Aryl hydrocarbon receptor-mediated suppression of expression of the low-molecular-weight prekininogen gene in mice

Differential mRNA display showed that a cDNA band disappeared after treatme nt of mice with 3-methylcholanthrene (MC). The cDNA encoded low-molecular-w eight (LMW) prekininogen, known to be the precursor of a potent vasodilator , bradykinin. MC is generally known to bind to aryl hydrocarbon receptor (A hR) as an initial event to cause effects in vivo. In accordance with the re sults, Northern blot analysis for LMW prekininogen mRNA using total RNAs fr om wild-type and AhR-null mice indicated that the suppression of the mRNA e xpression by MC was seen in wild-type mice but not in AhR-null mice. The ex pression of LMW prekininogen mRNA was almost completely lost within I h aft er treatment of mice with MC, while a clear increase of CYP1A2 mRNA, as a p ositive control, was noted 4 h after the treatment. The plasma concentratio n of bradykinin released from LMW prekininogen was decreased by MC in wild- type mice, but not in AhR-null mice. Based on these results, we conclude th at AhR inhibits bradykinin synthesis in mice via suppression of the express ion of LMW prekininogen. Possible mechanism(s) responsible for hypertension caused by treatment of mice with MC is also discussed. (C) 2001 Academic P ress.