Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis and Nrf2 dysfunction in aristolochic acid-induced nephropathy

• Published in: Scientific reports Vol. 5; no. 1; p. 12936
• Main Authors: Zhao, Ying-Yong, Wang, Hui-Ling, Cheng, Xian-Long, Wei, Feng, Bai, Xu, Lin, Rui-Chao, Vaziri, Nosratola D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2015; Nature Publishing Group
• Subjects: 631/553/2711; 692/699/1585/3182; Animals; Aristolochic acid; Aristolochic Acids - pharmacology; Disease Models, Animal; Fibrosis; Fibrosis - metabolism; Histology; Humanities and Social Sciences; Inflammation - metabolism; Ingestion; Kidney - drug effects; Kidney - metabolism; Kidneys; Lipid metabolism; Lipids; Lipids - physiology; Male; Metabolites; Metabolomics; Metabolomics - methods; Molecular modelling; multidisciplinary; Nephritis, Interstitial - chemically induced; Nephritis, Interstitial - metabolism; Nephropathy; NF-E2-Related Factor 2 - metabolism; NF-kappa B; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pathogenesis; Phospholipids; Rats; Rats, Sprague-Dawley; Renal function; Rodents; Science; Transforming Growth Factor beta - metabolism; Triglycerides; Western blotting
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep12936

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.