C-type natriuretic Peptide down-regulates expression of its cognate receptor in rat aortic smooth muscle cells

Endocrinology. 2005 Nov;146(11):4968-74. doi: 10.1210/en.2005-0262. Epub 2005 Aug 18.


The C-type natriuretic (CNP) peptide signals through the type B natriuretic peptide receptor (NPR-B) in vascular smooth muscle cells to activate the particulate guanylyl cyclase activity intrinsic to that receptor and raise cellular cyclic GMP levels. In the present study, we demonstrate that CNP down-regulates the expression of this receptor leading to a reduction in NPR-B activity. Pretreatment of rat aortic smooth muscle cells with CNP reduces NPR-B activity, NPR-B protein levels, NPR2 (NPR-B gene) mRNA levels, and NPR2 promoter activity. The decrease in NPR2 promoter activity is dependent on DNA sequence present between -441 and -134 relative to the transcription start site. The reduction in NPR2 gene expression appears to operate through generation of cyclic GMP. 8-Bromo cyclic GMP, a membrane-permeable cyclic GMP analog, reduced NPR2 mRNA levels and NPR2 promoter activity. Atrial natriuretic peptide, which signals through the type A natriuretic peptide receptor (NPR-A) to increase cyclic GMP levels in these cells, also reduced NPR-B mRNA levels and inhibited NPR-B promoter activity; however, this inhibition was not additive with that produced by CNP, implying that the two ligands traffic over a common signal transduction pathway. This report provides the first documentation that CNP is capable of autoregulating the expression of its cognate receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / metabolism*
  • Atrial Natriuretic Factor / pharmacology
  • Cells, Cultured
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / metabolism
  • Cyclic GMP / pharmacology
  • DNA / genetics
  • Down-Regulation*
  • Drug Combinations
  • Guanylate Cyclase / drug effects
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / metabolism*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / metabolism*
  • Natriuretic Peptide, C-Type / pharmacology*
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Atrial Natriuretic Factor / drug effects
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / metabolism*
  • Transcription Initiation Site


  • Drug Combinations
  • RNA, Messenger
  • Natriuretic Peptide, C-Type
  • 8-bromocyclic GMP
  • Atrial Natriuretic Factor
  • DNA
  • Guanylate Cyclase
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A
  • atrial natriuretic factor receptor B
  • Cyclic GMP