Nephrotoxicity is the major dose-limiting adverse effect of methotrexate (MTX). Umbelliferone (UMB) is a known coumarin derivative. The current study aimed to investigate possible protective effects of UMB against MTX-induced nephrotoxicity. Adult male albino rats were divided into: control group, UMB group (30 mg/kg, p.o), MTX group (single i.p. injection of 20 mg/kg) and MTX + UMB group. Serum urea and creatinine were evaluated. The renoprotective effects of UMB were evaluated by estimation of renal Nrf-2/Keap-1 and P₃₈MAPK/NF-κB, GSH, MDA, NO₂⁻ contents and SOD activity. Moreover, expression of Bcl-2, Bax and caspase-3 were determined. The results demonstrated that UMB significantly reduced serum creatinine and urea levels with alleviations of histopathological abrasions induced by MTX. It limited oxidative stress via lowering both renal MDA and NO₂⁻ contents and restoring renal content of reduced GSH and SOD activity with downregulation of Keap-1 and upregulation of Nrf-2. UMB downregulated P₃₈MAPK and NF-κB expression levels. In addition, UMB increased Bcl-2 protein expression while decreasing both Bax and caspase-3 expression levels. Importantly, UMB enhanced the cytotoxic activity of MTX human cancer cell lines. In conclusion, UMB possess marked renoprotective effects against MTX-induced renal damage through modulating oxidative stress, inflammation and apoptosis with enhancement of its cytotoxic activity.

肾毒性是甲氨蝶呤（MTX）的主要剂量限制性副作用。伞形酮（UMB）是一种已知的香豆素衍生物。当前的研究旨在调查UMB对MTX诱导的肾毒性的可能的保护作用。成年雄性白化病大鼠分为：对照组，UMB组（30 mg / kg，口服），MTX组（单次ip注射20 mg / kg）和MTX + UMB组。评估血清尿素和肌酐。UMB的肾脏保护作用是由肾的Nrf-2的估计评价/ Keap-1和P ₃₈ MAPK / NF-κB，GSH，MDA，NO ₂ ^-含量和SOD活性。此外，测定了Bcl-2，Bax和caspase-3的表达。结果表明，UMB显着降低了血清肌酐和尿素水平，减轻了MTX引起的组织病理学擦伤。它通过降低两肾MDA和NO限于氧化应激₂ ^-含量和恢复与Keap-1的下调和上调的Nrf-2的还原型GSH和SOD活性的肾内容。UMB下调P ₃₈MAPK和NF-κB表达水平。此外，UMB增加了Bcl-2蛋白的表达，同时降低了Bax和caspase-3的表达水平。重要的是，UMB增强了MTX人类癌细胞系的细胞毒活性。总之，UMB通过调节氧化应激，炎症和细胞凋亡并增强其细胞毒性活性，对MTX诱导的肾脏损害具有明显的肾脏保护作用。