Direct inhibitory effects of simvastatin on matrix accumulation in cultured murine mesangial cells

Background 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-Co) reductase inhibit ors have been demonstrated to suppress glomerular injuries in various renal diseases. These agents inhibit in vitro proliferation of several cell type s, including mesangial cells. This effect indicates the ability to ameliora te mesangioproliferative lesions, independent of the improvement of hyperch olesterolemia. On the other hand, it is not clear whether HMG-CoA reductase inhibitors directly regulate extracellular matrix (ECM) accumulation from mesangial cells. Methods. In this study, to examine the in vitro effects of simvastatin, an HMG-CoA reductase inhibitor, on mRNA expressions of matrix proteins, growth factors, and matrix turnover proteins. we incubated cultured murine mesang ial cells stimulated by fetal calf serum (FCS) with or without simvastatin for 24 hours, and Northern analysis was performed. Results. Simvastatin showed a slightly suppressive effect on mRNA expressio n of type IV collagen and fibronectin and a slightly up-regulative effect o n that of type I collagen, whereas mRNA expression of type III collagen was markedly up-regulated, mRNA expression of platelet-derived growth factor ( PDGF)-B chain and PDGF receptor beta-subunit was suppressed, whereas that o f transforming growth factor-beta (TGF-beta) was not affected by simvastati n. Concerning matrix turnover proteins, simvastatin markedly reduced mRNA e xpression of plasminogen activator inhibitor-1 (PAI-1) without affecting th e expression of tissue-type plasminogen activator (tPA). Conclusion. These results suggest type-specific modulation of matrix protei n production independent of TGF-beta and the suppressive effects of autocri ne PDGF by administration of HMG-CoA reductase inhibitors in mesangial cell s. Moreover, the beneficial effects of these agents on matrix protein accum ulation may be through promoting ECM degradation derived from PAI-1 suppres sion.