Effect of simvastatin on proliferative nephritis and cell-cycle protein expression

Background. mesangial cell proliferation is important in subsequent mesangi al matrix expansion in glomerular injury. Therefore, the regulation of mesa ngial cell proliferation may be critical in the treatment of glomerulonephr itis. Inhibition of 3-hydro-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibits the production of mevalonate and has been shown to suppress proli feration in many cell types, including mesangial cells in vitro. It is expe cted that HMG-CoA reductase inhibitor may suppress mesangial cell prolifera tion and subsequent progression of glomerulonephritis. Recently, the tight relationship between cell-cycle regulatory protein expression and mesangial cell proliferation in experimental glomerulonephritis was demonstrated, Th e aim of the present study is to examine the effect of simvastatin, one of the HMG-CoA reductase inhibitors, on the glomerular cell proliferation and on the expression of CDK2 or p27Kip1 in mesangial cells in experimental glo merulonephritis in vivo. Methods. The effect of simvastatin on a rat mesangial proliferative glomeru lonephritis induced by antithymocyte antibody (anti-Thy 1.1 GN) was studied . Administration of simvastatin or vehicle (for control GN) were started fr om two days before disease induction, and was continued to the day of nephr ectomy. Nephrectomy was done at days 0, 2, 4, 7, 12 and 20 after disease in duction. Immunohistochemistry for proliferating cells. macrophages, or-smoo th muscle actin, type IV collagen and PDGF-B chain was performed, respectiv ely, in addition to conventional periodic-acid Schiff staining. Double immu nostaining for CDK2/OX-7 or p27Kip1/OX-7 was also done, respectively. Results. There was no difference in the degree of the initial injuries betw een simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell pr oliferation (about 70% of proliferation was suppressed at day 4). At day 4, alpha-smooth muscle actin expression was also decreased in simvastatin-tre ated GN rats. Inhibition of macrophage recruitment into glomeruli by simvas tatin was also a prominent feature (about 30% decrease in the number of glo merular macrophages at day 2), Simvastatin significantly suppressed subsequ ent mesangial matrix expansion and type IV collagen accumulation in glomeru li. Although it might simply reflect the reduction in mesangial cells. glom erular PDGF-B chain expression was reduced. There was no significant differ ence in plasma lipids levels at day 2 and day 4. In vehicle-treated GN rats , the number of CDK2+/OX-7+ cells (CDK2-expressed mesangial cells) in glome ruli increased significantly from day 4 to day 7. Although simvastatin supp ressed mesangial cell proliferation, the increase in the number of glomerul ar CDK2+/OX7+ cells was also attenuated by simvastatin treatment, There was no difference in the number of p27Kip1 +/OX-7+ cells (p27Kip1-expressed me sangial cells) in the glomerulus between vehicle-treated and simvastatin-tr eated GN rots. Conclusion. Simvastatin suppressed mesangial cell proliferation and subsequ ent matrix expansion, and macrophage infiltration into glomeruli in anti-Th y 1.1 GN rats. The antiproliferative effect of simvastatin in this model wa s also associated with the reduction of CDK2 expression in mesangial cells.