Interaction of nobiletin with methotrexate ameliorates 7-OH methotrexate-induced nephrotoxicity through endoplasmic reticulum stress-dependent PERK/CHOP signaling pathway. (March 2021)

• Record Type: Journal Article
• Authors: Song, Yurong; Liu, Linlin; Liu, Bin; Liu, Rui; Chen, Youwen; Li, Chenxi; Liu, Guangzhi; Song, Zhiqian; Lu, Cheng; Lu, Aiping; Liu, Yuanyan
• Is Part Of: Pharmacological research. Volume 165(2021)
• Publication Date: 2021-03
• Subjects: Methotrexate (PubChem CID: 126941) -- Nobiletin (PubChem CID: 72344) -- 7−OH Methotrexate (PubChem CID: 5484402); 7−OH MTX -- Acute kidney injury -- Endoplasmic reticulum stress -- Nobiletin -- PERK/CHOP signaling pathway; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105371
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: The 7−OH MTX was the main culprit for MTX nephrotoxicity. PERK/CHOP mediated ER stress was screened as key pathway by RNA-seq analysis. Nobiletin could ameliorate the nephrotoxicity of 7−OH MTX through PERK/CHOP pathway. Nobiletin could maintain Ca 2+ homeostasis and reduce the production of ROS. Abstract: Drug-induced nephrotoxicity is a frequent adverse event that contributes to acute kidney injury with tubular and/or glomerular lesions. Methotrexate (MTX) is a folate analog used against a myriad of malignancies and autoimmune diseases. Unfortunately, ambiguous renal toxicology limits its safe clinical usage. Based on our previous studies, 7−OH MTX as an overlooked oxidative metabolite of MTX was proposed to be the main culprit responsible for nephrotoxicity, while nobiletin, a naturally occurring polymethoxylated flavonoid screened from our prepared total phenolic extracts of Citrus aurantium L. (TPE-CA), was employed as a therapeutic agent for drug-drug interactions. According to the present study, nobiletin can ameliorate the renal accumulation of 7−OH MTX through the interaction with aldehyde oxidase. RNA-seq analysis revealed that 7−OH MTX was mainly related to protein processing in endoplasmic reticulum (ER) stress, with the PERK/CHOP pathway selected as the most significant for metabolic nephrotoxicity. Meanwhile, the cross-linked proteins and conducted signals were investigated by western blotting and further verified by GSK inhibition analyses. These results indicated that nobiletin protected renal function from MTX-induced nephrotoxicity by modulating metabolism and ameliorated the metabolic toxicity of 7−OH MTX on ER stress-induced PERK/CHOP conduction by maintaining Ca 2+ homeostasis and reducing the production of reactive oxygen species.