DESTABILIZATION OF NATRIURETIC PEPTIDE C-RECEPTOR MESSENGER-RNA BY PHORBOL-MYRISTATE ACETATE

Natriuretic peptide C receptor (NPR-C) expression in rat mesangial cel ls is downregulated by platelet-derived growth factor (PDGF) and the p rotein kinase C agonist phorbol myristate acetate (PMA). This study sh ows that PDGF and PMA diminish NPR-C mRNA abundance and that PMA does so by accelerating the degradation of the transcript. Exposure to PMA (0.1 mu M) decreased mesangial cell NPR-C mRNA levels by more than 50% within 3 h and I-125-atrial natriuretic peptide binding by approximat ely 50% within 6 h. Disappearance of NPR-C transcripts after PMA treat ment was more than twice as rapid as that seen after inhibition of RNA transcription with actinomycin D. Treatment with PDGF A/B (10 ng/ml) also produced downregulation of NPR-C mRNA, but the rate of transcript disappearance was similar to that seen after actinomycin D. Coincubat ion with actinomycin D inhibited the rapid disappearance of NPR-C mRNA with PMA. NPR-C mRNA levels increased four-to eightfold within 6 h af ter treatment with the protein synthesis inhibitor cycloheximide, but simultaneous treatment with PMA or PDGF still decreased the level of N PR-C mRNA despite the presence of cycloheximide. These results indicat e that NPR-C expression is rapidly regulated by changes in the rate of catabolism of its mRNA through a protein kinase C-activated mechanism that depends on transcription. Treatment with cycloheximide induces N PR-C mRNA, but downregulation of this mRNA by either PDGF or PMA does not depend on synthesis of new protein.