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PPARα agonist protects Aristolochic acid‐induced nephropathy by increasing mediated lipid metabolism (LB554)
Author(s) -
Yeh ChingHua,
Wei TsuiShan,
Hsing ChungHsi
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb554
Subject(s) - clofibrate , lipid metabolism , cd36 , chemistry , endocrinology , medicine , kidney , lipotoxicity , pharmacology , receptor , insulin resistance , insulin
Backgrounds: Aristolochic acids is a nephrotoxic compounds found in some Chinese herbal medicine which induces aristolochic acids‐induced nephropathy (AAN). This study aimed to investigate the role of PPARα□and it mediated lipid metabolism in AAN. Materials and Methods: In vivo, mice were intreperitoneally injected with AA 5 mg/kg for continuous five days to induce AAN. Clofibrate (150 mg/kg) and statin (1 mg/kg) were administrated by gavage for two weeks before AA injection. Kidney injury and renal function changes were observed in AAN mice. The gene expression related to lipid metabolism as well as inflammation, fibrosis and cell death in the kidney of AAN mice were analyzed by RT‐PCR and western blot. In vitro, PPARα□and cellular lipid regulating gene changes in rat renal tubular (NRK52E) cell were analyzed under AA stimulation with or without PPARα□agonists including clofibrate, fenofibrate and OEA treatment. The protective effects of statin or clofibrate on cell viability were determined by MTT and LDH assays. The biomarkers for renal damage such as BMP‐7, Bcl‐xL, caspase 3 and connexin 43 were also analyzed. Results: In the AA‐injected mice, clofibrate, but not statin, improved the renal function and increase the renal PPARα expression. Clofibrate recovered the expression of lipid metabolism‐related genes such as adipocyte protein 2(aP2), lipoprotein lipase(LpL), CD36, fatty acid synthase(FAS) and ApoE in the kidney of mice which decreased by AA treatment. In addition, clofibrate treatment decreased inflammatory genes, TNF‐α, IL‐1β, MCP‐1, iNOS, Cox‐1 and Cox‐2 in the kidney of AAN mice. Moreover, clofibrate increased renal expression of BMP‐7, Bcl‐xL and connexin 43 expression while reduced TGF‐β, collagen IV, fibronectin, RAGE and caspase 3 in AAN mice. In AA‐stimulated NRK52Es, PPARα agonists prevented AA‐induced renal cell death, inflammation and abnormality of lipid metabolism. The renal protective effect of PPARα in NRK52E cell was blocked by treating with PPARα antagonist, MK886. Conclusion: Clofibrate could attenuates aristolochic acid nephropathy by increasing PPARα activity and it mediated lipid metabolism.