title: Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy.
abstract: Alternative medicines are commonly used for the disease prevention and treatment worldwide. Aristolochic acid (AAI) nephropathy (AAN) is a common and rapidly progressive interstitial nephropathy caused by ingestion of Aristolochia herbal medications. Available data on pathophysiology and molecular mechanisms of AAN are limited and were explored here. SD rats were randomized to AAN and control groups. AAN group was treated with AAI by oral gavage for 12 weeks and observed for additional 12 weeks. Kidneys were processed for histological evaluation, Western blotting, and metabolomics analyses using UPLC-QTOF/HDMS. The concentrations of two phosphatidylcholines, two diglycerides and two acyl-carnitines were significantly altered in AAI treated rats at week 4 when renal function and histology were unchanged. Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-κB, TGF-β, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides. In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology. These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN.
authors.affiliation: 1] Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, the College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China [2] Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine, MedSci 1, C352, UCI Campus, Irvine, California, 92897, USA.
authors.forename: Ying-Yong
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Department of nephrology, Shanghai Jimin Hospital, No. 338 Huaihai West Road, Shanghai 200052, China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: National Institutes for Food and Drug Control, State Food and Drug Administration, No. 2 Tiantan Xili, Beijing, 100050, China.
authors.forename: Xian-Long
authors.initials: XL
authors.lastname: Cheng
authors.affiliation: National Institutes for Food and Drug Control, State Food and Drug Administration, No. 2 Tiantan Xili, Beijing, 100050, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.affiliation: Solution Centre, Waters Technologies (Shanghai) Ltd., No. 1000 Jinhai Road, Shanghai 201203, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Bai
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 11 North Third Ring Road, Beijing 100029, China.
authors.forename: Rui-Chao
authors.initials: RC
authors.lastname: Lin
authors.affiliation: Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine, MedSci 1, C352, UCI Campus, Irvine, California, 92897, USA.
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000502:physiology*; D008297:Male; D055432:Metabolomics / Q000379:methods; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014280:Triglycerides
chemical_list: D034341:Aristolochic Acids; D008055:Lipids; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D016212:Transforming Growth Factor beta; D014280:Triglycerides; C000228:aristolochic acid I