Lovastatin inhibits lipopolysaccharide-induced NF-κB 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-κB 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 NFκB activation in human mesangial cells. Methods. Cultured human mesangial cells were stimulated with bacterial lipopolysaccharide (LPS) in the presence or absence of lovastatin. NF-κB activity was measured by electrophoretic mobility shift assay (EMSA). Results. LPS-stimulated mesangial cells exhibited an NF-κB-like activity as assessed by EMSA competition assays, and supershift assays with antibodies against the p50 and p65 subunits of NF-κB. Treatment of mesangial cells with lovastatin in the presence of exogenous cholesterol resulted in a significant reduction of the LPS-induced NF-κB activity. In the presence of either mevalonate or the mevalonate metabolite farnesyl pyrophosphate, the lovastatin inhibition of NF-κB activation was substantially reversed, supporting a role for mevalonate metabolites in LPS-induced mesangial cell NF-κB activation. Conclusions. These data suggest an additional mechanism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-κB activation and the subsequent proliferative and inflammatory responses.