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

Methotrexate (MTX) is an immunosuppressant used for the treatment of cancer and autoimmune dis-eases. MTX has a major adverse effect, acute kidney injury, which limits its use. Mangiferin (MF) is a nat-ural 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 PPARy, a well-known transcriptional regulator of the immune response. Pretreating rats with PPARy inhibitor, BADGE, reduced the reno-protective activity of MF. Furthermore, MF treatment sig-nificantly reduced MTX-induced upregulation of the pro-inflammatory (NFKB, interleukin-1 ss, TNF-a, 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-y-dependent manner.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).