title: A nuclear receptor, hepatocyte nuclear factor 4, differently contributes to the human and mouse angiotensinogen promoter activities.
abstract: Angiotensinogen (AGT), mainly produced in the liver, is the precursor of angiotensin II, an important regulator of blood pressure and electrolyte homeostasis. We previously showed, in hepatoma-derived HepG2 cells that a hepatocyte nuclear factor 4 (HNF4) potentiated human AGT (hAGT) promoter activity and identified its binding sites (termed regions C and J) in the hAGT promoter region. We also showed in transgenic mouse (TgM) that the hAGT is abundantly expressed in the kidney where the level of endogenous mouse AGT (mAGT) expression is low. To elucidate molecular mechanisms of the AGT gene activation in the kidney, we first investigated the HNF4 and AGT expression in the mouse kidney. Northern blot, in situ hybridization and immunohistochemical analyses revealed that the hAGT and HNF4 were both expressed in the proximal tubular (PT) cells of the kidney. We then transfected the hAGT reporter constructs into immortalized mouse PT (mProx) cells and found that regions C and J contributed additively to the HNF4-potentiated hAGT promoter activity. Curiously, no obvious HNF4 binding motif was found in the corresponding region of the mAGT promoter and co-transfected HNF4 failed to activate this promoter in neither HepG2 nor mProx cells. These results suggest that the high-level hAGT expression in the TgM kidney is, at least in part, due to a presence of high-affinity HNF4 binding sites in its promoter.
authors.affiliation: Graduate School of Life and Environmental Sciences, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Oishi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Date
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimamoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito
authors.forename: Keiko
authors.initials: K
authors.lastname: Hirota
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kon
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
mesh_terms: D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D000808:Angiotensinogen