1,25 dihydroxyvitamin d amplifies type a natriuretic peptide receptor expression and activity in target cells.
1,25 dihydroxyvitamin D (VD) has been shown to exert a number of beneficial effects on cardiovascular function, including reduction in BP and inhibition of cardiac hypertrophy. In an effort to identify a possible mechanistic link between VD and these salutary effects, the role of VD in controlling the activity and expression of the type A natriuretic peptide receptor (NPR-A), a receptor that signals reductions in BP and suppression of cellular growth in the myocardium and vascular wall, was investigated. VD, as well as the nonhypercalcemic analogue RO-25-6760, increased NPR-A-dependent cyclic guanosine monophosphate production and NPR-A gene expression in cultured rat aortic smooth muscle cells. The increase in NPR-A expression was associated with an increase in NPR-A gene promoter activity that was critically dependent on the presence of a functional VD receptor response element located approximately 495 bp upstream from the transcription start site of the gene. This element was associated with the VD receptor/retinoid X receptor complex in vitro. Mutation of this element resulted in complete elimination of the VD-dependent induction of the NPR-A gene promoter but did not affect osmotic stimulation of the promoter. Treatment of rats with RO-25-6760 for 7 d increased the atrial natriuretic peptide-dependent excretion of sodium and cyclic guanosine monophosphate without affecting mean arterial BP or plasma calcium levels. This was associated with a twofold increase in NPR-A mRNA levels in the inner medulla. Amplification of NPR-A activity represents a plausible mechanism to account for at least some of the beneficial effects that VD exerts on cardiovascular function.
Chen
Songcang
S
Diabetes Center, University of California at San Francisco, 3rd and Parnassus Avenue, San Francisco, CA 94143-0540, USA.
Ni
Xi-Ping
XP
Humphreys
Michael H
MH
Gardner
David G
DG
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006152:Cyclic GMP / Q000502:physiology; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000378:metabolism*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011336:Probability; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D014158:Transcription, Genetic / Q000187:drug effects*; D014807:Vitamin D / Q000494:pharmacology*
D012333:RNA, Messenger; C113532:Ro 25-6760; D014807:Vitamin D; D002762:Cholecalciferol; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP