Fluvastatin attenuates IGF-1-induced ERK1/2 activation and cell proliferation by mevalonic acid depletion in human mesangial cells.
OBJECTIVE
Insulin-like growth factor (IGF)-1 is a major mitogenic growth factor for mesangial cells (MCs). Statins slow the progression of chronic kidney disease by affecting inflammatory cell signaling pathways, in addition to improving lipid profile, however, no studies have investigated the effects of fluvastatin on mitogen-activated protein (MAP) kinase activity or MC proliferation in kidney cells. We investigated the effects of fluvastatin on IGF-1-induced activation of intracellular signal pathways and MC proliferation, and examined the inhibitory mechanisms of fluvastatin.


METHODS
Western blotting and cell proliferation assay were used.


RESULTS
IGF-1 induced phosphorylation of extracellular-related kinase (ERK)1/2, MAP or ERK kinase (MEK)1/2, and Akt, expression of cyclin D1, and MC proliferation in cultured human MCs. Fluvastatin or PD98059, an MEK1 inhibitor, completely abolished IGF-1-induced MEK1/2 and ERK1/2 phosphorylation and MC proliferation, whereas inhibition of Akt had no effect on MC proliferation. Mevalonic acid prevented fluvastatin inhibition of IGF-1-induced MEK1/2 and ERK1/2 phosphorylation, cyclin D1 expression, and MC proliferation.


CONCLUSIONS
Fluvastatin inhibits IGF-1-induced activation of the MAP kinase pathway and MC proliferation by mevalonic acid depletion, and might have renoprotective effects by inhibiting IGF-1-mediated MC proliferation.
Shibata
Tatsuya
T
The Second Department of Internal Medicine, University of Occupational and Environmental Health School of Medicine, Kitakyushu 807-8555, Japan.
Tamura
Masahito
M
Kabashima
Narutoshi
N
Serino
Ryota
R
Tokunaga
Masaki
M
Matsumoto
Mika
M
Miyamoto
Tetsu
T
Miyazaki
Mieko
M
Furuno
Yumi
Y
Takeuchi
Masaaki
M
Abe
Haruhiko
H
Okazaki
Masahiro
M
Otsuji
Yutaka
Y
D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D000077340:Fluvastatin; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects
D005229:Fatty Acids, Monounsaturated; D005419:Flavonoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D008798:Mevalonic Acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one