Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis.
Angiotensin II (ANG II) induces cell-cycle arrest of cultured proximal tubular cells, resulting in cellular hypertrophy. This ANG II-mediated hypertrophy is associated with the induction of p27(Kip1), an inhibitor of G1 phase cyclin-dependent kinase cyclin complexes. We have recently demonstrated that ANG II-mediated expression of p27(Kip1) and induction of cellular hypertrophy depend on the generation of reactive oxygen species (ROS). The effects of ROS are mediated by stimulation of mitogen-activated protein (MAP) kinases. p44/42 MAP kinase directly phosphorylates p27(Kip1) at serine-threonine residues and increases thereby its half-life time. AT2-receptor activation has been implicated in apoptosis and/or cell differentiation. Recent studies, however, revealed a more indirect role of hypoxia in the antiproliferative effects of ANG II transduced through AT2 receptors. We found that SM-20 is down-regulated in ANG II-stimulated PC12 cells that express only AT2 receptors. It turned out that SM20 is the rat homologue of a dioxygenase that regulates hypoxia-inducible factor 1 (HIF-1). ANG II induces HIF-1alpha by a posttranscriptional mechanism suggesting that SM20 down-regulation leads to stabilization of HIF-1. Thus, ANG II-induced ROS generation plays a pivotal role in several pathophysiological situations, leading to renal growth regulation and remodeling after injury.
Wolf
Gunter
G
Department of Medicine, Division of Nephrology, University of Jena, Jena, Germany. Gunter.Wolf@med.uni-jena.de
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D006984:Hypertrophy; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009995:Osmosis; D016716:PC12 Cells; D010766:Phosphorylation; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3