Atrial natriuretic peptide attenuates ANG II-induced hypertrophy of renal tubular cells

ANG II arrests LLC-PK1 cells in the G(1) phase of the cell cycle and induce s hypertrophy, an effect mediated by induction of p27(Kip1). We studied whe ther atrial natriuretic peptide (ANP) may modulate ANG II-induced hypertrop hy and p27(Kip1) expression in tubular LLC-PK1 cells. ANP, through its frag ments 3-28 and 4-27, prevented ANG II-induced cell cycle arrest. ANP inhibi ted >80% of ANG II-induced p27(Kip1) protein expression (Western blots). AN P stimulated expression of MKP-1, a phosphatase involved in dephosphorylati on of p44/42 mitogen-activated protein (MAP) kinase, up to 12 h. ANP preven ted the ANG II-mediated phosphorylation peak of MAP kinase after 12 h of st imulation. 8-Bromo-cGMP mimicked all the effects of ANP. Transfection with MKP-1 antisense, but not sense, oligonucleotides abolished the modifying ro le of ANP on ANG II-mediated cell cycle arrest. The effect of ANP on ANG II -mediated hypertrophy of LLC-PK1 cells is regulated on the level of MAP kin ase phosphorylation, a key step in the induction of p27(Kip1). Although ANP and ANG II both stimulate generation of reactive oxygen species, ANP addit ionally induces expression of MKP-1, leading to interference with ANG II-me diated MAP kinase phosphorylation.