observe ameliorative effects of L-carnitine (LC) toward renal toxicity ca...

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Bibliographic Details
Published in:Journal of applied toxicology Vol. 43; no. 11; pp. 1667 - 1675
Main Authors: Radwan, Sara M, Alqulaly, Mustafa, Elsaeed, Magdy Y, Elshora, Shimaa Z, Atwa, Asmaa H, Wasfey, Eman F
Format: Journal Article
Language:English
Published: England Wiley Subscription Services, Inc 01-11-2023
Subjects:
Antioxidants
Apoptosis
BAX protein
Bcl-2 protein
Carnitine
Caspase
Heme oxygenase (decyclizing)
Inflammation
Interleukin 6
Kidneys
Lipid peroxidation
Lipids
Methotrexate
Oxidation
Oxidative stress
Psoriasis
Rheumatoid arthritis
Side effects
SIRT1 protein
Skin diseases
Superoxide dismutase
Toxicity
Tumor necrosis factor-TNF
methotrexate
L-carnitine
heme oxygenase-1
nephrotoxicity
SIRT1
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Summary:Methotrexate (MTX) is a chemotherapeutic agent used for treating several types of cancer as well as psoriasis and rheumatoid arthritis, but its use is limited due to its nephrotoxicity. The purpose of this research work was to observe ameliorative effects of L-carnitine (LC) toward renal toxicity caused by MTX and mechanisms responsible for these effects. Thirty-two male Sprague-Dawley rats were divided into four groups (eight rats/group), control group (received saline), MTX group (20 mg/kg/i.p. once), LC group (500 mg/kg/i.p. for 5 days), and MTX + LC group (received a single MTX dose 20 mg/kg/i.p. followed by LC 500 mg/kg/i.p. for 5 days). Histopathological examinations, lipid oxidation marker, malondialdehyde (MDA), and the antioxidant superoxide dismutase (SOD) as well as inflammatory (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]) and apoptotic markers (Bax, Bcl2, and caspase-3) were used to assess renal toxicity. Moreover, the protein levels of silent information regulator 1 (SIRT1) and its downstream signaling targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2) in addition to heme oxygenase-1 (HO-1) were measured. LC significantly protected against MTX-induced nephrotoxicity. It ameliorated MTX-induced renal histopathological changes and diminished MTX-induced renal oxidative stress, renal inflammation, and apoptosis. LC also upregulated the expression of SIRT1 and PGC-1 as well as Nrf2 and HO-1. By controlling the expression of renal SIRT1/PGC-1/Nrf2/HO-1, LC displayed antioxidant, anti-inflammatory, and anti-apoptotic activities. Hence, using LC supplements may help prevent negative MTX side effects.
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ISSN:0260-437X
1099-1263
DOI:10.1002/jat.4503