Curcumin treatment attenuates methotrexate-induced nephrotoxicity in rats by inhibiting inflammation and fibrosis.

The present study aimed to investigate the protective effects of curcumin (CMN) against methotrexate (MTX)-induced nephrotoxicity in rats. Eighteen male Wistar albino rats were randomly assigned to three equal groups. The control group received 1 mL/kg dimethyl sulfoxide intragastrically for 14 days. The MTX group received a single intraperitoneal dose of 20 mg/kg of MTX on the eleventh day of the experiment. MTX + CMN group received 100 mg/kg/day of CMN (dissolved in dimethyl sulfoxide) intragastrically for 14 days and a single intraperitoneal dose of 20 mg/kg of MTX on day eleven. At the end of the experiment, samples were collected for biochemical, histological and immunohistochemical analyses. MTX administration significantly elevated serum levels of urea, creatinine, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and induced marked histological damage and renal fibrosis compared to the control group. Immunohistochemical analysis revealed significantly increased immunoreactivity of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor-kappa B (NFkB), tumor necrosis factor-alpha (TNFα), and prokineticin-2 (PK2) in the MTX group compared to control group. In contrast, nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) immunoreactivity were markedly reduced. CMN treatment significantly improved biochemical and histological alterations and reduced collagen deposition in renal tissue. Furthermore, CMN markedly attenuated NFkB, TNFα, PK2, and Keap1 immunoreactivity, while enhancing Nrf2/HO-1 immunoreactivity induced by MTX administration. These findings suggest that CMN may serve as a potential therapeutic strategy for mitigating MTX-induced nephrotoxicity through anti-inflammatory, antioxidant, and antifibrotic mechanisms, possibly mediated by modulation of NFkB, TNFα, PK2, and Keap1/Nrf2/HO-1 signaling pathways.