title: JNK-dependent AP-1 activation is required for aristolochic acid-induced TGF-β1 synthesis in human renal proximal epithelial cells.
abstract: Chronic aristolochic acid nephropathy (CAAN) is a chronic and progressive tubulointerstitial nephropathy characterized by extensive interstitial fibrosis. Aristolochic acid (AA) could induce overexpression of transforming growth factor-β1 (TGF-β1) in a human renal proximal tubule epithelial cells line (HKC), which has been implicated in the pathogenesis of CAAN. The present studies in HKC cells showed 1) AA could activate JNK in time- and dose-dependent manners and JNK inhibitor SP600125 could inhibit AA-induced TGF-β1 promoter activity and TGF-β1 synthesis; 2) AA-induced JNK activation and TGF-β1 synthesis were significantly inhibited by kinase-inactive mutants of MEKK4, MKK4, or MKK7; 3) AA could upregulate luciferase activity derived by a wild-type TGF-β1 promoter, but not by an AP-1 binding-deficient TGF-β1 promoter; and 4) AA could upregulate expression of c-Fos, phospho-c-Jun, and phospho-ATF2. The above data suggest AA-induced TGF-β1 overexpression in HKC cells may be mainly mediated by the JNK signaling pathway. Both the upstream kinases of JNK including MEKK4, MKK4, and MKK7, and the downstream transcription factor of JNK, AP-1, may also participate in this process.
authors.affiliation: Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
authors.forename: Hong-liang
authors.initials: HL
authors.lastname: Rui
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Yi-pu
authors.initials: YP
authors.lastname: Chen
mesh_terms: D034341:Aristolochic Acids / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
chemical_list: D034341:Aristolochic Acids; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; C000228:aristolochic acid I; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4