Lovastatin inhibits lipopolysaccharide-induced NF-kappaB activation in human mesangial cells.
BACKGROUND
HMG-CoA reductase inhibitors have been shown to reduce glomerular injury in different models of progressive renal damage. The transcription factor NF-kappaB plays a major role in the induced expression of genes involved in cellular proliferation and inflammatory responses that could be important in the pathogenesis of glomerular injury. We therefore examined the effects of the HMG-CoA reductase inhibitor lovastatin on NFkappaB activation in human mesangial cells.


METHODS
Cultured human mesangial cells were stimulated with bacterial lipopolysaccharide (LPS) in the presence or absence of lovastatin. NF-kappaB activity was measured by electrophoretic mobility shift assay (EMSA).


RESULTS
LPS-stimulated mesangial cells exhibited an NF-kappaB-like activity as assessed by EMSA competition assays, and supershift assays with antibodies against the p50 and p65 subunits of NF-kappaB. Treatment of mesangial cells with lovstatin in the presence of exogenous cholesterol resulted in a significant reduction of the LPS-induced NF-kappaB activity. In the presence of either mevalonate or the mevalonate metabolite farnesyl pyrophosphate, the lovastatin inhibition of NF-kappaB activation was substantially reversed, supporting a role for mevalonate metabolites in LPS-induced mesangial cell NF-kappaB activation.


CONCLUSIONS
These data suggest an additional mechanism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-kappaB activation and the subsequent proliferative and inflammatory responses.
Guijarro
C
C
Department of Nephrology, Division of Medicine, Hennepin County Medical Center, Minneapolis, MN 55455, USA.
Kim
Y
Y
Schoonover
C M
CM
Massy
Z A
ZA
O'Donnell
M P
MP
Kasiske
B L
BL
Keane
W F
WF
Kashtan
C E
CE
D001483:Base Sequence; D001769:Blood; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D015345:Oligonucleotide Probes / Q000235:genetics; D013997:Time Factors
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D008148:Lovastatin; D008798:Mevalonic Acid