title: Fluvastatin inhibits angiotensin II-induced nuclear factor kappa B activation in renal tubular epithelial cells through the p38 MAPK pathway.
abstract: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of renal disease independent of cholesterol-lowering effect, but the mechanism of potential protective effect remains unclear. Here, we investigate the effect of fluvastatin on activation of nuclear factor-κB (NF-κB) induced by angiotensin II (AngII) in rat kidney tubule epithelial cells (NRK-52E). Electrophoretic mobility shift assays (EMSA) was used to detect NF-κB activation. Phosphorylation of cellular p38 mitogen-activated protein kinase (p38MAPK) was determined by western blot analysis. AngII stimulated the DNA-binding activity of NF-κB and phosphorylation of p38MAPK in cultured NRK-52E cells in a dose-dependent (10(-9)-10(-6) mol/l) manner (P < 0.01). AngII (10(-6) mol/l) induced a rapid (5 min) increase of the p38MAPK phosphorylation. NF-κB DNA-binding activity was increased at as early as 30 min, peaked at 2 h after AngII treatment. This stimulatory effect of AngII on NF-κB was blocked by SB203580 (a specific inhibitor of p38MAPK). Incubation of cells with fluvastatin significantly inhibited the AngII-induced NF-κB activation in a dose-dependent (10(-7)-10(-5) mol/l) manner (P < 0.05). Exogenous mevalonate (10(-4)mol/l) prevented the effect of fluvastatin on NF-κB activation. These results suggest the fluvastatin reduced AngII-induced NF-κB activation via the p38MAPK pathway in NRK-52E cells. The effect is at least partly due to blocking the biosynthesis of mevalonate.
authors.affiliation: Department of Nephrology, Zhongnan Hospital, Wuhan University, 430071, Wuhan, Hubei, People's Republic of China. gp6680@sina.com
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.forename: Hua
authors.initials: H
authors.lastname: Shui
authors.forename: Ruhan
authors.initials: R
authors.lastname: Jia
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D007211:Indoles / Q000494:pharmacology*; D007684:Kidney Tubules / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D016328:NF-kappa B; D000804:Angiotensin II; D000077340:Fluvastatin; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases