Reno-protective effect of mangiferin against methotrexate-induced kidney damage in male rats: PPARγ-mediated antioxidant activity

Seba Hassan Attia; Shimaa Mustafa Elshazly; Mahmoud Mohamed Abdelaal; Eman Soliman

doi:10.1016/j.jsps.2022.06.026

Reno-protective effect of mangiferin against methotrexate-induced kidney damage in male rats: PPARγ-mediated antioxidant activity

Saudi Pharm J. 2022 Sep;30(9):1252-1261. doi: 10.1016/j.jsps.2022.06.026. Epub 2022 Jul 1.

Authors

Seba Hassan Attia¹, Shimaa Mustafa Elshazly², Mahmoud Mohamed Abdelaal³, Eman Soliman²

Affiliations

¹ Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Egypt.
² Pharmacology and Toxicology Department, Faculty of Pharmacy, Zagazig University, Egypt.
³ Pharmacogonosy and Phytochemistry Department, Faculty of Pharmacy, Zagazig University, Egypt.

Abstract

Methotrexate (MTX) is an immunosuppressant used for the treatment of cancer and autoimmune diseases. MTX has a major adverse effect, acute kidney injury, which limits its use. Mangiferin (MF) is a natural bioactive xanthonoid used as a traditional herbal supplement to boost the immune system due to its potent anti-inflammatory and antioxidant activity. The present study evaluates the protective effect of MF against MTX-induced kidney damage. Male Wistar rats received MTX to induce nephrotoxicity or were pretreated with MF for 10 constitutive days before MTX administration. MF dose-dependently improved renal functions of MTX-treated rats and this activity was correlated with increased renal expression of PPARγ, a well-known transcriptional regulator of the immune response. Pretreating rats with PPARγ inhibitor, BADGE, reduced the reno-protective activity of MF. Furthermore, MF treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NFκB, interleukin-1ß, TNF-α, and COX-2), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (nitric oxide and iNOS) markers in the kidney. Importantly, BADGE treatment significantly reduced the anti-inflammatory and antioxidant activity of MF. Therefore, our data suggest that the reno-protective effect of MF against MTX-induced nephrotoxicity is due to inhibition of inflammation and oxidative stress in a PPAR-γ-dependent manner.

Keywords: ARE, antioxidant responsive element; BADGE, Bisphenol A diglycidyl ether; BUN, Blood urea nitrogen; COX2, cyclooxygenase 2; GSH, glutathione; GST, glutathione-S-transferase; Hmox1, hemoxygenase-1; IL-1ß, interleukin-1ß; IkBα, inhibitor of NFκB, alpha; KEAP1, Kelch-like-ECH-associated protein 1; MDA, malondialdehyde; MF, Mangiferin; MTX, methotrexate; Mangiferin; Methotrexate; NAG, N-acetyl-ß-D glucosaminidase; NFκB, nuclear factor-κB; NO, nitric oxide; Nephrotoxicity; Nrf2, nuclear factor-erythroid factor 2-related factor 2; Oxidative stress; PPARγ, Peroxisome proliferator-activated receptor-ү; Peroxisome proliferator-activated receptor-γ (PPAR-γ); ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase.