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-KB plays a major role in the induced expres-sion of genes involved in cellular proliferation and inflammatory responses that could be important in the pathogenesis of glomerular injury. We therefore exam-ined the effects of the HMG-CoA reductase inhibitor lovastatin on NF/cB activation in human mesangial cells. Methods. Cultured human mesangial cells were stimu-lated with bacterial lipopolysaccharide (LPS) in the presence or absence of lovastatin. NF-KB activity was measured by electrophoretic mobility shift assay (EMSA). Results. LPS-stimulated mesangial cells exhibited an NF-KB-like activity as assessed by EMSA competition assays, and supershift assays with antibodies against the p50 and p65 subunits of NF-KB. Treatment of mesangial cells with lovastatin in the presence of exogenous cholesterol resulted in a significant reduc-tion of the LPS-induced NF-KB activity. In the pres-ence of either mevalonate or the mevalonate metabolite farnesyl pyrophosphate, the lovastatin inhibition of NF-KB activation was substantially reversed, sup-porting a role for mevalonate metabolites in LPS-induced mesangial cell NF-KB activation. Conclusions. These data suggest an additional mechan-ism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-KB activation and the subsequent proliferative and inflammatory responses