Atrial natriuretic peptide suppresses the transcription of its guanylyl cyclase-linked receptor.
Atrial natriuretic peptide (ANP) treatment of rat aortic smooth muscle cells suppressed both 125I-ANP binding and ANP-dependent cGMP accumulation, suggesting reductions in the type C (NPR-C) and type A (NPR-A) natriuretic peptide receptor populations, respectively. NPR-A, but not NPR-C, mRNA levels were reduced in a dose-dependent fashion by ANP. The latter effect appeared to be due, at least in part, to suppression of NPR-A gene promoter activity. ANP effected a dose- and time-dependent reduction in a transiently transfected NPR-A luciferase reporter (-1575LUC). Analysis of 5' deletion mutants of the NPR-A promoter demonstrated that the ANP-dependent sequence lies between -1575 and -1290 relative to the transcription start site. Inhibition of the ANP promoter was also effected by brain natriuretic peptide, type C natriuretic peptide, and 8-bromo-cGMP, but not by the NPR-C-selective ligand cANF. In the case of 8-bromo-cGMP, the responsive element(s) was localized to the same 285-base pair region linked to the ANP effect above. These findings indicate that ANP autoregulates its own receptors in these cells and, at least in the case of NPR-A, it does so through suppression of receptor gene expression and receptor synthesis. This suppression may operate through a cGMP-dependent element located more than a kilobase upstream from the transcription start site.
Cao
L
L
Metabolic Research Unit, University of California, San Francisco 94143, USA.
Wu
J
J
Gardner
D G
DG
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*
D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP