Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2/Keap-1, P38MAPK/NF-κB, and apoptosis signaling pathways. (June 2018)

• Record Type: Journal Article
• Authors: Hassanein, Emad H.M.; Mohamed, Wafaa R.; Shalkami, Abdel-Gawad S.; Khalaf, Marwa M.; Hemeida, Ramadan A.M.
• Is Part Of: Food and chemical toxicology. Volume 116:Part B(2018)
• Page Start: 152
• Page End: 160
• Publication Date: 2018-06
• Subjects: Umbelliferone -- Methotrexate -- Nephrotoxicity -- Oxidative stress -- NF-kB -- Apoptosis; MTX Methotrexate -- UMB Umbelliferone -- ROS Reactive Oxygen Species -- NADPH nicotinamide adenine dinucleotide phosphate -- GSH reduced glutathione -- MDA malondialdhyde -- NO2 nitrite -- SOD superoxide dismutase -- qRT-PCR quantitative real time-polymerase chain reaction -- Nrf-2 nuclear factor erythroid 2–related factor 2 -- Keap-1 Kelch-like ECH-associated protein 1 -- P38MAPK P38 mitogen activated protein kinase -- NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells -- H&E hematoxylin and eosin -- Bcl-2 B-cell lymphoma 2 -- Bax Bcl-2-Associated-X-protein; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.03.041
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: 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 P38 MAPK/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 P38 MAPK 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. Highlights: Umbellifrone mitigated methotrexate-evoked increase of serum creatinine and BUN. Umbellifrone attenuated the renal histopathologic damage. Umbellifrone suppressed renal MDA, NO2 −, Keap-1 while elevated renal GSH, SOD and Nrf-2. Umbellifrone downregulated P38 MAPK and NF-κB levels. Umbellifrone downregulated Bax and caspase-3 expression while upregulated Bcl-2 expression.