Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-beta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells.
Oxidized low-density lipoprotein (Ox-LDL) might be involved in the progression of renal disease. Ox-LDL stimulation of plasminogen activator inhibitor-1 (PAI-1) expression via transforming growth factor-beta (TGF-beta)/Smad signaling in mesangial cells required activation of extracellular signal-regulated kinase (ERK). Mevalonate depletion by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, decreases the levels of farnesyl pyrophosphate (FPP) for isoprenylation of Ras. We postulate that statins may ameliorate the Ox-LDL-induced mesangial matrix accumulation by inhibiting Ras/ERK activation with subsequent downregulation of TGF-beta target genes. Quiescent mesangial cells were incubated for 18 h with and without the presence of lovastatin before 50 microg/mL of Ox-LDL treatment for 1 h. Lovastatin inhibited markedly the stimulatory effects of Ox-LDL on ERK1/2 activation, nuclear Smad3 expression, TGF-beta1 and PAI-1 mRNA and protein expression, and PAI-1 luciferase activity. These inhibitory effects of lovastatin were reversed almost completely by mevalonate or FPP. Similar to lovastatin, FTI-277, which is an inhibitor of Ras farnesylation, decreased the Ox-LDL-induced activation of ERK/Smad3 and induction of TGF-beta1/PAI-1. These results indicate that lovastatin prevents the Ox-LDL-induced Ras/ERK activation that results in inhibition of Smad3 activation in mesangial cells with subsequent downregulation of TGF-beta target genes. Thus, statins seem to have antifibrotic effects through their anti-TGF-beta response that are relevant in the treatment of chronic renal disease with dyslipidemia.
Department of Pathology, Seoul National University College of Medicine, Chongno-gu, Yongon-dong 28, Seoul, Korea.
Chi Young
CY
Song
Bong Cho
BC
Kim
Hyun Soon
HS
Lee
D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C099252:oxidized low density lipoprotein; D008148:Lovastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins