The renin-angiotensin system plays a key role in the regulation of blood pressure. Angiotensinogen (ANG), mainly synthesized in the liver, is the first substrate of renin-angiotensin system. We had previously found that hepatocyte nuclear factor 4 (HNF-4) dramatically activates the human ANG promoter. It is generally known that HNF-4 and peroxisome proliferator-activated receptor α (PPARα) bind to response elements composed of two core motifs, RG(G/T)TCA, or a closely related sequence separated by 1 nucleotide (DR1 element). To examine whether or not PPARα activates the human ANG promoter, we used the reporter gene containing the sequence from −1222 to +44 of the human ANG gene promoter. PPARα and RXR heterodimer activated this promoter, and the PPARα responsive region was the same site that we had previously mapped as a binding site for HNF-4. Although the human ANG promoter was not induced by PPARα ligand bezafibrate in HepG2 cells, this reporter gene was inducible by bezafibrate treatment in HeLa cells, which do not express endogenous HNF-4. We suspected that the high level expression of HNF-4 in HepG2 cells might interfere with the effect of bezafibrate on the human ANG promoter. To confirm this model, we cotransfected HNF-4 expression vector with PPARα expression vector into HeLa cells. The bezafibrate-dependent activation of the ANG promoter was inhibited by HNF-4. These results suggest that PPARα and HNF-4 competitively affect the human ANG promoter through the C region.

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