Guanylyl cyclase/natriuretic peptide receptor-A signaling antagonizes the vascular endothelial growth factor-stimulated MAPKs and downstream effectors AP-1 and CREB in mouse mesangial cells

摘要: Along with its natriuretic, diuretic, and vasodilatory properties, atrial natriuretic peptide (ANP), guanylyl cyclase/natriuretic receptor-A (GC-A/NPRA) exhibit an inhibitory effect on cell growth proliferation. However, the signaling pathways mediating this inhibition are not well understood. The objective of study was to determine ANP–NPRA system mitogen-activated protein kinases (MAPKs) downstream proliferative transcription factors involving activating protein-1 (AP-1) cAMP-response element binding (CREB) in agonist-stimulated mouse mesangial cells (MMCs). We found that ANP inhibited vascular endothelial factor (VEGF)-stimulated phosphorylation MAPKs (Erk1, Erk2, JNK, p38), a greater extent NPRA-transfected (50–60 %) relative vector-transfected (25–30 %). analyses phosphorylated revealed VEGF-stimulated activation CREB, AP-1 subunits (c-jun c-fos). Gel shift assays demonstrated CREB DNA-binding ability by 67 62 %, respectively. addition kinase G (PKG) inhibitor, KT-5823, restored MAPKs, AP-1, demonstrating integral role cGMP/PKG NPRA-mediated effects. Our results delineate underlying mechanisms through which ANP-NPRA exerts down-stream effector molecules, critical for