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 guanylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated protein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity in rat mesangial cells overexpressing NPRA. Agonist hormones such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunoreactive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated activity of MAPK/ERK2 by 65-75% in cells overexpressing NPRA, whereas in vector-transfected cells, its inhibitory effect was only 18-20%. NPRA antagonist A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activity. ANP also inhibited the PDGF-stimulated [(3)H]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20-25% inhibition in vector-transfected cells. These results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cells in a PKG-dependent manner.
Pandey
K N
KN
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA. kpandey@mailhost.tcs.tulane.edu
Nguyen
H T
HT
Li
M
M
Boyle
J W
JW
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D019332:Endothelin-1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011233:Precipitin Tests; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D044005:Tetrahydroisoquinolines; D000804:Angiotensin II; C078792:A 71915; D005346:Fibroblast Growth Factors; D009320:Atrial Natriuretic Factor; D011494:Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP; D013936:Thymidine