Natriuretic peptide receptor-A negatively regulates mitogen-activated protein kinase and proliferation of mesangial cells: Role of cGMP-dependent protein kinase

We have examined the effect of atrial natriuretic peptide (ANP) and its gua nylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated pr otein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity i n rat mesangial cells overexpressing NPRA. Agonist hormones such as platele t-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunorea ctive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated a ctivity of MAPK/ERK2 by 65-75% in cells overexpressing NPRA, whereas in vec tor-transfected cells, its inhibitory effect was only 18-20%. NPRA antagoni st A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activi ty. ANP also inhibited the PDGF-stimulated [H-3]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20-25% inhibition i n vector-transfected cells. These results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cell s in a PKG-dependent manner. (C) 2000 Academic Press.