Angiotensin II inhibits renin gene transcription via the protein kinase C pathway.
Angiotensin II (ANGII) inhibits renin gene expression in vivo, a mechanism considered to be a physiologically important negative feedback of the renin-angiotensin-system. How this particular effect of ANGII is achieved at the cellular level is unknown. Our study therefore aimed to determine whether ANGII exerts a direct effect on renin gene expression and, if so, to characterise the molecular mechanisms involved. In the mouse renal juxtaglomerular cell line As4.1, ANGII decreased steady-state renin mRNA levels and prorenin secretion time and concentration (EC(50) 100 nmol/l) dependently. The effects of ANGII were blunted by the protein kinase C (PKC) inhibitor bisindolylmaleimide I and mimicked by the PKC activator phorbol 12-myristate-13-acetate (PMA) (EC(50) 10 nmol/l). ANGII also inhibited renin promoter activity PKC-dependently. The inhibitory sequences triggered by ANGII appear to reside within the first 2.9 kb in the 5'-flanking region of the mouse ren1c gene but are not related to the two canonical activator protein-1 (AP-1) binding sites at positions -16 to -22 and -141 to -147. In summary, our data suggest that ANGII acts directly on renal juxtaglomerular cells to inhibit renin gene transcription through the PKC pathway. Since the PKC pathway can be activated by a variety of hormones it represents a powerful and probably rather important downstream pathway in the control of renin gene expression.
Institut für Physiologie, Universität Regensburg, 93040 Regensburg, Germany.
Markus W H
MW
Müller
Vladimir
V
Todorov
Bernhard K
BK
Krämer
Armin
A
Kurtz
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D007606:Juxtaglomerular Apparatus / Q000502:physiology*; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012083:Renin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D007211:Indoles; D008301:Maleimides; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D011493:Protein Kinase C; D012083:Renin; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate