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Dose-dependent renoprotective effect of vanillic acid on methotrexate-induced nephrotoxicity via its anti-apoptosis, antioxidant, and anti-inflammatory properties

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Abstract

Methotrexate-induced nephrotoxicity is a medical emergency which is associated with a variety of side effects. Vanillic acid (VA), as an antioxidant, removes free radical oxygen to protect cell defense. Therefore, this study investigated VA’s beneficial effects on nephrotoxicity induced by methotrexate through its anti-apoptosis, antioxidant, and anti-inflammatory properties. Our study included five groups of male Wistar rats (n = 8): sham, MTX (Methotrexate) group: rats receiving methotrexate (20 mg/kg, intraperitoneally) on Day 2. Moreover, the remaining groups consisted of animals that received vanillic acid (25, 50, and 100 mg/kg, orally for seven days) plus MTX on the 2nd day. The rats were deeply anesthetized on the eighth day to obtain blood and renal tissue samples. The results showed that MTX can increase blood urea nitrogen and creatinine. However, VA (50 and 100 mg/kg) improved renal function as approved by histological findings. Compared with MTX-treated rats, VA enhanced the contents of total antioxidant capacity (TAC) and reduced renal malondialdehyde (MDA). Moreover, VA reduced mRNA expressions of caspase-3 and Bcl-2-associated x protein (Bax) and caused mRNA overexpression of the renal B-cell lymphoma-2 (Bcl-2), and Nrf-2 (Nuclear factor erythroid 2-related factor 2) compared to the MTX group. Also, VA administration significantly reduced inflammatory agents. Overall, VA protects the kidneys against methotrexate-induced nephrotoxicity via anti-apoptosis, antioxidant, and anti-inflammatory properties. Our results revealed that the most effective dose of VA was 100 mg/kg.

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Data availability

All data generated or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

VA:

Vanillic acid

MTX:

Methotrexate

TAC:

Total antioxidant capacity

MDA:

Malondialdehyde

BAX:

Bcl-2-associated x protein

Bcl-2:

B-cell lymphoma-2

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukine-1β

NS:

Normal saline

BUN:

Blood urea nitrogen

Cr:

Creatinine

qRT‑PCR:

Quantitative real‑time PCR

H&E:

Hematoxylin-eosin

ANOVA:

One-way analysis of variance

NF-κβ:

Nuclear factor-κB

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

Nrf-2:

Nuclear factor erythroid 2-related factor 2

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Acknowledgements

This paper was extracted from an MD thesis written by Ms. Mahla Hasanzadeh Shoshtari, a student of medicine at Jundishapur University of Medical Sciences, Ahvaz, Iran. The authors would like to express their gratitude for the assistance of the Persian Gulf Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences.

Funding

This work was supported financially by the Persian Gulf Physiology Research Center (APRC-0102) funded by the Vice Chancellor of Research, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Negin Amini, Mahla Hassanzadeh Shoshtari, Mahin Dianat & Mohammad Badavi

  2. Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Negin Amini, Mahin Dianat & Mohammad Badavi

  3. Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Negin Amini & Fereshteh Nejaddehbashi

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  1. Negin Amini
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  2. Mahla Hassanzadeh Shoshtari
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  4. Mahin Dianat
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  5. Mohammad Badavi
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Contributions

NA designed the study and wrote the manuscript. MH contributed to the data collection. MB performed the data analysis and interpreted the results. FN performed molecular analysis and the histology. Mahin Dianat contributed to the data analysis. All authors read and approved the final version of the manuscript.The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Negin Amini.

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Ethical considerations

The current research was confirmed by the Animal Ethics Committee of Ahvaz Jundishapur University of Medical Sciences, Iran (IR.AJUMS.ABHC.REC.1401.009).

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This is an animal study.

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Amini, N., Shoshtari, M.H., Nejaddehbashi, F. et al. Dose-dependent renoprotective effect of vanillic acid on methotrexate-induced nephrotoxicity via its anti-apoptosis, antioxidant, and anti-inflammatory properties. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02866-y

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