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Human kininogen gene is transactivated by the farnesoid X receptor Zhao A; Lew JL; Huang L; Yu J; Zhang T; Hrywna Y; Thompson JR; de Pedro N; Blevins RA; Pelaez F; Wright SD; Cui JJ Biol Chem 2003[Aug]; 278 (31): 28765-70Human kininogen belongs to the plasma kallikreinkinin system. High molecular weight kininogen is the precursor for two-chain kinin-free kininogen and bradykinin. It has been shown that the two-chain kinin-free kininogen has the properties of anti-adhesion, anti-platelet aggregation, and anti-thrombosis, whereas bradykinin is a potent vasodilator and mediator of inflammation. In this study we show that the human kininogen gene is strongly up-regulated by agonists of the farnesoid X receptor (FXR), a nuclear receptor for bile acids. In primary human hepatocytes, both the endogenous FXR agonist chenodeoxycholate and synthetic FXR agonist GW4064 increased kininogen mRNA with a maximum induction of 8-10-fold. A more robust induction of kininogen expression was observed in HepG2 cells, where kininogen mRNA was increased by chenodeoxycholate or GW4064 up to 130-140-fold as shown by real time PCR. Northern blot analysis confirmed the up-regulation of kininogen expression by FXR agonists. To determine whether kininogen is a direct target of FXR, we examined the sequence of the kininogen promoter and identified a highly conserved FXR response element (inverted repeat, IR-1) in the proximity of the kininogen promoter (-66/-54). FXR/RXRalpha heterodimers specifically bind to this IR-1. A construct of a minimal promoter with the luciferase reporter containing this IR-1 was transactivated by FXR. Deletion or mutation of this IR-1 abolished FXR-mediated promoter activation, indicating that this IR-1 element is responsible for the promoter transactivation by FXR. We conclude that kininogen is a novel and direct target of FXR, and bile acids may play a role in the vasodilation and anti-coagulation processes.|*Transcriptional Activation[MESH]|Binding Sites[MESH]|Blotting, Northern[MESH]|Carcinoma, Hepatocellular/metabolism[MESH]|Chenodeoxycholic Acid/pharmacology[MESH]|DNA-Binding Proteins/agonists/*physiology[MESH]|DNA/metabolism[MESH]|Gene Deletion[MESH]|Gene Expression Regulation/drug effects[MESH]|Hepatocytes/metabolism[MESH]|Humans[MESH]|Isoxazoles/pharmacology[MESH]|Kininogens/*genetics[MESH]|Liver Neoplasms/metabolism[MESH]|Mutagenesis, Site-Directed[MESH]|Polymerase Chain Reaction[MESH]|Promoter Regions, Genetic/genetics[MESH]|RNA, Messenger/analysis[MESH]|Receptors, Cytoplasmic and Nuclear[MESH]|Receptors, Retinoic Acid/physiology[MESH]|Repetitive Sequences, Nucleic Acid[MESH]|Retinoid X Receptors[MESH]|Transcription Factors/agonists/*physiology[MESH]|Transfection[MESH]|Tumor Cells, Cultured[MESH] |
