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IJPER · Lens · Protection of Hesperidin against Methotrexate-Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

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Article · Volume 55, Issue 4 · pp. 1066–1073

Protection of Hesperidin against Methotrexate-Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

Mohamed Aly Morsy1,2, Azza Ali Kamel El-Sheikh2,3, Ahmed Ragaa Nour Ibrahim4,5, Mahmoud El-Daly6

  1. 1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, SAUDI ARABIA.
  2. 2Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, EGYPT.
  3. 3Basic Health Sciences Department, Faculty of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, SAUDI ARABIA.
  4. 4Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, SAUDI ARABIA.
  5. 5Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, EGYPT.
  6. 6Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, EGYPT.

Abstract

Background: Methotrexate (MTX), a successfully used chemotherapeutic in the treatment of various malignancies and autoimmune diseases, might cause severe nephrotoxicity. Here, we aimed at investigating possible nephroprotective effects of hesperidin (HES), a flavanone present in citrus fruits, against MTX-induced toxicity.Methods: Rats were divided into control, HES, MTX, and MTX/HES groups, where HES was administered in a dose of 100 mg/kg/day orally for 8 days and MTX in a single i.p. dose of 20 mg/kg on day 5 of the experiment.Results: Pretreatment with HES significantly improved MTX-induced deteriorated kidney function and structure, as well as reversed MTX effects on renal tumor necrosis factor (TNF)-α level and caspase 3 expression. MTX upregulated renal breast cancer resistance protein (BCRP); an efflux transporter that extrudes MTX from the kidney. Unfortunately, MTX/HES did not show a further increase in BCRP expression but rather showed downregulation. MTX also caused downregulation of renal nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expressions, whereas HES reversed the MTX effect and upregulated renal Nrf2/HO-1.Conclusion: HES conferred protection against MTX-mediated nephrotoxicity, at least in part via anti-inflammatory and anti-apoptotic mechanisms. Nrf2/HO-1 pathway, but not BCRP, may have a role in HES-induced nephroprotection against MTX toxicity.

Keywords: Methotrexate; Hesperidin; Nrf2; HO-1; TNF-α; Caspase 3; BCRP

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