Abstract
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.
Copyright 2000 Academic Press.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiotensin II / metabolism
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Animals
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Atrial Natriuretic Factor / metabolism
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Cell Division
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Cells, Cultured
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Cyclic GMP / metabolism
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Cyclic GMP-Dependent Protein Kinases / physiology*
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Endothelin-1 / metabolism
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Enzyme Inhibitors / metabolism
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Fibroblast Growth Factors / metabolism
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Glomerular Mesangium / cytology
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Glomerular Mesangium / metabolism*
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Guanylate Cyclase / antagonists & inhibitors
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Guanylate Cyclase / metabolism*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Peptide Fragments / metabolism
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Platelet-Derived Growth Factor / metabolism
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Precipitin Tests
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Protein Kinase Inhibitors
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Protein Kinases / metabolism
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Rats
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Receptors, Atrial Natriuretic Factor / antagonists & inhibitors
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Receptors, Atrial Natriuretic Factor / metabolism*
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Tetrahydroisoquinolines
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Thymidine / metabolism
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Time Factors
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Transfection
Substances
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Endothelin-1
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Enzyme Inhibitors
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Peptide Fragments
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Platelet-Derived Growth Factor
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Protein Kinase Inhibitors
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Tetrahydroisoquinolines
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Angiotensin II
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A 71915
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Fibroblast Growth Factors
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Atrial Natriuretic Factor
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Protein Kinases
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Cyclic GMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Guanylate Cyclase
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Receptors, Atrial Natriuretic Factor
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atrial natriuretic factor receptor A
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Cyclic GMP
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Thymidine