C-type natriuretic Peptide down-regulates expression of its cognate receptor in rat aortic smooth muscle cells.
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.
Rahmutula
Dolkun
D
Department of Medicine and Diabetes Center, 1109 HSW, University of California at San Francisco, San Francisco, California 94143-0540, USA.
Gardner
David G
DG
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D015536:Down-Regulation; D004338:Drug Combinations; D006162:Guanylate Cyclase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D000099242:Atrial Natriuretic Factor Receptor B
D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP; D004247:DNA; D004338:Drug Combinations; D006162:Guanylate Cyclase; D020098:Natriuretic Peptide, C-Type; D012333:RNA, Messenger; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B; C016276:8-bromocyclic GMP; C091715:atrial natriuretic factor receptor A