Involvement of NOD1/NF-κB/MAPK pathway in the protective effect of procyanidin B2 against methotrexate-induced nephrotoxicity
Objective Methotrexate (MTX) is a very effective agent used to treat rheumatoid arthritis and malignant diseases. Despite its usefulness, the long-term use of MTX is associated with multiorgan toxicities, including kidney injury. Thus, there is a necessity to explore a renoprotective agent with low side effects. Procyanidin B2 (PCB2), a natural flavonoid, possesses antioxidant and anti-inflammatory activities. This study aims to investigate the potential protective efficacy of PCB2 against MTX-induced nephrotoxicity. Methods Rats were allocated into four groups: control group, PCB2 group (40 mg/kg, p.o), MTX-intoxicated group (20 mg/kg, i.p.), and PCB2+MTX group. PCB2 was administered daily for ten days, while MTX was injected as a single dose on day 8. Oxidative stress and inflammatory biomarkers in kidney tissues were assessed using biochemical, histological, and immunohistochemical examinations. Results MTX markedly elevated the levels of kidney malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), while glutathione (GSH) level and superoxide dismutase (SOD) activity were significantly reduced. In addition, rats intoxicated with MTX exhibited positive and strong immunoreactions for nucleotide-binding oligomerization domain 1 (NOD1), nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinase (MAPK). The administration of PCB2 significantly prevented tissue injury and restored the altered parameters. Conclusions PCB2 reduced oxidative stress and inflammatory responses, indicating potential protective effects against MTX-induced kidney damage.