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

Abstract

Background. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been demonstrated to suppress glomerular injuries in various renal diseases. However, it is not fully clear whether HMG-CoA reductase inhibitors directly regulate matrix protein accumulation in mesangial cells.

Methods. We investigated the effect of simvastatin (SIM), an HMG-CoA reductase inhibitor, on DNA synthesis in cultured murine mesangial cells stimulated by fetal calf serum (FCS). We then determined whether SIM affected the expression of regulatory factors of cell growth and matrix protein accumulation, using Northern analysis.

Results. SIM dose-dependently inhibited FCS-induced DNA synthesis after 24 h of incubation. SIM treatment for 24 h suppressed the mRNA expression of platelet-derived growth factor (PDGF)-B chain, PDGF receptor β-subunit and c-myc, while the expression of transforming growth factor β (TGF-β) was not affected. Concerning matrix protein synthesis, the mRNA expression of type IV collagen was suppressed, whereas that of type III collagen was markedly upregulated. As for matrix turnover proteins, SIM had a markedly suppressive effect on the mRNA expression of plasminogen activator inhibitor-1 (PAI-1), with a constant expression of tissue-type plasminogen activator (tPA).

Conclusions. These results indicate that SIM may sup-press mesangial cell proliferation in part through the downregulation of PDGF, PDGF-receptor, and c-myc mRNA expressions. In addition, the suppression of the synthesis of collagen IV and PAI-1 appears to be a direct inhibitory effect of SIM on glomerular matrix accumulation.